The overall goal of the proposed study is to identify new genes harboring rare mutations that
considerably increase the risk of colorectal cancer (CRC). These mutations can underlie the
observed familial aggregation of Lynch syndrome-like colorectal cancer cases called Familial
Colorectal Cancer Type X (FCCTX). FCCTX is a Mendelian cancer syndrome with dominant
mode of inheritance and incomplete penetrance. The first aim of the mentored-phase of this
application is to identify novel candidate genes associated with risk of colorectal cancer in
FCCTX patients using selective capture of protein-coding sequences in the human genome
("exome") followed by massively parallel resequencing of 10 patients with FCCTX. This
approach has recently been successful in identifying novel genes causing Mendelian diseases.
The identified candidate variants will be genotyped in the family members of the individuals with
sequenced exomes for segregation analysis. During independent (R00) phase, the candidate
genes will be resequenced in a large number of colorectal cancer cases and controls to find the
spectrum of mutations in sporadic colorectal cancer and their presence in general population. In
addition, the candidate genes will be resequenced in a large cohort of FCCTX families to find
other individuals carrying mutations in these genes. The new genes and potentially pathways
involved into development of colorectal cancer can become potential targets for colorectal
cancer therapy. The proposed study represents also a proof of concept for the new strategy of
exome resequencing for detecting of cancer predisposing genes. The low-cost, high throughput
technologies for exome resequencing may facilitate the discovery of new candidate genes and
mutations in familial cancer.
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