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1.	Arver, Brita, et al. (författare) Bilateral Prophylactic Mastectomy in Swedish Women at High Risk of Breast Cancer: A National Survey. 2011 Ingår i: Annals of surgery. - : Lippincott Williams and Wilkins; 1999. - 1528-1140 .- 0003-4932. ; 253:6, s. 1147-1154 Tidskriftsartikel (refereegranskat)abstract BACKGROUND/OBJECTIVE:: This study attempted a national inventory of all bilateral prophylactic mastectomies performed in Sweden between 1995 and 2005 in high-risk women without a previous breast malignancy. The primary aim was to investigate the breast cancer incidence after surgery. Secondary aims were to describe the preoperative risk assessment, operation techniques, complications, histopathological findings, and regional differences. METHODS:: Geneticists, oncologists and surgeons performing prophylactic breast surgery were asked to identify all women eligible for inclusion in their region. The medical records were reviewed in each region and the data were analyzed centrally. The BOADICEA risk assessment model was used to calculate the number of expected/prevented breast cancers during the follow-up period. RESULTS:: A total of 223 women operated on in 8 hospitals were identified. During a mean follow-up of 6.6 years, no primary breast cancer was observed compared with 12 expected cases. However, 1 woman succumbed 9 years post mastectomy to widespread adenocarcinoma of uncertain origin. Median age at operation was 40 years. A total of 58% were BRCA1/2 mutation carriers. All but 3 women underwent breast reconstruction, 208 with implants and 12 with autologous tissue. Four small, unifocal, invasive cancers and 4 ductal carcinoma in situ were found in the mastectomy specimens. The incidence of nonbreast related complications was low (3%). Implant loss due to infection/necrosis occurred in 21 women (10%) but a majority received a new implant later. In total, 64% of the women underwent at least 1unanticipated secondary operation. CONCLUSIONS:: Bilateral prophylactic mastectomy is safe and efficacious in reducing future breast cancer in asymptomatic women at high risk. Unanticipated reoperations are common. Given the small number of patients centralization seems justified.
2.	Couch, Fergus J., et al. (författare) Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer 2016 Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13 Tidskriftsartikel (refereegranskat)abstract Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
3.	Kuchenbaecker, KB, et al. (författare) Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers 2014 Ingår i: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-542X .- 1465-5411. ; 16:6, s. 3416- Tidskriftsartikel (refereegranskat)
4.	Lawrenson, Kate, et al. (författare) Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus 2016 Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7 Tidskriftsartikel (refereegranskat)abstract A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
5.	Osorio, Ana, et al. (författare) DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. 2014 Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:4 Tidskriftsartikel (refereegranskat)abstract Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7×10-3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8×10-3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
6.	Peterlongo, P, et al. (författare) Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 2015 Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - : American Association for Cancer Research. - 1538-7755 .- 1055-9965. ; 24:1, s. 308-316 Tidskriftsartikel (refereegranskat)
7.	Rebbeck, Timothy R, et al. (författare) Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. 2015 Ingår i: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 313:13, s. 1347-1361 Tidskriftsartikel (refereegranskat)abstract Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.
8.	Staffas, Anna, 1982, et al. (författare) Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia. 2011 Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:22, s. 5905-5913 Tidskriftsartikel (refereegranskat)abstract Mutation status of the FLT3, NPM1, CEBPA, and WT1 genes and gene expression levels of ERG, MN1, BAALC, FLT3, and WT1 have been identified as possible prognostic markers in acute myeloid leukemia (AML). We have performed a thorough prognostic evaluation of these genetic markers in pediatric AML patients enrolled in the NOPHO 1993 or NOPHO 2004 protocols. Mutation status and expression levels were analyzed in 185 and 149 patients respectively. Presence of FLT3-ITD was associated with significantly inferior event-free survival (EFS), whereas presence of an NPM1 mutation in the absence of FLT3-ITD correlated with significantly improved EFS. Furthermore, high levels of ERG and BAALC transcripts were associated with inferior EFS. No significant correlation with survival was seen for mutations in CEBPA and WT1 or with gene expression levels of MN1, FLT3, and WT1. In multivariate analysis, the presence of FLT3-ITD and high BAALC expression were identified as independent prognostic markers of inferior EFS. We conclude that analysis of the mutational status of FLT3 and NPM1 at diagnosis is important for prognostic stratification of pediatric AML patients and that determination of the BAALC gene expression level can add valuable information.
9.	Staffas, Anna, 1982, et al. (författare) Response: High ERG gene expression is an unfavorable prognostic marker in pediatric acute myeloid leukemia 2012 Ingår i: Blood. - Washington DC : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 119:4, s. 1087-1088 Tidskriftsartikel (refereegranskat)
10.	Andersson, Andreas, et al. (författare) Public support for healthcare-mediated disclosure of hereditary cancer risk information: Results from a population-based survey in Sweden 2020 Ingår i: Hereditary Cancer in Clinical Practice. - : Springer Science and Business Media LLC. - 1731-2302 .- 1897-4287. ; 18:1 Tidskriftsartikel (refereegranskat)abstract Background Targeted surveillance of at-risk individuals in families with increased risk of hereditary cancer is an effective prevention strategy if relatives are identified, informed and enrolled in screening programs. Despite the potential benefits, many eligible at-risk relatives remain uninformed of their cancer risk. This study describes the general public's opinion on disclosure of hereditary colorectal cancer (CRC) risk information, as well as preferences on the source and the mode of information. Methods A random sample of the general public was assessed through a Swedish citizen web-panel. Respondents were presented with scenarios of being an at-risk relative in a family that had an estimated increased hereditary risk of CRC; either 10% (moderate) or 70% (high) lifetime risk. A colonoscopy was presented as a preventive measure. Results were analysed to identify significant differences between groups using the Pearson's chi-square (chi(2)) test. Results Of 1800 invited participants, 977 completed the survey (54%). In the moderate and high-risk scenarios, 89.2 and 90.6% respectively, would like to receive information about a potential hereditary risk of CRC (chi 2,p = .755). The desire to be informed was higher among women (91.5%) than men (87.0%, chi 2,p = .044). No significant differences were found when comparing different age groups, educational levels, place of residence and having children or not. The preferred source of risk information was a healthcare professional in both moderate and high-risk scenarios (80.1 and 75.5%). However, 18.1 and 20.1% respectively would prefer to be informed by a family member. Assuming that healthcare professionals disclosed the information, the favoured mode of information was letter and phone (38.4 and 33.2%). Conclusions In this study a majority of respondents wanted to be informed about a potential hereditary risk of CRC and preferred healthcare professionals to communicate this information. The two presented levels of CRC lifetime risk did not significantly affect the interest in being informed. Our data offer insights into the needs and preferences of the Swedish population, providing a rationale for developing complementary healthcare-assisted communication pathways to realise the full potential of targeted prevention of hereditary CRC.
