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| Item Type: | Article |
|---|---|
| Title: | BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer |
| Creators Name: | Weber-Lassalle, N. and Hauke, J. and Ramser, J. and Richters, L. and Groß, E. and Blümcke, B. and Gehrig, A. and Kahlert, A.K. and Müller, C.R. and Hackmann, K. and Honisch, E. and Weber-Lassalle, K. and Niederacher, D. and Borde, J. and Thiele, H. and Ernst, C. and Altmüller, J. and Neidhardt, G. and Nürnberg, P. and Klaschik, K. and Schroeder, C. and Platzer, K. and Volk, A.E. and Wang-Gohrke, S. and Just, W. and Auber, B. and Kubisch, C. and Schmidt, G. and Horvath, J. and Wappenschmidt, B. and Engel, C. and Arnold, N. and Dworniczak, B. and Rhiem, K. and Meindl, A. and Schmutzler, R.K. and Hahnen, E. |
| Abstract: | BACKGROUND: Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial. METHODS: To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants. RESULTS: BRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02-36.57, P < 0.0001) and in the subgroup of index patients with late-onset OC (OR = 29.91, 95% CI = 14.99-59.66, P < 0.0001). No significant association of BRIP1 LoF mutations with familial BC was observed (OR = 1.81 95% CI = 1.00-3.30, P = 0.0623). In the subgroup of familial BC index patients without a family history of OC there was also no apparent association (OR = 1.42, 95% CI = 0.70-2.90, P = 0.3030). In 1027 familial BC index patients with a family history of OC, the BRIP1 mutation prevalence was significantly higher than that observed in controls (OR = 3.59, 95% CI = 1.43-9.01; P = 0.0168). Based on the negative association between BRIP1 LoF mutations and familial BC in the absence of an OC family history, we conclude that the elevated mutation prevalence in the latter cohort was driven by the occurrence of OC in these families. Compared with controls, predicted damaging rare missense variants were significantly more prevalent in OC (P = 0.0014) but not in BC (P = 0.0693) patients. CONCLUSIONS: To avoid ambiguous results, studies aimed at assessing the impact of candidate predisposition gene mutations on BC risk might differentiate between BC index patients with an OC family history and those without. In familial cases, we suggest that BRIP1 is a high-risk gene for late-onset OC but not a BC predisposition gene, though minor effects cannot be excluded. |
| Keywords: | Breast Cancer, Ovarian Cancer, BRIP1 Gene, Germline Mutations |
| Source: | Breast Cancer Research |
| ISSN: | 1465-5411 |
| Publisher: | BioMed Central |
| Volume: | 20 |
| Number: | 1 |
| Page Range: | 7 |
| Date: | 24 January 2018 |
| Official Publication: | https://doi.org/10.1186/s13058-018-0935-9 |
| PubMed: | View item in PubMed |
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