BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer

Abstract

BackgroundGermline 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.MethodsTo 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.ResultsBRIP1 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.ConclusionsTo 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.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0935-9) contains supplementary material, which is available to authorized users.

The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants

“…4,5,28 However, it should be noted that recent studies have indicated that NBN is not significantly associated with HBOC, whereas BRIP1 has instead been associated with a significant risk for ovarian cancer but not breast cancer. 13,29 Our PV detection rate of 8.4% in these core genes is comparable to a previous report of the GC-HBOC. 5 These PVs we detected include two deleterious variants in BRCA1 that were previously missed by less comprehensive and sensitive screening methods.…”

“…Most of the PVs (20/237; 8.4%) identified were found in genes that have a moderate to high risk for HBOC ( BRCA1, ATM, CHEK2, CDH1, PALB2, RAD51C and NBN ) according to the GC‐HBOC . However, it should be noted that recent studies have indicated that NBN is not significantly associated with HBOC, whereas BRIP1 has instead been associated with a significant risk for ovarian cancer but not breast cancer . Our PV detection rate of 8.4% in these core genes is comparable to a previous report of the GC‐HBOC .…”

Exome sequencing in 51 early onset non‐familial CRC cases

“…We cannot exclude or verify this potential diagnosis clinically. BRIP1 has been shown to be a moderate‐risk ovarian cancer gene (Ramus et al., ; Weber‐Lassalle et al., ), most often caused by truncating variants (ClinVar). Two CRC patients with truncating BRIP1 variants and either familial CRC or polyposis have recently been reported (Martin‐Morales et al., ; Rosenthal et al., ).…”

Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?

“…However, monoallelic PV/LPVs in the BRIP1 gene lead to a higher risk of OC that is estimated to be around 6% during a lifetime [127,132]. In contrast to the PALB2 gene, the risk of BC for BRIP1 PV/LPV carriers is estimated to be low or none [133][134][135], and there is insufficient evidence for risk management [54]. For the risk of OC, according to the NCCN guidelines, RRSO is an option that should be evaluated at 45-50 years or earlier based on family history [54].…”