11.	Andrae, Johanna, et al. (författare) Analysis of Mice Lacking the Heparin-Binding Splice Isoform of Platelet-Derived Growth Factor A 2013 Ingår i: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 33:20, s. 4030-4040 Tidskriftsartikel (refereegranskat)abstract Platelet-derived growth factor A-chain (PDGF-A) exists in two evolutionarily conserved isoforms, PDGF-Along and PDGF-Ashort, generated by alternative RNA splicing. They differ by the presence (in PDGF-Along) or absence (in PDGF-Ashort) of a carboxyterminal heparin/heparan sulfate proteoglycan-binding motif. In mice, similar motifs present in other members of the PDGF and vascular endothelial growth factor (VEGF) families have been functionally analyzed in vivo, but the specific physiological importance of PDGF-A(long) has not been explored previously. Here, we analyzed the absolute and relative expression of the two PDGF-A splice isoforms during early postnatal organ development in the mouse and report on the generation of a Pdgfa allele (Pdgfa(Delta ex6) incapable of producing PDGF-A(long) due to a deletion of the exon 6 splice acceptor site. In situations of limiting PDGF-A signaling through PDGF receptor alpha (PDGFR alpha), or in mice lacking PDGF-C, homozygous carriers of Pdgfa(Delta ex6) showed abnormal development of the lung, intestine, and vertebral column, pinpointing developmental processes where PDGF-A(long) may play a physiological role.
12.	Antoniou, Antonis C., et al. (författare) A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population 2010 Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:10, s. 885-892 Tidskriftsartikel (refereegranskat)abstract Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P-trend = 2.3 x 10(-9) to Ptrend = 3.9 x 10(-7)), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P-trend = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P-trend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 x 10(-7) to Ptrend = 8 x 10(-5); rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P-trend = 1.1 x 10(-7)).
13.	Antoniou, Antonis C., et al. (författare) Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers 2011 Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:16, s. 3304-3321 Tidskriftsartikel (refereegranskat)abstract Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [ hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
14.	Antoniou, A. C., et al. (författare) Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers 2009 Ingår i: Human Molecular Genetics. - [Antoniou, Antonis C.; McGuffog, Lesley; Peock, Susan; Cook, Margaret; Frost, Debra; Oliver, Clare; Platte, Radka; Pooley, Karen A.; Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge, England. [Sinilnikova, Olga M.; Leone, Melanie] Univ Lyon, CNRS, Hosp Civils Lyon,Ctr Leon Berard,UMR5201, Unite Mixte Genet Constitut Canc Frequents, Lyon, France. [Healey, Sue; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Chenevix-Trench, Georgia] Queensland Inst Med Res, Brisbane, Qld 4029, Australia. [Nevanlinna, Heli; Heikkinen, Tuomas] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Simard, Jacques] Univ Laval, Quebec City, PQ, Canada. [Simard, Jacques] Univ Quebec, Ctr Hosp, Canada Res Chair Oncogenet, Canc Genom Lab, Quebec City, PQ, Canada. Peter MacCallum Canc Inst, Melbourne, Vic 3002, Australia. [Neuhausen, Susan L.; Ding, Yuan C.] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA. [Couch, Fergus J.; Wang, Xianshu; Fredericksen, Zachary] Mayo Clin, Rochester, MN USA. [Peterlongo, Paolo; Peissel, Bernard; Radice, Paolo] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Peterlongo, Paolo; Radice, Paolo] Fdn Ist FIRC Oncol Molecolare, Milan, Italy. [Bonanni, Bernardo; Bernard, Loris] Ist Europeo Oncol, Milan, Italy. [Viel, Alessandra] IRCCS, Ctr Riferimento Oncol, Aviano, Italy. [Bernard, Loris] Cogentech, Consortium Genom Technol, Milan, Italy. [Szabo, Csilla I.] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [Foretova, Lenka] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Zikan, Michal] Charles Univ Prague, Dept Biochem & Expt Oncol, Fac Med 1, Prague, Czech Republic. [Claes, Kathleen] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. [Greene, Mark H.; Mai, Phuong L.] US Natl Canc Inst, Clin Genet Branch, Rockville, MD USA. [Rennert, Gad; Lejbkowicz, Flavio] CHS Natl Canc Control Ctr, Haifa, Israel. [Rennert, Gad; Lejbkowicz, Flavio] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [Rennert, Gad; Lejbkowicz, Flavio] B Rappaport Fac Med, Haifa, Israel. [Andrulis, Irene L.; Glendon, Gord] Canc Care Ontario, Ontario Canc Genet Network, Toronto, ON M5G 2L7, Canada. [Andrulis, Irene L.] Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Samuel Lunenfeld Res Inst, Toronto, ON, Canada. [Andrulis, Irene L.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Gerdes, Anne-Marie; Thomassen, Mads] Odense Univ Hosp, Dept Biochem Pharmacol & Genet, DK-5000 Odense, Denmark. [Sunde, Lone] Aarhus Univ Hosp, Dept Clin Genet, DK-8000 Aarhus, Denmark. [Caligo, Maria A.] Univ Pisa, Div Surg Mol & Ultrastructural Pathol, Dept Oncol, Pisa, Italy. [Caligo, Maria A.] Pisa Univ Hosp, Pisa, Italy. [Laitman, Yael; Kontorovich, Tair; Cohen, Shimrit; Friedman, Eitan] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel. [Kaufman, Bella] Chaim Sheba Med Ctr, Inst Oncol, IL-52621 Tel Hashomer, Israel. [Kaufman, Bella; Friedman, Eitan] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Dagan, Efrat; Baruch, Ruth Gershoni] Rambam Med Ctr, Genet Inst, Haifa, Israel. [Harbst, Katja] Lund Univ, Dept Oncol, S-22100 Lund, Sweden. [Barbany-Bustinza, Gisela; Rantala, Johanna] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden. [Ehrencrona, Hans] Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden. [Karlsson, Per] Sahlgrenska Univ, Dept Oncol, Gothenburg, Sweden. [Domchek, Susan M.; Nathanson, Katherine L.] Univ Penn, Philadelphia, PA 19104 USA. [Osorio, Ana; Benitez, Javier] Ctr Invest Biomed Red Enfermedades Raras CIBERERE, Inst Salud Carlos III, Madrid, Spain. [Osorio, Ana; Benitez, Javier] Spanish Natl Canc Ctr CNIO, Human Canc Genet Programme, Human Genet Grp, Madrid, Spain. [Blanco, Ignacio] Catalan Inst Oncol ICO, Canc Genet Counseling Program, Barcelona, Spain. [Lasa, Adriana] Hosp Santa Creu & Sant Pau, Genet Serv, Barcelona, Spain. [Hamann, Ute] Deutsch Krebsforschungszentrum, Neuenheimer Feld 580 69120, D-6900 Heidelberg, Germany. [Hogervorst, Frans B. L.] Netherlands Canc Inst, Dept Pathol, Family Canc Clin, NL-1066 CX Amsterdam, Netherlands. