| 1. |
- Antoniou, Antonis C., et al.
(author)
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Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers
- 2011
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:16, s. 3304-3321
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Journal article (peer-reviewed)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.
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| 2. |
- Arver, Brita, et al.
(author)
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Bilateral Prophylactic Mastectomy in Swedish Women at High Risk of Breast Cancer: A National Survey.
- 2011
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In: Annals of surgery. - : Lippincott Williams and Wilkins; 1999. - 1528-1140 .- 0003-4932. ; 253:6, s. 1147-1154
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Journal article (peer-reviewed)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.
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| 3. |
- Arver, Brita, et al.
(author)
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First BRCA1 and BRCA2 gene testing implemented in the health care system of Stockholm
- 2001
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In: Genetic Testing. - : Mary Ann Liebert Inc. - 1557-7473 .- 1090-6576. ; 5:1, s. 41282-41282
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Journal article (peer-reviewed)abstract
- The aim of the study was to optimize the criteria for the BRCA1 and BRCA2 gene testing and to improve oncogenetic counseling in the Stockholm region. Screening for inherited breast cancer genes is laborious and a majority of tested samples turn out to be negative. The frequencies of mutations in the BRCA1 and BRCA2 genes differ across populations. Between 1997 and 2000, 160 families with breast and/or ovarian cancer were counseled and screened for mutations in the two genes. Twenty-five BRCA1 and two BRCA2 disease-causing mutations were found. Various factors associated with the probability of finding a BRCA1 mutation in the families were estimated. Age of onset in different generations and other malignancies were also studied. Families from our region in which both breast and ovarian cancer occur were likely to carry a BRCA1 mutation (34%). In breast-only cancer families, mutations were found only in those with very early onset. All breast-only cancer families with a mutation had at least one case of onset before 36 years of age and a young median age of onset (< 43 years). Other malignancies than breast and ovarian cancers did not segregate in the BRCA1 families and surveillance for other malignancies is not needed, in general. Decreasing age of onset with successive generations was common and must be taken into account when surveillance options are considered.
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| 4. |
- Arver, Brita
(author)
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Hereditary breast/ovarian cancer : implementation of BRCA1 and BRCA2 testing
- 2001
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Doctoral thesis (other academic/artistic)abstract
- Breast cancer is the most common malignancy among women in the western world. Most cases are sporadic but in 5 to 10 % an inherited genetic mutation is the main cause of the disease. Families with inherited breast cancer are characterized by multiple breast cancer cases, early age of onset, frequently occurring bilaterality and in many families women affected by ovarian cancer are found. Two important genes involved in hereditary breast or breast/ovarian cancer have been identified, BRCA1 on chromosome 17q and BRCA2 on chromosome 13q The genes are suppose to be tumor suppressor genes and both are suggested to participate in DNA repair. The entire function of the two genes is not yet fully known. Families in which a mutated BRCA 1 or BRCA2 gene can be suspected are offered genetic screening. If a mutation is revealed, predictive testing in healthy family members is a possibility. Identified mutation carriers have a greatly increased risk of breast and ovarian cancer and are offered regular surveillance and preventive measures. Family members without the mutation can be relieved from substantial cancer worries for themselves and for their offspring. In order to estimate the contribution of BRCA1 and BRCA2 germ line mutations in different breast or breast/ovarian cancer families from the Stockholm region, three screening studies were performed. Initially no restriction with respect to age at onset was made, but when in 1997 the procedure was implemented into clinical practice age-related screening criteria were employed in families with breast cancer only in order to optimize the outcome. Different mutation screening methods were used and successively evaluated. Healthy members of families with a revealed mutation in a breast/ovarian or a hereditary colon cancer gene were offered genetic predictive testing. The Psycho-social consequences of pre-symptomatic testing were evaluated in a 15 month follow-up study. BRCA1 mutations were consistently found in one third of the breast/ovarian cancer families (Paper 1, 11 IV). In breast cancer-only families BRCA1 mutations were found 1-2 % (Paper I and II). When age- related screening criteria were introduced this figure increased to 7% and the criteria could be further limited in the breast cancer-only families without loss of sensitivity (Paper IV). More than 50% of the BRCA1 aberrations detected were one of three founder mutations, 2594deIC, 3166insTGAGA or 3745delT (Paper 1, 11 and IV). Tumors other than breast and ovarian cancers were not overrepresented in the BRCA1 families (Paper IV). BRCA2 mutations were found to be rare in the Stockholm region and consistently found in 1-2 % of the families despite limited screening criteria (Paper III and IV). No family with the common Icelandic BRCA2 founder mutation was found (Paper 111). In many breast-cancer-only families no mutations were found, and other genes than BRCA1 and BRCA2 are likely to segregate in the breast cancer families in the Stockholm region (Paper 1, 11, 11, and IV). Independent of the screening methods used in paper 1, 11, 111 and IV, the frequency of disease causing mutations were approximately identical. Toward the end of the project when the entire genes were sequenced automatically, only an expected moderately increased number of BRCA2 missense mutations were found (Paper IV). Predictive genetic testing for germ I ine mutations in the BRCA1, BRCA2 hMLH1 or hMSH2 genes, preceded by extensive information and surveillance did not impair mental health of the people at risk. The individual's response to the test result was not predicted by the presence or absence of a mutation. Non carriers may also benefit from follow-ups (Paper V).
