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| 2. |
- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 5. |
- Figlioli, G, et al.
(författare)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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| 6. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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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.
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| 10. |
- Couch, Fergus J., et al.
(författare)
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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
- 2016
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13
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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.
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| 11. |
- Durno, C., et al.
(författare)
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Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance
- 2021
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 39:25
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.
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| 16. |
- Benjamin, L. A., et al.
(författare)
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Antiphospholipid antibodies and neurological manifestations in acute COVID-19: A single-centre cross-sectional study
- 2021
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Ingår i: Eclinicalmedicine. - : Elsevier BV. - 2589-5370. ; 39
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Tidskriftsartikel (refereegranskat)abstract
- Background: A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear. Methods: This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [a beta(2)GPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I b2GPI (aD1 beta 2GPI) IgG. Findings: There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups (p < 0.001). Moderate-high titre of aPS/PT IgG was found in 2 out of 3 (67%) patients with acute disseminated encephalomyelitis [ADEM]. aPS/PT IgG titres negatively correlated with oxygen requirement (FiO(2) R=-0.15 p = 0.040) and was associated with venous thromboembolism (p = 0.043). In contrast, aCL IgA (p < 0.001) and IgG (p < 0.001) was associated with non-neurological COVID-hospitalised controls compared to the other groups and correlated positively with D-dimer and creatinine but negatively with FiO(2). Interpretation: Our findings show that aPS/PT IgG is associated with COVID-19-associated ADEM. In contrast, aCL IgA and IgG are seen much more frequently in non-neurological hospitalised patients with COVID-19. Characterisation of antiphospholipid antibody persistence and potential longitudinal clinical impact are required to guide appropriate management. (C) 2021 The Author(s). Published by Elsevier Ltd.
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| 18. |
- Hamdi, Yosr, et al.
(författare)
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Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression : identification of a modifier of breast cancer risk at locus 11q22.3
- 2017
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 161:1, s. 117-134
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
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| 19. |
- Paterson, R. W., et al.
(författare)
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Do cerebrospinal fluid transfer methods affect measured amyloid β42, total tau, and phosphorylated tau in clinical practice?
- 2015
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Ingår i: Alzheimer's & Dementia. - : Elsevier Inc.. - 1552-5260 .- 1552-5279. ; 1:3, s. 380-384
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Cerebrospinal fluid (CSF) neurodegenerative markers are measured clinically to support a diagnosis of Alzheimer's disease. Several preanalytical factors may alter the CSF concentrations of amyloid β 1-42 (Aβ1-42) in particular with the potential to influence diagnosis. We aimed to determine whether routine handling of samples alters measured biomarker concentration compared with that of prompt delivery to the laboratory. Methods: Forty individuals with suspected neurodegenerative diseases underwent diagnostic lumbar punctures using a standardized technique. A sample of each patient's CSF was sent to the laboratory by four different delivery methods: (1) by courier at room temperature; (2) by courier, on ice; (3) using standard hospital portering; and (4) after quarantining for >24 hours. Aβ1-42, total tau (t-tau), and phosphorylated tau (p-tau) levels measured using standard enzyme-linked immunosorbent assay techniques were compared between transfer methods. Results: There were no significant differences in Aβ1-42, t-tau, or p-tau concentrations measured in samples transported via the different delivery methods despite significant differences in time taken to deliver samples. Discussion: When CSF is collected in appropriate tubes, transferred at room temperature, and processed within 24 hours, neurodegenerative markers can be reliably determined. © 2015 The Authors.
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| 20. |
- Cloutier, B. Tessier, et al.
(författare)
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Breast Cancer in Systemic Lupus Erythematosus
- 2013
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Ingår i: Oncology. - : S. Karger AG. - 1423-0232 .- 0030-2414. ; 85:2, s. 117-121
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Evidence points to a decreased breast cancer risk in systemic lupus erythematosus (SLE). We analyzed data from a large multisite SLE cohort, linked to cancer registries. Methods: Information on age, SLE duration, cancer date, and histology was available. We analyzed information on histological type and performed multivariate logistic regression analyses of histological types according to age, SLE duration, and calendar year. Results: We studied 180 breast cancers in the SLE cohort. Of the 155 cases with histology information, 11 were referred to simply as 'carcinoma not otherwise specified'. In the remaining 144 breast cancers, the most common histological type was ductal carcinoma (n = 95; 66%) followed by lobular adenocarcinoma (n = 11; 8%), 15 cancers were of mixed histology, and the remaining ones were special types. In our regression analyses, the independent risk factors for lobular versus ductal carcinoma was age [odds ratio (OR) 1.07, 95% confidence interval (Cl) 1.01-1.14] and for the 'special' subtypes it was age (OR 1.06, 95% Cl 1.01-1.10) and SLE duration (OR 1.05, 95% CI 1.00-1.11). Conclusions: Generally, up to 80% of breast cancers are ductal carcinomas. Though our results are not definitive, in the breast cancers that occur in SLE, there may be a slight decrease in the ductal histological type. In our analyses, age and SLE duration were independent predictors of histological status. Copyright (C) 2013 S. Karger AG, Basel
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| 23. |
- Narod, SA, et al.
(författare)
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Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers
- 2002
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105. ; 94:23, s. 1773-1779
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Tidskriftsartikel (refereegranskat)abstract
- Background: Oral contraceptive use has been associated with an increase in the risk of breast cancer in young women. We examined whether this association is seen in women at high risk of breast cancer because they carry a mutation in one of two breast cancer susceptibility genes, BRCA1 and BRCA2. Methods: We performed a matched case-control study on 1311 pairs of women with known deleterious BRCA1 and/or BRCA2 mutations recruited from 52 centers in 11 countries. Women who had been diagnosed with breast cancer were matched to control subjects by year of birth, country of residence, mutation (BRCA1 or BRCA2), and history of ovarian cancer. All study subjects completed a questionnaire about oral contraceptive use. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived by conditional logistic regression. All statistical tests were two-sided. Results: Among BRCA2 mutation carriers, ever use of oral contraceptives was not associated with an increased risk of breast cancer (OR = 0.94, 95% CI = 0.72 to 1.24). For BRCAI mutation carriers, ever use of oral contraceptives was associated With a modestly increased risk of breast cancer (OR = 1.20, 95 % CI = 1.02 to 1.40). However, compared with BRCA1 mutation carriers who never used oral contraceptives, those who used oral contraceptives for at least 5 years had an increased risk of breast cancer (OR = 1.33, 95% CI = 1.11 to 1.60), as did those who used oral contraceptives before age 30 (OR = 1.29, 95% CI = 1.09 to 1.52), those who were diagnosed with breast cancer before age 40 (OR = 1.38, 95% CI = 1.11 to 1.72), and those who first used oral contraceptives before 1975 (OR = 1.42, 95 % CI = 1.17 to 1.75). Conclusions: Among BRCA1 mutation carriers, women who first used oral contraceptives before 1975, who used them before age 30, or who used them for 5 or more years may have an increased risk of early-onset breast cancer. Oral contraceptives do not appear to be associated with risk of breast cancer in BRCA2 carriers, but data for BRCA2 carriers are limited.
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| 24. |
- Vigorito, Elena, et al.
(författare)
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Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95% CI: 0.68 to 0.79, p-value 2x 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95% CI: 0.59 to 0.80, p-value 1.0 x 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.
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