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Collee, J. Margriet] Erasmus Univ, Dept Clin Genet, Rotterdam Family Canc Clin, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Devilee, Peter] Dept Genet Epidemiol, Leiden, Netherlands. [Wijnen, Juul] Leiden Univ, Med Ctr, Ctr Human & Clin Genet, Leiden, Netherlands. [Ligtenberg, Marjolijn J.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [van der Luijt, Rob B.] Univ Utrecht, Med Ctr, Dept Clin Mol Genet, NL-3508 TC Utrecht, Netherlands. [Aalfs, Cora M.] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands. [Waisfisz, Quinten] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [van Roozendaal, Cornelis E. P.] Univ Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [Evans, D. Gareth; Lalloo, Fiona] Cent Manchester Univ Hosp, NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Eeles, Rosalind] Inst Canc Res, Translat Canc Genet Team, London SW3 6JB, England. [Eeles, Rosalind] Royal Marsden NHS Fdn Trust, London, England. [Izatt, Louise] Guys Hosp, Clin Genet, London SE1 9RT, England. [Davidson, Rosemarie] Ferguson Smith Ctr Clin Genet, Glasgow, Lanark, Scotland. [Chu, Carol] Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England. [Eccles, Diana] Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England. [Cole, Trevor] Birmingham Womens Hosp Healthcare, NHS Trust, W Midlands Reg Genet Serv, Birmingham, W Midlands, England. [Hodgson, Shirley] Univ London, Dept Canc Genet, St Georges Hosp, London, England. [Godwin, Andrew K.; Daly, Mary B.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Stoppa-Lyonnet, Dominique] Univ Paris 05, Paris, France. [Stoppa-Lyonnet, Dominique] Inst Curie, INSERM U509, Serv Genet Oncol, Paris, France. [Buecher, Bruno] Inst Curie, Dept Genet, Paris, France. [Bressac-de Paillerets, Brigitte; Remenieras, Audrey; Lenoir, Gilbert M.] Inst Cancrol Gustave Roussy, Dept Genet, Villejuif, France. [Bressac-de Paillerets, Brigitte] Inst Cancerol Gustave Roussy, INSERM U946, Villejuif, France. [Caron, Olivier] Inst Cancerol Gustave Roussy, Dept Med, Villejuif, France. [Lenoir, Gilbert M.] Inst Cancerol Gustave Roussy, CNRS FRE2939, Villejuif, France. [Sevenet, Nicolas; Longy, Michel] Inst Bergonie, Lab Genet Constitutionnelle, Bordeaux, France. [Longy, Michel] Inst Bergonie, INSERM U916, Bordeaux, France. [Ferrer, Sandra Fert] Hop Hotel Dieu, Ctr Hosp, Lab Genet Chromosom, Chambery, France. [Prieur, Fabienne] CHU St Etienne, Serv Genet Clin Chromosom, St Etienne, France. [Goldgar, David] Univ Utah, Dept Dermatol, Salt Lake City, UT 84112 USA. [Miron, Alexander; Yassin, Yosuf] Dana Farber Canc Inst, Boston, MA 02115 USA. [John, Esther M.] No Calif Canc Ctr, Fremont, CA USA. [John, Esther M.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Buys, Saundra S.] Univ Utah, Hlth Sci Ctr, Huntsman Canc Inst, Salt Lake City, UT USA. [Hopper, John L.] Univ Melbourne, Melbourne, Australia. [Terry, Mary Beth] Columbia Univ, New York, NY USA. [Singer, Christian; Gschwantler-Kaulich, Daphne; Staudigl, Christine] Med Univ Vienna, Div Special Gynecol, Dept OB GYN, Vienna, Austria. [Hansen, Thomas V. O.] Univ Copenhagen, Rigshosp, Dept Clin Biochem, DK-2100 Copenhagen, Denmark. [Barkardottir, Rosa Bjork] Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland. [Kirchhoff, Tomas; Pal, Prodipto; Kosarin, Kristi; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA. [Piedmonte, Marion] Roswell Pk Canc Inst, GOG Stat & Data Ctr, Buffalo, NY 14263 USA. [Rodriguez, Gustavo C.] Evanston NW Healthcare, NorthShore Univ Hlth Syst, Evanston, IL 60201 USA. [Wakeley, Katie] Tufts Univ, New England Med Ctr, Boston, MA 02111 USA. [Boggess, John F.] Univ N Carolina, Chapel Hill, NC 27599 USA. [Basil, Jack] St Elizabeth Hosp, Edgewood, KY 41017 USA. [Schwartz, Peter E.] Yale Univ, Sch Med, New Haven, CT 06510 USA. [Blank, Stephanie V.] New York Univ, Sch Med, New York, NY 10016 USA. [Toland, Amanda E.] Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. [Toland, Amanda E.] Ohio State Univ, Div Human Canc Genet, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Montagna, Marco; Casella, Cinzia] IRCCS, Ist Oncologico Veneto, Immunol & Mol Oncol Unit, Padua, Italy. [Imyanitov, Evgeny N.] NN Petrov Inst Res Inst, St Petersburg, Russia. [Allavena, Anna] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Schmutzler, Rita K.; Versmold, Beatrix; Arnold, Norbert] Univ Cologne, Dept Obstet & Gynaecol, Div Mol Gynaeco Oncol, Cologne, Germany. [Engel, Christoph] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany. [Meindl, Alfons] Tech Univ Munich, Dept Obstet & Gynaecol, Munich, Germany. [Ditsch, Nina] Univ Munich, Dept Obstet & Gynecol, Munich, Germany. Univ Schleswig Holstein, Dept Obstet & Gynaecol, Campus Kiel, Germany. [Niederacher, Dieter] Univ Duesseldorf, Dept Obstet & Gynaecol, Mol Genet Lab, Dusseldorf, Germany. [Deissler, Helmut] Univ Ulm, Dept Obstet & Gynaecol, Ulm, Germany. [Fiebig, Britta] Univ Regensburg, Inst Human Genet, Regensburg, Germany. [Suttner, Christian] Univ Heidelberg, Inst Human Genet, Heidelberg, Germany. [Schoenbuchner, Ines] Univ Wurzburg, Inst Human Genet, D-8700 Wurzburg, Germany. [Gadzicki, Dorothea] Med Univ, Inst Cellular & Mol Pathol, Hannover, Germany. [Caldes, Trinidad; de la Hoya, Miguel] Hosp Clinico San Carlos 28040, Madrid, Spain. : Oxford University Press. - 0964-6906 .- 1460-2083. ; 18:22, s. 4442-4456 Tidskriftsartikel (refereegranskat)abstract Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 × 10-4]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.
