High frequency of pathogenic non-founder germline mutations in BRCA1 and BRCA2 in families with breast and ovarian cancer in a founder population

Abstract

BackgroundPathogenic BRCA1 founder mutations (c.4035delA, c.5266dupC) contribute to 3.77% of all consecutive primary breast cancers and 9.9% of all consecutive primary ovarian cancers. Identifying germline pathogenic gene variants in patients with primary breast and ovarian cancer could significantly impact the medical management of patients. The aim of the study was to evaluate the rate of pathogenic mutations in the 26 breast and ovarian cancer susceptibility genes in patients who meet the criteria for BRCA1/2 testing and to compare the accuracy of different selection criteria for second-line testing in a founder population.MethodsFifteen female probands and 1 male proband that met National Comprehensive Cancer Network (NCCN) criteria for BRCA1/2 testing were included in the study and underwent 26-gene panel testing. Fourteen probands had breast cancer, one proband had ovarian cancer, and one proband had both breast and ovarian cancer. In a 26-gene panel, the following breast and/or ovarian cancer susceptibility genes were included: ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MEN1, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2. All patients previously tested negative for BRCA1 founder mutations.ResultsIn 44% (7 out of 16) of tested probands, pathogenic mutations were identified. Six probands carried pathogenic mutations in BRCA1, and one proband carried pathogenic mutations in BRCA2. In patients, a variant of uncertain significance was found in BRCA2, RAD50, MRE11A and CDH1. The Manchester scoring system showed a high accuracy (87.5%), high sensitivity (85.7%) and high specificity (88.9%) for the prediction of pathogenic non-founder BRCA1/2 mutations.ConclusionA relatively high incidence of pathogenic non-founder BRCA1/2 mutations was observed in a founder population. The Manchester scoring system predicted the probability of non-founder pathogenic mutations with high accuracy.

A Large Case-Control Study Performed in Spanish Population Suggests That RECQL5 Is the Only RECQ Helicase Involved in Breast Cancer Susceptibility

“…Biallelic mutations in all of them, except for RECQL5, are related to chromosome instability and cancerpredisposition syndromes, including the recently described RECON syndrome [16,24,25,28]. Several studies have pointed out these helicases, especially RECQL1 and RECQL5, as new BC susceptibility genes; however, whether any of them have a role is still under debate [3,15,22,31,41,42]. In an attempt to clear the doubts about the involvement of the RECQ helicases in this disease, we sequenced the whole coding sequence of the five genes in 1993 BRCAX Spanish patients and compared the results with approximately 50,000 control individuals from gnomAD.…”

“…BLM was also proposed in 2012 as a putative BC susceptibility gene in the Russian population, where the pathogenic variant c.1642C>T; p.Gln548Ter was repeatedly found in BC cases [17], a finding that was supported by another study of in Slavic populations one year later [18]. The role of BLM in various steps of the homologous recombination pathway [19] had positioned it as a perfect candidate BC susceptibility gene; however, as with RECQL1, there are no conclusive results about its role in the disease, since subsequent studies have not supported the initial findings [13,14,[20][21][22][23]. In this regard, it is worth noting a recent study in which more than 14,000 patients and almost 5000 controls were analyzed, with no evidences of association of the founder mutation in BLM with BC susceptibility [23].…”

BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer

“…The aim of this work was to analyze the presence of somatic variants in TP53 , BRCA1 , and BRCA2 in EOC by massive parallel sequencing, estimating the proportion of these variants in tumor samples and their association with progression‐free survival (PFS) and overall survival (OS). Previous studies carried out in the Brazilian population have focused in describing germline variants in BRCA1/2 and TP53 in EOC patients 13,35–41 . The present study was carried out in a cohort of Brazilian patients, using an integrated analysis of germline and somatic (tumoral) variants.…”

“…Previous studies carried out in the Brazilian population have focused in describing germline variants in BRCA1/2 and TP53 in EOC patients. 13,[35][36][37][38][39][40][41] The present study was carried out in a cohort of Brazilian patients, using an integrated analysis of germline and somatic (tumoral) variants. Our data contribute to a better characterization of these tumors, in view of the ongoing development of therapies targeting tumors with functional deficiency in HR genes.…”

Inherited variants in XRCC2 and the risk of breast cancer

“…They also described ten breast-cancer families with protein-truncating or probably deleterious rare missense variants in XRCC2 among 689 multiple-case families [11]. Based on this, the XRCC2 gene has been included in several clinical cancer genetic test panels [3, 14, 15].…”