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| 5. |
- Bai, Lucy, et al.
(author)
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Body image problems in women with and without breast cancer 6-20 years after bilateral risk-reducing surgery : A prospective follow-up study
- 2019
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In: Breast. - : Elsevier BV. - 0960-9776 .- 1532-3080. ; 44, s. 120-127
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Journal article (peer-reviewed)abstract
- PURPOSE: To prospectively follow-up and investigate women's perceptions of the cosmetic outcome of their implant-based breast reconstruction, body image, sexuality, anxiety/depressive symptoms, and health-related quality of life (HRQoL) 6-20 years after bilateral risk-reducing mastectomy (RRM), or complementary RRM after breast cancer diagnosis, due to increased risk of hereditary breast cancer.PATIENTS AND METHODS: Women with and without previous breast cancer diagnosis that underwent RRM between March 1997 and September 2010 were invited (n = 200). We compared 146 (73%) sets of long-term questionnaire responses (e.g., EORTC QLQ-BRR26, Body Image Scale, Sexuality Activity Questionnaire, Hospital Anxiety and Depression Scale, and SF-36) with responses one year after surgery. Women with and without previous breast cancer were compared at the long-term assessment point.RESULTS: The HRQoL and anxiety/depressive symptoms remained unchanged compared with one year after surgery, and there were no between-group differences. The negative impact on body image persisted in both groups for most of the items. 'Sexual discomfort' increased significantly for women with previous breast cancer (p = 0.016). Women with previous breast cancer also reported more problems with 'Disease treatment/surgery related symptoms' (p = 0.006) and 'Sexuality' (p = 0.031) in the EORTC QLQ-BRR26 questionnaire.CONCLUSION: Problems with body image appeared to persist long time post-RRM. No differences in HRQoL were found at the long-term follow-up between women with and without previous breast cancer. The results of this investigation might be of use in improving future counselling before risk-reducing surgery for women in the decision-making process.
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| 6. |
- Bai, Lucy, et al.
(author)
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Clinical assessment of breast symmetry and aesthetic outcome : Can 3D imaging be the gold standard?
- 2023
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In: Journal of Plastic Surgery and Hand Surgery. - 2000-656X .- 2000-6764. ; 57:1-6, s. 145-152
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Journal article (peer-reviewed)abstract
- There is a lack of an accurate standardised objective method to assess aesthetic outcome after breast surgery. In this methodological study, we investigated the intra- and inter-observer reproducibility of breast symmetry and volume assessed using three-dimensional surface imaging (3D-SI), evaluated the reproducibility depending on imaging posture, and proposed a new combined volume-shape-symmetry (VSS) parameter. Images were acquired using the VECTRA XT 3D imaging system, and analysed by two observers using VECTRA Analysis Module. Breast symmetry was measured through the root mean square distance. All women had undergone bilateral risk-reducing mastectomy and immediate breast reconstruction. The reproducibility and correlations of breast symmetry and volume measurements were compared using Bland-Altman's plots and tested with Spearman's rank correlation coefficient. 3D surface images of 58 women were analysed (348 symmetry measurements, 696 volume measurements). The intra-observer reproducibility of breast symmetry measurements was substantial-excellent, the inter-observer reproducibility was substantial, and the inter-posture reproducibility was substantial. For measurements of breast volumes, the intra-observer reproducibility was excellent, the inter-observer reproducibility was moderate-substantial, and the inter-posture reproducibility was substantial-excellent. The intra-observer reproducibility of VSSVSS was excellent while the inter-observer reproducibility was substantial for both observers, independent of posture. There were no statistically strong correlations between breast symmetry and volume differences. The intra-observer reproducibility was found to be substantial-excellent for several 3D-SI measurements independent of imaging posture. However, the inter-observer reproducibility was lower than the intra-observer reproducibility, indicating that 3D-SI in its present form is not a great assessment for symmetry.