15.	Augustinsson, Annelie, et al. (författare) Genetic testing in women with early-onset breast cancer : a Traceback pilot study 2021 Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 190:2, s. 307-315 Tidskriftsartikel (refereegranskat)abstract Purpose: In Sweden, a Traceback approach, i.e., a retrospective genetic outreach activity, among cancer patients is not normally used in clinical practice. In this pilot study, we wanted to evaluate a Traceback strategy for possible future clinical implementation and investigate why not all women with early-onset breast cancer underwent genetic testing when they were first diagnosed. Methods: Out of all women (n = 409) diagnosed with breast cancer at ≤ 35 years in Southern Sweden between 2000 and 2017, 63 had not previously been tested. These women were offered an analysis of the genes BRCA1, BRCA2, PALB2, CHEK2, and ATM through a standardized letter. Subsequently, women with normal test results were informed through a letter and carriers of pathogenic variants were contacted through a telephone call and offered in-person genetic counseling. All tested women were asked to complete a follow-up questionnaire regarding previously not having attended genetic counseling and testing and their experiences of the current retrospective approach. Results: Out of the invited women, 29 (46%) underwent genetic testing and 27 (43%) answered the questionnaire. Pathogenic variants were identified in BRCA1 (n = 2), CHEK2 (n = 1), and ATM (n = 1). The main reason for previously not having undergone genetic testing was not having received any information from their physicians. Most study participants were satisfied with both written pre- and post-test information. Conclusion: The process with retrospective identification, written pre-test information, and genetic testing, followed by in-person counseling for carriers of pathogenic variants only, was well accepted. This has implications for future Traceback implementation programs.
16.	Augustinsson, Annelie, et al. (författare) Retrospective genetic testing (Traceback) in women with early-onset breast cancer after revised national guidelines : a clinical implementation study Ingår i: Breast Cancer Research and Treatment. - 0167-6806. Tidskriftsartikel (refereegranskat)abstract Purpose: This study focused on identifying a hereditary predisposition in women previously diagnosed with early-onset breast cancer through a retrospective outreach activity (Traceback). The objectives were to evaluate the possible clinical implementation of a simplified Traceback strategy and to identify carriers of pathogenic variants among previously untested women. Methods: Three hundred and fifteen Traceback-eligible women diagnosed with breast cancer at 36–40 years in Southern Sweden between 2000 and 2019 were identified and offered an analysis of the genes ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, and RAD51D through a standardized letter. Women who chose to participate were asked about their experiences through a questionnaire. The workload for the study personnel was measured and recorded. Results: One hundred and seventy-six women underwent genetic testing and pathogenic variants were identified in 9.7%: ATM (n = 6), BARD1 (n = 1), BRCA1 (n = 3), CHEK2 (n = 5), and PALB2 (n = 2). Women with normal test results were informed through a standardized letter. Carriers of pathogenic variants were contacted by telephone and offered in-person genetic counseling. One hundred and thirty-four women returned the subsequent questionnaire. Most study participants were satisfied with both written pre- and post-test information and many expressed their gratitude. The extra workload as compared to routine clinical genetic counseling was modest (8 min per patient). Conclusion: The insights from the participants’ perspectives and sentiments throughout the process support the notion that the Traceback procedure is a safe and an appreciated complement to routine genetic counseling. The genetic yield of almost 10% also suggests that the associated extra workload for genetic counselors could be viewed as acceptable in clinical implementation scenarios.
17.	Augustinsson, Annelie, et al. (författare) Variations in the Referral Pattern for Genetic Counseling of Patients with Early-Onset Breast Cancer : A Population-Based Study in Southern Sweden 2020 Ingår i: Public Health Genomics. - : S. Karger AG. - 1662-8063 .- 1662-4246. ; 23:3-4, s. 100-109 Tidskriftsartikel (refereegranskat)abstract Swedish national breast cancer guidelines recommend that all women diagnosed with breast cancer (BC) at the age of 35 years or younger should be referred to their regional oncogenetic clinic for genetic counseling and testing, regardless of family history of cancer. The main objective of this study was to evaluate whether place of residence at BC diagnosis and treating hospital were associated with the fact that not all BC patients diagnosed at ≤35 years in the southern part of Sweden have attended genetic counseling and testing. Between 2000 and 2013, 279 women in the South Swedish Health Care Region were diagnosed with BC at ≤35 years. Information regarding place of residence at BC diagnosis, treating hospital, time of registration and first meeting at the Oncogenetic Clinic in Lund, and genetic testing was collected. With a follow-up period until August 2018, 64% were registered at the clinic (60% underwent genetic testing) and 36% were not. BC patients from 2 counties and from rural settings with a population of <10,000 inhabitants were significantly less likely to be registered at the clinic. Our results suggest that place of residence at BC diagnosis and treating hospital were associated with the probability of referral for genetic counseling and testing for women diagnosed with BC at ≤35 years in the South Swedish Health Care Region. We propose, as a generalizable finding, that further educational and outreach activities within the health care system and the community may be needed to ensure that all women diagnosed with early-onset BC receive proper genetic counseling.
18.	Baccarani, Michele, et al. (författare) Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia : a European LeukemiaNet Study 2009 Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 113:19, s. 4497-4504 Tidskriftsartikel (refereegranskat)abstract Imatinib mesylate (IM), 400 mg daily, is the standard treatment of Philadelphia-positive (Ph(+)) chronic myeloid leukemia (CML). Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. To investigate whether the systematic use of a higher dose of IM could lead to better results, 216 patients with Ph(+) CML at high risk (HR) according to the Sokal index were randomly assigned to receive IM 800 mg or 400 mg daily, as front-line therapy, for at least 1 year. The CCgR rate at 1 year was 64% and 58% for the high-dose arm and for the standard-dose arm, respectively (P = .435). No differences were detectable in the CgR at 3 and 6 months, in the molecular response rate at any time, as well as in the rate of other events. Twenty-four (94%) of 25 patients who could tolerate the full 800-mg dose achieved a CCgR, and only 4 (23%) of 17 patients who could tolerate less than 350 mg achieved a CCgR. This study does not support the extensive use of high-dose IM (800 mg daily) front-line in all CML HR patients. This trial was registered at www.clinicaltrials.gov as #NCT00514488.
