When a cancer patient presents with strong family history of cancer, it is recommended that the patient goes through a clinical panel sequencing to see if he or she has mutations in known list of genes that can greatly increase the risk of cancer. Mutations in BRCA1/2 are well known examples that can confer high risk of breast or ovarian cancer and identifying these mutations in cancer predisposition genes are important for prevention and treatment of cancer. While more than 150 cancer predisposition genes have been identified, some patients with family history of cancer often do not harbor any mutations in the predisposition genes, and we lack a systematic approach other than the clinical panel sequencing to assess the patients. To address this, we performed whole genome sequencing on multiple familial cancer families to gain information not only on the list of known predisposition genes, but also on whole genetic material of the patients. Leveraging this dataset of larger scope, we are going to investigate the missing genetic explanation behind the strong aggregation of cancer in families. We will first use a comprehensive computational approach to identify germline variants in both coding or non-coding regions of cancer related genes, which follow the monogenic mode of inheritance. In addition, we will calculate polygenic risk score of cancer to evaluate if common risk alleles with moderate to small effects can collectively confer great cancer risk observed in the familial cancer cases. We plan to finish the study within 24 to 30 months after we receive the genomic data. We hope that a successful study will expand our knowledge of inherited genetic architecture for cancer susceptibility in familial cancer aggregation with which we can provide the patients and families with better prevention and treatment plans.
