Novel mutations in actionable breastcancer genes by targeted sequencing in anethnically homogenous cohort

Abstract

Background:Genetic testing is becoming an essential tool for breast cancer (BC) diagnosis and treatment pathway,and particularly important for early detection and cancer prevention. The purpose of this study was to explore the diagnostic yield of targeted sequencing of the high priority BC genes.

Methods:We have utilized a cost-effective targeted sequencing approach of high priority actionable BC genes(BRCA1,BRCA2,ERBB2 and TP53)in a homogeneous patient cohort from Bangladesh (n= 52) by using tumor and blood samples.

Results:Blood derived targeted sequencing revealed 25.58% (11/43) clinically relevant mutations (both pathogenic and variants of uncertain significance (VUS)), with 13.95% (6/43) of samples carrying a pathogenic mutations. We have identified and validated five novel pathogenic germline mutations in this cohort, comprising of two frameshift deletions inBRCA2,and missense mutations inBRCA1,BRCA2andERBB2gene respectively. Furthermore, we have identified three pathogenic mutations and a VUS within three tumor samples, including a sample carrying pathogenic mutations impacting bothTP53(c.322dupG; a novel frameshift insertion) andBRCA1genes (c.116G > A). 22% of tissue samples had a clinically relevantTP53mutation. Although the cohort is small, we have found pathogenic mutations to be enriched inBRCA2(9.30%, 4/43) compare toBRCA1(4.65%, 2/43). The frequency of germline VUS mutations found to be similar in bothBRCA1(4.65%; 2/43) andBRCA2(4.65%; 2/43) compared toERBB2(2.32%; 1/43).

Conclusions:This is the first genetic study of BC predisposition genes in this population, implies that genetic screening through targeted sequencing can detect clinically significant and actionable BC-relevant mutations.