19.	Brédart, Anne, et al. (författare) Clinicians’ use of breast cancer risk assessment tools according to their perceived importance of breast cancer risk factors : an international survey 2019 Ingår i: Journal of Community Genetics. - : Springer Science and Business Media LLC. - 1868-310X .- 1868-6001. ; 10:1, s. 61-71 Tidskriftsartikel (refereegranskat)abstract The BOADICEA breast cancer (BC) risk assessment model and its associated Web Application v3 (BWA) tool are being extended to incorporate additional genetic and non-genetic BC risk factors. From an online survey through the BOADICEA website and UK, Dutch, French and Swedish national genetic societies, we explored the relationships between the usage frequencies of the BWA and six other common BC risk assessment tools and respondents’ perceived importance of BC risk factors. Respondents (N = 443) varied in age, country and clinical seniority but comprised mainly genetics health professionals (82%) and BWA users (93%). Oncology professionals perceived reproductive, hormonal (exogenous) and lifestyle BC risk factors as more important in BC risk assessment compared to genetics professionals (p values < 0.05 to 0.0001). BWA was used more frequently by respondents who gave high weight to breast tumour pathology and low weight to personal BC history as BC risk factors. BWA use was positively related to the weight given to hormonal BC risk factors. The importance attributed to lifestyle and BMI BC risk factors was not associated with the use of BWA or any of the other tools. Next version of the BWA encompassing additional BC risk factors will facilitate more comprehensive BC risk assessment in genetics and oncology practice.
20.	Brédart, Anne, et al. (författare) Use of the BOADICEA Web Application in clinical practice : appraisals by clinicians from various countries 2018 Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 17:1, s. 31-41 Tidskriftsartikel (refereegranskat)abstract The ‘BOADICEA’ Web Application (BWA) used to assess breast cancer risk, is currently being further developed, to integrate additional genetic and non-genetic factors. We surveyed clinicians’ perceived acceptability of the existing BWA v3. An online survey was conducted through the BOADICEA website, and the British, Dutch, French and Swedish genetics societies. Cross-sectional data from 443 participants who provided at least 50% responses were analysed. Respondents varied in age and, clinical seniority, but mainly comprised women (77%) and genetics professionals (82%). Some expressed negative opinions about the scientific validity of BOADICEA (9%) and BWA v3 risk presentations (7–9%). Data entry time (62%), clinical utility (22%) and ease of communicating BWA v3 risks (13–17%) received additional negative appraisals. In multivariate analyses, controlling for gender and country, data entry time was perceived as longer by genetic counsellors than clinical geneticists (p < 0.05). Respondents who (1) considered hormonal BC risk factors as more important (p < 0.01), and (2) communicated numerical risk estimates more frequently (p < 0.001), judged BWA v3 of lower clinical utility. Respondents who carried out less frequent clinical activity (p < 0.01) and respondents with ‘11 to 15 years’ seniority (p < 0.01) had less favourable opinions of BWA v3 risk presentations. Seniority of ‘6 to 10 years’ (p < 0.05) and more frequent numerical risk communication (p < 0.05) were associated with higher fear of communicating the BWA v3 risks to patients. The level of genetics training did not affect opinions. Further development of BWA should consider technological, genetics service delivery and training initiatives.
21.	Catucci, Irene, et al. (författare) Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility 2018 Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 20:4, s. 452-457 Tidskriftsartikel (refereegranskat)abstract PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.ConclusionOur data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.Genetics in Medicine advance online publication, 24 August 2017; doi:10.1038/gim.2017.123.
22.	Couch, FJ, et al. (författare) Common variants at the 19p13.1 and ZNF365 loci are associated with ER subtypes of breast cancer and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 2012 Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1538-7755 .- 1055-9965. ; 21:4, s. 645-657 Tidskriftsartikel (refereegranskat)
23.	Cross, N C P, et al. (författare) Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. 2015 Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 29:5, s. 999-1003 Forskningsöversikt (refereegranskat)abstract Treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors has advanced to a stage where many patients achieve very low or undetectable levels of disease. Remarkably, some of these patients remain in sustained remission when treatment is withdrawn, suggesting that they may be at least operationally cured of their disease. Accurate definition of deep molecular responses (MRs) is therefore increasingly important for optimal patient management and comparison of independent data sets. We previously published proposals for broad standardized definitions of MR at different levels of sensitivity. Here we present detailed laboratory recommendations, developed as part of the European Treatment and Outcome Study for CML (EUTOS), to enable testing laboratories to score MR in a reproducible manner for CML patients expressing the most common BCR-ABL1 variants.Leukemia advance online publication, 27 February 2015; doi:10.1038/leu.2015.29.
24.	Dominguez, Mev, et al. (författare) Functional implications of the p.Cys680Arg mutation in the MLH1 mismatch repair protein. 2014 Ingår i: Molecular Genetics & Genomic Medicine. - : Wiley. - 2324-9269. ; 2:4, s. 352-355 Tidskriftsartikel (refereegranskat)abstract In clinical genetic diagnostics, it is difficult to predict whether genetic mutations that do not greatly alter the primary sequence of the encoded protein causing unknown functional effects on cognate proteins lead to development of disease. Here, we report the clinical identification of c.2038 T>C missense mutation in exon 18 of the human MLH1 gene and biochemically characterization of the p.Cys680Arg mutant MLH1 protein to implicate it in the pathogenicity of the Lynch syndrome (LS). We show that the mutation is deficient in DNA mismatch repair and, therefore, contributing to LS in the carriers.
25.	Dunning, AM, et al. (författare) Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170 2016 Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 48:4, s. 374- Tidskriftsartikel (refereegranskat)
26.	Edsjö, Anders, et al. (författare) Building a precision medicine infrastructure at a national level : The Swedish experience 2023 Ingår i: Cambridge Prisms: Precision Medicine. - : Cambridge University Press. - 2752-6143. ; 1 Forskningsöversikt (refereegranskat)abstract Precision medicine has the potential to transform healthcare by moving from one-size-fits-all to personalised treatment and care. This transition has been greatly facilitated through new high-throughput sequencing technologies that can provide the unique molecular profile of each individual patient, along with the rapid development of targeted therapies directed to the Achilles heels of each disease. To implement precision medicine approaches in healthcare, many countries have adopted national strategies and initiated genomic/precision medicine initiatives to provide equal access to all citizens. In other countries, such as Sweden, this has proven more difficult due to regionally organised healthcare. Using a bottom-up approach, key stakeholders from academia, healthcare, industry and patient organisations joined forces and formed Genomic Medicine Sweden (GMS), a national infrastructure for the implementation of precision medicine across the country. To achieve this, Genomic Medicine Centres have been established to provide regionally distributed genomic services, and a national informatics infrastructure has been built to allow secure data handling and sharing. GMS has a broad scope focusing on rare diseases, cancer, pharmacogenomics, infectious diseases and complex diseases, while also providing expertise in informatics, ethical and legal issues, health economy, industry collaboration and education. In this review, we summarise our experience in building a national infrastructure for precision medicine. We also provide key examples how precision medicine already has been successfully implemented within our focus areas. Finally, we bring up challenges and opportunities associated with precision medicine implementation, the importance of international collaboration, as well as the future perspective in the field of precision medicine.
