Double Heterozygosity of BRCA2 and STK11 in Familial Breast Cancer Detected by Exome Sequencing

Abstract

Background: Germ-line mutations of BRCA1 and BRCA2 genes are responsible for approximately 25-30% of dominantly inherited familial breast cancers; still a big part of genetic component is unknown. The aim of this study was to investigate genetic causes of familial breast cancer in a pedigree with recessive pattern of inheritance.

Methods: We applied exome sequencing as a useful approach in heterogeneous diseases gene identification in present study for familial breast cancer. Sanger sequencing was applied for validation and segregation analysis of mutations.

Results: Here, we describe a family with three affected sisters of early-onset invasive ductal carcinoma due to heterozygous frame shift mutation rs80359352 in BRCA2 gene as the first report in Iranian patients in association with a novel missense SNP of STK11 (p.S422G). These mutations are inherited from their normal father.

Conclusion: Despite apparent recessive pattern of inheritance a dominant gene (here BRCA2) can be involved in pathogenesis of hereditary breast cancer which can be explained by incomplete penetrance of BRCA2 mutations.

Keywords: BRCA2, Familial breast cancer, rs80359352, STK11, Iran