Constitutional Genetic Analysis in Familial Cancer Cases to Identify markers for Cancer Predisposition

Abstract

Cancer is a multi-step and multi-etiology, complex disorder with germline and somatic genetic alterations playing a role in interaction with the external environment. Genetic alterations that affect the structure, function and number of corresponding proteins in multiple genes along with the shared role of environment and lifestyle may lead to cancer. Cancer occurrences when run in the families more often than would be expected by chance then it is termed as Familial Cancer. Global incidence of familial cancer is 15 to 25% of the total cancer cases. A study done in South India on HBOC reported a strong history of familial breast and ovarian cancer, with alterations in BRCA1, BRCA2 and CHEK2 (Dr. Thangarajan). A recent study reported the occurrence of Breast cancer in the presence of MRE11 without any alterations in BRCA1 and BRCA2. Similarly, our study on familial cancer in Gujarat aims to identify the rare and novel germline genetic alterations which may improve cancer risk assessment, diagnosis and prognosis. Inclusion criteria consists of families with more than two cases of cancers. The information was obtained by collecting family medical history and pedigree charts were made to identify disease inheritance patterns within a family. Blood samples of family members (affected and non-affected) were collected with their consent. DNA Isolation and NGS-WES analysis was carried out for members showing strong family history. Data Mining and BioInfoanalysis of the obtained is done using open sources like ATLAS, 1000 genome project, Clingen, ClinVar etc. It will provide information in identifying individuals with higher disease risk of cancer in a given family. The classification of constitutional variants is done as per the ACMG guidelines. Our project aims to put on record the rare and novel possibly pathogenic variants which can be included in existing gene panels to improve clinical management