27.	Elander, Johanna, et al. (författare) Extended genetic diagnostics for children with profound sensorineural hearing loss by implementing massive parallel sequencing. Diagnostic outcome, family experience and clinical implementation 2022 Ingår i: International Journal of Pediatric Otorhinolaryngology. - : Elsevier BV. - 0165-5876. ; 159 Tidskriftsartikel (refereegranskat)abstract Objectives: The aim of this study was to investigate genetic outcomes, analyze the family experience, and describe the process of implementing genetic sequencing for children with profound sensorineural hearing loss (SNHL) at a tertial audiological center in southern Sweden. Design: This is a prospective pilot study including eleven children with profound bilateral SNHL who underwent cochlear implant surgery. Genetic diagnostic investigation was performed with whole exome sequencing (WES) complemented with XON-array to identify copy number variants, using a manually curated gene panel incorporating 179 genes associated with non-syndromic and syndromic SNHL. Mitochondrial DNA (mtDNA) from blood was examined separately. A patient reported experience measures (PREM) questionnaire was used to evaluate parental experience. We also describe here the process of implementing WES in an audiology department. Results: Six female and five male children (mean 3.4 years, SD 3.5 years), with profound bilateral SNHL were included. Genetic variants of interest were found in six subjects (55%), where three (27%) could be classified as pathogenic or likely pathogenic. Among the six cases, one child was found to have a homozygous pathogenic variant in MYO7A and two children had homozygous likely pathogenic variants in SLC26A4 and PCDH15, respectively. One was carrying a compound heterozygote frameshift variant of uncertain significance (VUS) on one allele and in trans, a likely pathogenic deletion on the other allele in PCDH15. Two subjects had homozygous VUS in PCDH15 and ADGRV1, respectively. In five of the cases the variants were in genes associated with Usher syndrome. For one of the likely pathogenic variants, the finding was related to Pendred syndrome. No mtDNA variants related to SNHL were found. The PREM questionnaire revealed that the families had difficulty in fully understanding the results of the genetic analysis. However, the parents of all eleven (100%) subjects still recommended that other families with children with SNHL should undergo genetic testing. Specifically addressed referrals for prompt complementary clinical examination and more individualized care were possible, based on the genetic results. Close clinical collaboration between different specialists, including physicians of audiology, audiologists, clinical geneticists, ophthalmologists, pediatricians, otoneurologists, physiotherapists and hearing habilitation teams was initiated during the implementation of the new regime. For all professionals involved, a better knowledge of the diversity of the genetic background of hearing loss was achieved. Conclusions: Whole exome sequencing and XON-array using a panel of genes associated with SNHL had a high diagnostic yield, added value to the families, and provided guidance for further examinations and habilitation for the child. Great care should be taken to thoroughly inform parents about the genetic test result. Collaborations between departments were intensified and knowledge of hearing genomics was increased among the staff.
28.	Engel, C., et al. (författare) Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 2010 Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 19:11, s. 2859-2868 Tidskriftsartikel (refereegranskat)abstract Background: The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population.Methods: To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).Results: The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; Ptrend = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; Ptrend = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers.Conclusions: CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers.Impact: The combined application of these and other recently identified genetic riskmodifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers.
29.	Figlioli, G, et al. (författare) The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases 2020 Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:2 Tidskriftsartikel (refereegranskat)abstract Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2–4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.
30.	Fioretos, Thoas, et al. (författare) Implementing precision medicine in a regionally organized healthcare system in Sweden 2022 Ingår i: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 28:10, s. 1980-1982 Tidskriftsartikel (refereegranskat)
31.	Glodzik, Dominik, et al. (författare) Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers 2020 Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1 Tidskriftsartikel (refereegranskat)abstract Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.
32.	Gorcenco, Sorina, et al. (författare) Clinical and genetic analyses of a Swedish patient series diagnosed with ataxia 2024 Ingår i: Journal of Neurology. - 0340-5354. ; 271:1, s. 526-542 Tidskriftsartikel (refereegranskat)abstract Hereditary ataxia is a heterogeneous group of complex neurological disorders. Next-generation sequencing methods have become a great help in clinical diagnostics, but it may remain challenging to determine if a genetic variant is the cause of the patient’s disease. We compiled a consecutive single-center series of 87 patients from 76 families with progressive ataxia of known or unknown etiology. We investigated them clinically and genetically using whole exome or whole genome sequencing. Test methods were selected depending on family history, clinical phenotype, and availability. Genetic results were interpreted based on the American College of Medical Genetics criteria. For high-suspicion variants of uncertain significance, renewed bioinformatical and clinical evaluation was performed to assess the level of pathogenicity. Thirty (39.5%) of the 76 families had received a genetic diagnosis at the end of our study. We present the predominant etiologies of hereditary ataxia in a Swedish patient series. In two families, we established a clinical diagnosis, although the genetic variant was classified as “of uncertain significance” only, and in an additional three families, results are pending. We found a pathogenic variant in one family, but we suspect that it does not explain the complete clinical picture. We conclude that correctly interpreting genetic variants in complex neurogenetic diseases requires genetics and clinical expertise. The neurologist’s careful phenotyping remains essential to confirm or reject a diagnosis, also by reassessing clinical findings after a candidate genetic variant is suggested. Collaboration between neurology and clinical genetics and combining clinical and research approaches optimizes diagnostic yield.
33.	Halldorsdottir, Anna M., et al. (författare) Genome Wide Array Based Methylation Profiling Reveals Preferential Methylation of Homeobox Transcription Factor Genes In Mantle Cell Lymphoma and Pro Apoptotic Genes In Chronic Lymphocytic Leukemia 2010 Ingår i: Blood. - 1528-0020 .- 0006-4971. ; 116:21, s. 239-239 Konferensbidrag (refereegranskat)
34.	Halldórsdóttir, Anna M., et al. (författare) High-resolution genomic screening in mantle cell lymphoma : specific changes correlate with genomic complexity, the proliferation signature and survival 2011 Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 50:2, s. 113-121 Tidskriftsartikel (refereegranskat)abstract Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) and numerous copy number aberrations (CNAs). Recently, gene expression profiling defined a proliferation gene expression signature in MCL where high scores predict shorter survival. We investigated 31 MCL cases using high-density single nucleotide polymorphism arrays and correlated CNA patterns with the proliferation signature and with clinical data. Many recurrent CNAs typical of MCL were detected, including losses at 1p (55%), 8p (29%), 9q (29%), 11q (55%), 13q (42%) and 17p (32%), and gains at 3q (39%), 8q (26%), 15q (23%) and 18q (23%). A novel deleted region at 20q (16%) contained only one candidate gene, ZFP64, a putative tumor suppressor. Unsupervised clustering identified subgroups with different patterns of CNAs, including a subset (19%) characterized by the presence of 11q loss in all cases and by the absence of 13q loss, and 3q and 7p gains. Losses at 1p, 8p, 13q and 17p were associated with increased genomic complexity. High proliferation signature scores correlated with increased number of large (>15 Mbp) CNAs (P = 0.03) as well as copy number gains at 7p (P = 0.02) and losses at 9q (P = 0.04). Furthermore, large/complex 13q losses were associated with improved survival (P < 0.05) as were losses/copy number neutral LOH at 19p13 (P = 0.01). In summary, this high-resolution genomic analysis identified novel aberrations and revealed that several CNAs correlated with genomic complexity, the proliferation status and survival.
