Abstract
Genetic diversity of germline variants in breast cancer (BC) predisposition genes is unexplored in miscegenated populations, such those living in Latin America. We evaluated 1663 Brazilian BC patients, who underwent hereditary multigene panel testing (20–38 cancer susceptibility genes), to determine the spectrum and prevalence of pathogenic/likely pathogenic (P/LP) variants and variants of uncertain significance (VUS). Associations between P/LP variants and BC risk were estimated in a case–control analysis of BC patients and 18,919 Brazilian reference controls (RC). In total, 335 (20.1%) participants carried germline P/LP variants: 167 (10.0%) in BRCA1/2, 122 (7.3%) in BC actionable non-BRCA genes and 47 (2.8%) in candidate genes or other cancer predisposition genes. Overall, 354 distinctive P/LP variants were identified in 23 genes. The most commonly mutated genes were: BRCA1 (27.4%), BRCA2 (20.3%), TP53 (10.5%), monoallelic MUTYH (9.9%), ATM (8.8%), CHEK2 (6.2%) and PALB2 (5.1%). The Brazilian variant TP53 R337H (c.1010G>A, p.Arg337His), detected in 1.6% of BC patients and 0.1% of RC, was strongly associated with risk of BC, OR = 17.4 (95% CI: 9.4–32.1; p < 0.0001); monoallelic MUTYH variants c.1187G>A and c.536A>G, detected in 1.2% (0.9% RC) and 0.8% (0.4% RC) of the patients, respectively, were not associated with the odds of BC, the former with OR = 1.4 (95% CI: 0.8–2.4; p = 0.29) and the latter with OR = 1.9 (95% CI: 0.9–3.9; p = 0.09). The overall VUS rate was 46.1% for the entire patient population. Concluding, the use of multigene panel testing almost doubled the identification of germline P/LP variants in clinically actionable predisposition genes in BC patients. In Brazil, special attention should be given to TP53 P/LP variants.
Highlights
Breast cancer (BC) is the most common cancer in women worldwide
Panels have been widely available in Brazil within the past 7 years, but no study has yet assessed the prevalence and mutational spectrum of germline variants in BC susceptibility genes other than BRCA1/2 and TP53 in a large cohort of individuals with BC, who were referred for genetic evaluation
We report the results from 1663 consecutive individuals with a history of BC who were referred for multigene panel testing
Summary
Breast cancer (BC) is the most common cancer in women worldwide. In Brazil, an average of 66,280 women are diagnosed with carcinoma of the breast every year, accounting for 29.7% of all cancers in the female p opulation. In Brazil, the majority of the inherited BC studies focused on the analyses of BRCA1/2 as well as TP53, given the relatively high population frequency of the TP53 R337H ( known as, c.1010G>A, p.Arg337His) variant in people from the South and Southeast regions of B razil. Finding a mutation in a gene where the cancer risks and/or management strategies are not known, as well as the identification of higher numbers of variants of uncertain significance (VUS), can make the results cumbersome and challenging for a physician to interpret and guide t reatment. Panels have been widely available in Brazil within the past 7 years, but no study has yet assessed the prevalence and mutational spectrum of germline variants in BC susceptibility genes other than BRCA1/2 and TP53 in a large cohort of individuals with BC, who were referred for genetic evaluation. We report the results from 1663 consecutive individuals with a history of BC who were referred for multigene panel testing
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