Identification of predisposition genes associated with breast and thyroid carcinomas by exome sequencing

Abstract

It is estimated that 5 to 10% of human cancers are associated with hereditary cancer syndromes (HCS), while 15% of the cases belong to familial cancer aggregation. The etiology of solid tumors, including breast carcinoma (BC) and thyroid carcinoma (TC), is multifactorial, dependent on environmental and genetic factors that play a role in the etiology of the disease. However, a significant number of these tumors is associated with a hereditary component. Therefore, the identification and characterization of predisposing and genetic risk factors are essential for the diagnosis, prognosis and genetic counseling of affected patients and their families. In this context, the technology of Whole Exoma Sequencing (WES), involving hybridization-based capture of the protein coding sequences (exoma), has been used for searching specific variations mainly related with monogenic hereditary diseases. It is estimated that 85% of the mutations with large effects on disease-related traits occur on the protein coding sequences, distributed in exonic regions and/or in splicing sites. Clinical observation in Hospital AC Camargo indicates a familial cancer aggregation with patients presenting both primary tumors, BC and TC, and also with family members presenting one of these tumors. Thus, this study aims to identify predisposition genes associated with BC and TC by sequencing the whole exome of members of 30 families with a history of BC and TC selected by defined criteria. The selected probands were negative for mutations in genes related to major hereditary syndromes associated with these tumors (BRCA1, BRCA2, CHEK2 and TP53). The detection and identification of new genetic alterations will permit to expand the syndromes associated with these cancers and allow the identification of patients at risk of developing the disease, contributing to molecular diagnosis and genetic counseling in these families. (AU)