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| 7. |
- Bai, Lucy, et al.
(author)
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Patient-reported outcomes and 3-dimensional surface imaging after risk-reducing mastectomy and immediate breast reconstruction
- 2021
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In: Plastic and Reconstructive Surgery - Global Open. - 2169-7574. ; 9:5
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Journal article (peer-reviewed)abstract
- The cosmetic results after risk-reducing mastectomy (RRM) and immediate breast reconstruction (IBR) are intended to be long-lasting. Long-term follow-up of the cosmetic outcome can be evaluated subjectively by the women themselves through patient-reported outcome measures such as questionnaires, or by using data from three-dimensional surface imaging (3D-SI) to calculate the volume, shape, and symmetry of the reconstructed breasts as a more objective cosmetic evaluation. The study aim was to evaluate the correspondence between patient-reported measures and 3D-SI measurements.Methods: Questionnaires (EORTC QLQ-BRECON23 and BIS) were sent to women on average 13 [7-20] years after RRM and IBR. Items were preselected for comparison with 3D measurements of women imaged using the VECTRA XT 3D-imaging system at the long-term follow-up.Results: Questionnaire responses and 3D images of 58 women, 36 without and 22 with previous breast cancer (where 15 also received radiotherapy) before RRM and IBR, were analyzed. Median age at follow-up was 57 [41-73] years. Patient-reported satisfaction with the cosmetic outcome was positive for both groups. 3D measurements indicated more symmetrical cosmetic results for women without previous breast cancer. No statistically significant associations between patient-reported satisfaction and 3D measurements were found.Conclusions: Satisfaction with the long-term cosmetic outcome after RRM and IBR was, in general, positive when evaluated by the women. 3D-SI could be used as a more objective approach to assess the cosmetic outcome in terms of volume and shape-symmetry; however, it does not directly translate to the patient-reported satisfaction.
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| 8. |
- Catucci, Irene, et al.
(author)
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Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility
- 2018
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In: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 20:4, s. 452-457
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Journal article (peer-reviewed)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.
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| 9. |
- Chang-Claude, Jenny, et al.
(author)
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Age at menarche and menopause and breast cancer risk in the International BRCA1/2 Carrier Cohort Study
- 2007
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In: Cancer Epidemiology Biomarkers and Prevention. - 1055-9965. ; 16:4, s. 740-746
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Journal article (peer-reviewed)abstract
- Background: Early menarche and late menopause are important risk factors for breast cancer, but their effects on breast cancer risk in BRCA1 and BRCA2 carriers are unknown. Methods: We assessed breast cancer risk in a large series of 1,187 BRCA1 and 414 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study. Rate ratios were estimated using a weighted Cox-regression approach. Results: Breast cancer risk was not significantly related to age at menopause {hazard ratio [HR] for menopause below age 35 years, 0.60 [95% confidence interval (95% CI), 0.25-1.44]; 35 to 40 years, 1.15 [0.65-2.04]; 45 to 54 years, 1.02 [0.65-1.60]; ≥55 years, 1.12 [0.12-5.02], as compared with premenopausal women}. However, there was some suggestion of a reduction in risk after menopause in BRCA2 carriers. There was some evidence of a protective effect of oophorectomy (HR, 0.56; 95% CI, 0.29-1.09) and a significant trend of decreasing risk with increasing time since oophorectomy, but no apparent effect of natural menopause. There was no association between age at menarche and breast cancer risk, nor any apparent association with the estimated total duration of breast mitotic activity. Conclusions: These results are consistent with other observations suggesting a protective effect of oophorectomy, similar in relative effect to that in the general population. The absence of an effect of age at natural menopause is, however, not consistent with findings in the general population and may reflect the different natural history of the disease in carriers.
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| 10. |
- Couch, Fergus J., et al.
(author)
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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
- 2016
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13
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Journal article (peer-reviewed)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. |
- Gonzalez, Virginia, et al.