35.	Halldórsdóttir, Anna Margret, et al. (författare) Impact of TP53 mutation and 17p deletion in mantle cell lymphoma 2011 Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 25:12, s. 1904-1908 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
36.	Halldorsdottir, Anna Margret, et al. (författare) Mantle cell lymphoma displays a homogenous methylation profile : A comparative analysis with chronic lymphocytic leukemia 2012 Ingår i: American Journal of Hematology. - : John Wiley & Sons. - 0361-8609 .- 1096-8652. ; 87:4, s. 361-367 Tidskriftsartikel (refereegranskat)abstract Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5(+) B-cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e., IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high-resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor-prognostic IGHV unmutated subset #1 and 15 good-prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset displayed distinct genomic methylation profiles. After unsupervised hierarchical clustering, 17/20 MCL cases formed a cluster separate from CLL, while CLL subsets #1 and #4 formed subclusters. Surprisingly, few differentially methylated genes (n = 6) were identified between high vs. low proliferation MCL. In contrast, distinct methylation profiles were demonstrated for MCL and CLL. Importantly, certain functional classes of genes were preferentially methylated in either disease. For instance, developmental genes, in particular homeobox transcription factor genes (e.g., HLXB9, HOXA13), were more highly methylated in MCL, whereas apoptosis-related genes were enriched among targets methylated in CLL (e.g., CYFIP2, NR4A1). Results were validated using pyrosequencing, RQ-PCR and reexpression of specific genes. In summary, the methylation profile of MCL was homogeneous and no correlation with the proliferation signature was observed. Compared to CLL, however, marked differences were discovered such as the preferential methylation of homeobox genes in MCL.
37.	Halldorsdottir, Anna Margret, et al. (författare) Mantle cell lymphoma displays a homogenous methylation profile: A comparative analysis with chronic lymphocytic leukemia 2012 Ingår i: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 87:4, s. 361-367 Tidskriftsartikel (refereegranskat)abstract Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5(+) B-cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e., IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high-resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor-prognostic IGHV unmutated subset #1 and 15 good-prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset displayed distinct genomic methylation profiles. After unsupervised hierarchical clustering, 17/20 MCL cases formed a cluster separate from CLL, while CLL subsets #1 and #4 formed subclusters. Surprisingly, few differentially methylated genes (n = 6) were identified between high vs. low proliferation MCL. In contrast, distinct methylation profiles were demonstrated for MCL and CLL. Importantly, certain functional classes of genes were preferentially methylated in either disease. For instance, developmental genes, in particular homeobox transcription factor genes (e.g., HLXB9, HOXA13), were more highly methylated in MCL, whereas apoptosis-related genes were enriched among targets methylated in CLL (e.g., CYFIP2, NR4A1). Results were validated using pyrosequencing, RQ-PCR and reexpression of specific genes. In summary, the methylation profile of MCL was homogeneous and no correlation with the proliferation signature was observed. Compared to CLL, however, marked differences were discovered such as the preferential methylation of homeobox genes in MCL. Am. J. Hematol., 2012. (C) 2012 Wiley Periodicals, Inc.
38.	Hawranek, Carolina, 1982-, et al. (författare) Direct letters to relatives at risk of hereditary cancer-study protocol for a multi-center randomized controlled trial of healthcare-assisted versus family-mediated risk disclosure at Swedish cancer genetics clinics (DIRECT-study) 2023 Ingår i: TRIALS. - : BioMed Central (BMC). - 1745-6215. ; 24:1 Tidskriftsartikel (refereegranskat)abstract Background The results of germline genetic testing for hereditary cancer are of importance not only to the patients under investigation but also to their genetic at-risk relatives. Standard care is to encourage the proband (first family member under investigation) to pass on this risk information to the relatives. Previous research suggests that with family-mediated disclosure, only about a third of at-risk relatives contact health care to receive genetic counselling. In some studies, complementing family-mediated risk disclosure with healthcare-assisted risk disclosure almost doubles the uptake of genetic counselling in at-risk relatives. In this study, we evaluate healthcare-assisted direct letters to relatives at risk of hereditary cancer syndromes in a randomized controlled trial.MethodsProbands are recruited from Swedish outpatient cancer genetics clinics to this two-arm randomized controlled trial. The study recruits probands with either a pathogenic variant in a cancer susceptibility gene (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2) or probands with familial breast and colorectal cancer based on clinical and pedigree criteria. In both arms, probands receive standard care, i.e., are encouraged and supported to pass on information to relatives. In the intervention arm, the proband is also offered to have direct letters sent to the at-risk relatives. The primary outcome measure is the proportion of at-risk relatives contacting a Swedish cancer genetics clinic within 12 months of the proband receiving the test results.DiscussionThis paper describes the protocol of a randomized controlled clinical trial evaluating a healthcare-assisted approach to risk disclosure by offering the probands to send direct letters to their at-risk relatives. The results of this study should be informative in the future development of risk disclosure practices in cancer genetics clinics.
39.	Henriksson, Isabelle, et al. (författare) Hereditary colorectal cancer diagnostics in southern Sweden : retrospective evaluation and future considerations with emphasis on Lynch syndrome 2019 Ingår i: Journal of Community Genetics. - : Springer Science and Business Media LLC. - 1868-310X .- 1868-6001. ; 10:2, s. 259-266 Tidskriftsartikel (refereegranskat)abstract Overlapping phenotypes between different hereditary colorectal cancer (CRC) syndromes together with a growing demand for cancer genetic testing and improved sequencing technology call for adjusted patient selection and adapted diagnostic routines. Here we present a retrospective evaluation of family history of cancer, laboratory diagnostic procedure, and outcome for 372 patients tested for Lynch syndrome (LS), i.e., the single most common hereditary cause of CRC. Based on number of affected family members and age at cancer diagnosis in families with genetically confirmed LS, we developed local patient selection criteria for a simplified one-step gene panel mutation screening strategy targeting also less common Mendelian CRC syndromes. Pros and cons of this strategy are discussed.
