The association between cancer family history and ovarian cancer risk in BRCA1/2 mutation carriers: can it be explained by the mutation position?

Abstract

This observational study aimed to investigate whether the reported association between family history (FH) of breast cancer (BC) or ovarian cancer (OC) and OC risks in BRCA1/2 mutation carriers can be explained by mutation position on the gene. In total, 3310 female BRCA1/2 mutation carriers participating in a nationwide prospective cohort (Hereditary Breast and Ovarian Cancer in the Netherlands) were included. FH was classified according to cancer occurrence in first-degree relatives (BC only, OC only, both, neither) and mutations were classified according to their position on the gene (OC cluster region (OCCR), BC cluster region, neither). The main outcome was OC occurrence. Cox proportional-hazard models were applied to investigate the association between FH and OC risks before and after adjusting for mutation position. Of all women included, 202 were diagnosed with OC. A BC-only FH tended to be associated with lower OC risks when compared with a FH without BC/OC (HR: 0.79, 95% CI: 0.52-1.17; HR: 0.59, 95% CI: 0.33-1.07 for BRCA1 and BRCA2, respectively) while an OC-only FH tended to be associated with higher risks (HR: 1.58, 95% CI: 0.90-2.77; HR: 1.75, 95% CI: 0.70-4.37 for BRCA1 and BRCA2, respectively). After adjusting for mutation position, association between FH and OC risks was slightly smaller in magnitude (HR: 0.85, 95% CI: 0.55-1.30; HR: 0.64, 95% CI: 0.34-1.21 for BC-only FH in BRCA1 and BRCA2, respectively; HR: 1.46, 95% CI: 0.80-2.68; HR: 1.49, 95% CI: 0.44-4.02 for OC-only FH in BRCA1 and BRCA2, respectively), indicating that mutation position explains only part of the association. Considering the magnitude of the observed trend, we do not believe FH should be used to change counseling regarding OC prevention.

Prevalence and Spectrum of Germline BRCA1 and BRCA2 Variants of Uncertain Significance in Breast/Ovarian Cancer: Mysterious Signals From the Genome

“…Several studies showed a strong correlation between specific BRCA1/2 variants and changes in BC/OC relative risk, by identifying specific putative Breast Cancer Cluster Regions (BCCRs) and Ovarian Cancer Cluster Regions (OCCRs) located on the coding DNA sequences of BRCA1/2 genes (30)(31)(32)(33)(34). As regards the gene location of BRCA1 variants detected in our study cohort, most of them (14/21) were mainly located within the hypothetical cluster region present in the BRCA1 protein structure which includes the exon 11 (nucleotides: 861-4,218; codons: 248-1,366), with a greater distribution inside the serine cluster domain (SCD).…”

Evaluation of family history in individuals with heterozygous BRCA pathogenic variants diagnosed with breast or ovarian cancer in a single center in Italy

“…The association between an FH of EOC and a personal history of EOC did not reach statistical significance ( p : .076). The role of an FH of EOC as a predictor of EOC risk is already demonstrated, especially among BRCA1 mutation carriers (Texeira et al, 2018 ); this is highly relevant considering that EOC is the third most common gynecologic cancer and has the worst prognosis and the highest mortality rate (Bray et al, 2018 ; Coburn et al, 2017 ; Momenimovahed et al, 2019 ).…”

First-degree family history of prostate cancer is associated the risk of breast cancer and ovarian cancer

“…[ 3 , 4 ] Family history is a well-established risk factor for both cancers. [ 5 , 6 ] Compared to the women without a first-degree relative with breast cancer, those with a family history of breast cancer in first-degree relatives had a 2.1 times greater risk of developing breast cancer. [ 7 ] Women with a family history of ovarian cancer in first-degree relatives had a 3.1 times greater risk of developing ovarian cancer.…”