(author)
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Impact of preoperative breast MRI on 10-year survival outcome of patients included in the Swedish randomized multicenter POMB trial
- 2021
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In: BJS Open. - : Oxford University Press. - 2474-9842. ; 5:5
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Journal article (peer-reviewed)abstract
- ABSTRACTBackground: The value of preoperative breast magnetic resonance imaging (MRI) as an adjunct technique regarding its effect on re-excision rates has been a subject of discussion. No survival data regarding preoperative breast MRI are available from randomized studies. Methods: Ten-year follow-up of the previous randomized multicentre study (POMB) was reported, evaluating MRI and its effect on disease-free survival (DFS) and overall survival (OS). A total of 440 patients with newly diagnosed breast cancer were randomized to either preoperative MRI (n = 220) group or conventional imaging (n = 220; control) group. Kaplan–Meier plots were used to analyze DFS and OS. Cox regression was used to estimate hazard ratios (HRs). Results: The median follow-up time for each group was 10 years. DFS rates were 85.5% and 80.0% for the MRI and control groups, respectively (P = 0.099). The risk of relapse or death was 46% higher in the control group (HR 1.46, 95% confidence interval 0.93–2.29). OS rates after 10 years were 90.9% and 88.6% for the MRI and control groups, respectively (P = 0.427). The risk of death was 27% higher in the control group (HR 1.27, 95% confidence interval 0.71–2.29). Locoregional, distant, and contralateral recurrence outcomes combined, were increased in the control group (P = 0.048). A subgroup analysis of patients with breast cancer stages I–III showed that preoperative MRI improved DFS compared with conventional imaging but this did not reach statistical significance (P = 0.057). Conclusion: After 10 years of follow-up, preoperative breast MRI as an adjunct to conventional imaging resulted in slightly, but non-significantly, improved DFS and OS.ClinicalTrials.gov Identifier: POMB NCT01859936
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| 12. |
- Gonzalez, Virginia, et al.
(author)
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Preoperative MRI of the Breast (POMB) Influences Primary Treatment in Breast Cancer: A Prospective, Randomized, Multicenter Study
- 2012
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In: World Journal of Surgery. ; :38, s. 1685-1693
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Journal article (peer-reviewed)abstract
- Abstract Background Breast magnetic resonance imaging (MRI) has shown high sensitivity in determining tumor extent, multifocality, and occult contralateral breast cancer. Low specificity, unnecessary mastectomies, and costs are argu- ments against MRI. The purpose of this study was to determine whether preoperative breast MRI would affect primary surgical management, reduce reexcision/reopera- tion procedures, and influence the choice of neoadjuvant treatment in patients with newly diagnosed breast cancer. Methods This prospective, randomized, multicenter study included 440 breast cancer patients younger than aged 56 years from three, Swedish, large-volume breast units. Patients were randomly allocated on a 1:1 basis to either preoperative staging with breast MRI (n = 220) or no breast MRI (n = 220) (control group). Treatment planning of all patients was discussed at multidisciplinary team conferences. Results In patients randomized to the MRI group, who had an observed higher percentage of planned breast-con- serving surgery (BCS) compared with the control group, a change from suggested breast conservation to mastectomy occurred in 23 of 153 (15 %) patients. Breast MRI pro- vided additional information in 83 of 220 (38 %) patients, which caused a change in treatment plan in 40 (18 %). The breast reoperation rate was significantly lower in the MRI group: 11 of 220 (5 %) versus 33 of 220 (15 %) in the control group (p \ 0.001). The number of mastectomies, axillary reoperations, and the number of patients receiving neoadjuvant chemotherapy after definitive treatment did not differ significantly between the groups. Conclusions Preoperative staging with breast MRI in women younger than age 56 years altered the treatment plan in 18 % of the patients. Although a higher MRI- related conversion rate from breast conservation to mas- tectomy was found, the final numbers of mastectomies did not differ between the two groups. The breast reoperation rate in the MRI group was significantly reduced.
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| 13. |
- Hollestelle, Antoinette, et al.
(author)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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In: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Journal article (peer-reviewed)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.
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| 14. |
- Isaksson, Karin, et al.