40.	Hjorth-Hansen, Henrik, et al. (författare) Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006) 2015 Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 94:3, s. 243-250 Tidskriftsartikel (refereegranskat)abstract We randomised 46 newly diagnosed patients with chronic myeloid leukaemia (median age 56) to receive dasatinib 100mg QD or imatinib 400mg QD and report outcome as an intention-to-treat analysis with 36months follow-up. Early cytogenetic and molecular responses were superior in the dasatinib group, with a tendency that imatinib patients caught up with time. For instance, MR3.0 was reached at 3months in 36% vs. 8% (P=0.02), at 12months in 81% vs. 46% (P=0.02) and at 18months in 73% vs. 65% (n.s.) of the patients in the two groups. In contrast, MR4.5 was consistently superior in the dasatinib group at all time points from 6months onwards, reaching 61% vs. 21% (P<0.05) at 36months. Sixty-four vs. 71% of the patients in the dasatinib and imatinib arms, respectively, remained on assigned drug. Dasatinib dose was frequently reduced, but with maintained excellent effect. One imatinib patient progressed to blastic phase, but no CML-related deaths occurred. In conclusion, our data compare favourably with those of the dasatinib registration study, DASISION. The fast and deep molecular responses induced by dasatinib compared with imatinib may be exploited to increase the proportion of patients who can achieve a treatment-free remission after treatment discontinuation.
41.	Hollestelle, Antoinette, et al. (författare) No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer 2016 Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401 Tidskriftsartikel (refereegranskat)abstract Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
42.	Ilander, Mette Matilda, et al. (författare) Early Disease Relapse after Tyrosine Kinase Inhibitor Treatment Discontinuation in CML Is Related Both to Low Number and Impaired Function of NK-Cells 2014 Ingår i: Blood. - 0006-4971 .- 1528-0020. ; 124:21 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
43.	Ilander, Mette, et al. (författare) Mature, Adaptive-like CD56(DIM) NK Cells in Chronic Myeloid Leukemia Patients in Treatment Free Remission 2015 Ingår i: Blood. - 0006-4971 .- 1528-0020. ; 126:23 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
44.	Kanduri, Meena, 1974, et al. (författare) Distinct transcriptional control in major immunogenetic subsets of chronic lymphocytic leukemia exhibiting subset-biased global DNA methylation profiles. 2012 Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 7:12, s. 1435-42 Tidskriftsartikel (refereegranskat)abstract Chronic lymphocytic leukemia (CLL) can be divided into prognostic subgroups based on the IGHV gene mutational status, and is further characterized by multiple subsets of cases with quasi-identical or stereotyped B cell receptors that also share clinical and biological features. We recently reported differential DNA methylation profiles in IGHV-mutated and IGHV-unmutated CLL subgroups. For the first time, we here explore the global methylation profiles of stereotyped subsets with different prognosis, by applying high-resolution methylation arrays on CLL samples from three major stereotyped subsets: the poor-prognostic subsets #1 (n = 15) and #2 (n = 9) and the favorable-prognostic subset #4 (n = 15). Overall, the three subsets exhibited significantly different methylation profiles, which only partially overlapped with those observed in our previous study according to IGHV gene mutational status. Specifically, gene ontology analysis of the differentially methylated genes revealed a clear enrichment of genes involved in immune response, such as B cell activation (e.g., CD80, CD86 and IL10), with higher methylation levels in subset #1 than subsets #2 and #4. Accordingly, higher expression of the co-stimulatory molecules CD80 and CD86 was demonstrated in subset #4 vs. subset #1, pointing to a key role for these molecules in the crosstalk of CLL subset #4 cells with the microenvironment. In summary, investigation of three prototypic, stereotyped CLL subsets revealed distinct DNA methylation profiles for each subset, which suggests subset-biased patterns of transcriptional control and highlights a key role for epigenetics during leukemogenesis.
45.	Karrman, Kristina, et al. (författare) Clinical and cytogenetic features of a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias: rare T-cell receptor gene rearrangements are associated with poor outcome. 2009 Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1098-2264 .- 1045-2257. ; 48:9, s. 795-805 Tidskriftsartikel (refereegranskat)abstract Clinical characteristics and cytogenetic aberrations were ascertained and reviewed in a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias (T-ALLs) diagnosed between 1992 and 2006 in the Nordic countries. Informative karyotypic results were obtained in 249 (87%) cases, of which 119 (48%) were cytogenetically abnormal. Most (62%) of the aberrant T-ALLs were pseudodiploid. Structural changes were more common than numerical ones; 86% displayed at least one structural abnormality and 41% at least one numerical anomaly. The most frequent abnormalities were T-cell receptor (TCR) gene rearrangements (20%) [TCR;11p13 (10%), TCR;10q24 (3%), TCR;other (8%)], del(9p) (17%), +8 (14%), del(6q) (12%), and 11q23 rearrangements (6%). The TCR;other group comprised the rare rearrangements t(X;14)(p11;q11), t(X;7)(q22;q34), t(1;14)(p32;q11), ins(14;5)(q11;q?q?), inv(7)(p15q34), t(8;14)(q24;q11), t(7;11)(q34;p15), and t(12;14)(p13;q11). The clinical characteristics of this Nordic patient cohort agreed well with previous larger series, with a median age of 9.0 years, male predominance (male/female ratio 3.1), median white blood cell (WBC) count of 66.5 x 10(9)/l, and a high incidence of mediastinal mass and central nervous system involvement (59% and 9.5%, respectively). These features did not differ significantly among the various genetic subgroups. 5-year event-free survival (EFS) and overall survival for all patients were 0.61 (+/-0.03) and 0.67 (+/-0.03), respectively. In a multivariate analysis, two factors affected negatively the EFS, namely a WBC count of > or =200 x 10(9)/l (P < 0.001) and the presence of rare TCR rearrangements (P = 0.001). In conclusion, in this large series of childhood T-ALLs from the Nordic countries, the cytogenetic findings were not associated with risk of therapy failure with the exception of the TCR;other group. However, further prospective and collaborative investigations of this genetically heterogeneous entity are needed to confirm these results.
46.	Kuchenbaecker, Karoline B., et al. (författare) Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers 2017 Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 109:7 Tidskriftsartikel (refereegranskat)abstract Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 × 10-53). InBRCA2 carriers, the strongest association with BC risk was seen for the overall BCPRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 × 10-20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.
47.	Lilljebjörn, Henrik, et al. (författare) RNA-seq identifies clinically relevant fusion genes in leukemia including a novel MEF2D/CSF1R fusion responsive to imatinib. 2014 Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 28:4, s. 977-979 Tidskriftsartikel (refereegranskat)
48.	Mahon, Francois-Xavier, et al. (författare) Interim Analysis of a Pan European Stop Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia : The EURO-SKI study 2014 Ingår i: Blood. - 0006-4971 .- 1528-0020. ; 124:21 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
49.	Martrat, Griselda, et al. (författare) Exploring the link between MORF4L1 and risk of breast cancer 2011 Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 13:2 Tidskriftsartikel (refereegranskat)abstract Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P-trend = 0.45 and 0.05, P-2df = 0.51 and 0.14, respectively; and rs10519219, P-trend = 0.92 and 0.72, P-2df = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.
50.	Maxwell, Christopher A., et al. (författare) Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer 2011 Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885 .- 1544-9173. ; 9:11 Tidskriftsartikel (refereegranskat)abstract Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.

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