WholeGenome Sequencing of High-Risk Families to Identify New Mutational Mechanisms of Breast Cancer Predisposition.

摘要

As genes for inherited disease are increasingly well characterized by next generation sequencing approaches, it is clear that some mutations may act through promoters, enhancers, and other non-coding regulatory regions. Our hypothesis for this proposal is that much of the substantial remaining familial risk of breast cancer is due to a large number of individually rare alleles of moderate-to-severe effect located in the non-coding regions of the genome. For this proposal we will evaluate 30 large, extended kindreds severely affected with breast cancer, each of whom has been comprehensively evaluated in our lab by targeted genomic sequencing for mutations of all classes in all known breast cancer genes and by whole exome sequencing for coding region mutations exome-wide. These families are a unique discovery series for identification of regulatory mutations that may reveal new mutational mechanisms for breast cancer predisposition.