(author)
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Bilateral risk-reducing mastectomies with implant-based reconstructions followed long term : a consecutive series of 185 patients
- 2019
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In: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 43:9, s. 2262-2270
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Journal article (peer-reviewed)abstract
- BACKGROUND: Bilateral risk-reducing mastectomy (BRRM) is the most effective method to prevent breast cancer in genetically predisposed women and is often performed concomitantly with breast reconstruction. The reconstruction time varies and corrective surgeries are common.METHODS: This study evaluated 185 consecutive cases of BRRM and immediate breast reconstruction with implants with regard to surgical outcome and resource consumption. With an 18-year observation period, it was possible to compare permanent expander implants (PEIs) with permanent fixed volume implants (PIs).RESULTS: A minimum follow-up of 2 years for all participants but one was achieved. Seventy-five percent (n = 138) of the women received PEI and 25% (n = 47) PI. In a multivariate analysis including age, BMI (<25, ≥25), smoking (yes, no), implant type (PEI, PI), incision technique, operation time and specimen weight <350 g, ≥350 g), only BMI ≥25 was associated with an increased risk of an early complication (OR 7.1, 95% CI 2.44-20.4). As expected, there was a significant difference in median reconstruction time between PEI and PI (12.4 vs. 1.0 months, p < 0.001). The cumulative reoperation-free 2-year survival was significantly higher in the PI than in the PEI group (81% vs. 26%, p < 0.001).CONCLUSION: Implant-based reconstruction remains a valid option after BRRM in high-risk women. Whenever possible (low BMI and small breast volume without severe ptosis), permanent fixed volume implants can be safely recommended and are resource saving in comparison with permanent expander implants.
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| 15. |
- Karlsson, Anders, et al.
(author)
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The accuracy of incremental pre-operative breast MRI findings - Concordance with histopathology in the Swedish randomized multicenter POMB trial
- 2019
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In: European Journal of Radiology. - : ELSEVIER IRELAND LTD. - 0720-048X .- 1872-7727. ; 114, s. 185-191
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Journal article (peer-reviewed)abstract
- Purpose: The Pre-Operative MRI of the Breast (POMB) trial was a randomized, prospective, multicenter trial evaluating the impact of pre-operative breast MRI on treatment regimens and short-term surgical outcomes in women up to 56 years of age with breast cancer. The purpose of this study was to evaluate the performance of pre-operative breast MRI in the POMB trial with respect to incremental MRI findings - over conventional breast imaging methods - and their concordance with histopathology.Patients and methods: Two-hundred and ten patients (n = 210) participating in the POMB trial underwent preoperative breast MRI at two Swedish breast units. Positive predictive values (PPV) for the incremental MRI findings were calculated for three subgroups of patients with: 1. alteration/alterations of treatment plan; 2. no alteration of treatment plan; and, 3. MRI-related conversion from BCS to mastectomy. Area under the receiver operating characteristic curve (AUC) was calculated using in-breast BI-RADS based ratings for the whole MRI group.Results: After exclusions a total number of 99 incremental findings in 78 patients were eligible for statistical analysis resulting in a PPV = 74%: (95% CI 60-84%) in 39 patients with MRI related alterations of initial treatment plans and 27%: (95% CI 14-44%) in 39 patients without. Positive predictive values of incremental findings decisive for specific treatment alteration/s were 83% (95% CI 68-92%) in patients with any alteration of initial treatment plans and 91% (95% CI 70-98%) for patients (n = 20/22) with conversion from breast conserving surgery to mastectomy. The empirical AUC for the incremental findings in the whole MRI group was 85% (95% CI 78-91%).Conclusion: Breast MRI, performed and evaluated together with conventional breast imaging methods can provide relevant information at a high degree of accuracy in the pre-operative setting.
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| 16. |
- Lawrenson, Kate, et al.
(author)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)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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| 17. |
- Osorio, Ana, et al.
(author)
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DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
- 2014
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:4
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Journal article (peer-reviewed)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.
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| 18. |
- Walker, Logan C, et al.
(author)
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Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.
- 2010
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In: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-542X .- 1465-5411. ; 12:6
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Journal article (peer-reviewed)abstract
- Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.
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| 19. |
- Wendt, Camilla, et al.
(author)
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A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients
- 2021
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11, s. 1-9
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Journal article (peer-reviewed)abstract
- The risk of breast cancer associated with CHEK2:c.1100delC is 2-threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.
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| 20. |
- Zeng, Chenjie, et al.
(author)
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
- 2016
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18
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Journal article (peer-reviewed)abstract
- Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
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