Genomic Characterization of Polyps In Familial Adenomatous Polyposis Patients and Identification of Candidate Chemopreventive Drugs

<p><em>Familial adenomatous polyposis</em> (FAP) is an autosomal dominant disease characterized by <em>APC</em> germline mutations and the development of hundreds to thousands of premalignant adenomas in the gastrointestinal tract at a young age. If left untreated, these patients inevitably develop <em>colon cancer</em> (CRC) and small bowel tumors. We performed exome sequencing of samples from 12 FAP patients to characterize adenomas and to identify candidate genes of adenoma development that may serve as potential targets for chemoprevention drug development. From each patient, a blood and at least one polyp were sequenced with a total of 25 polyps analyzed. In some cases, normal mucosa samples were also sequenced. We characterized point mutations, insertions, deletions and chromosomal allelic imbalance. In addition, we performed RNA sequencing of 8 polyps and 4 normal mucosa samples from the colon and small bowel of 2 additional FAP patients.</p> <p>Somatic <em>APC</em> truncating mutations and loss of chromosome 5q were recurrent across polyps, although we found no recurrent intra-patient somatic <em>APC</em> point mutations, indicating intra-patient polyp heterogeneity. Oncogenic driver events such as activating <em>KRAS</em> mutations were identified in multiple polyps. Further, analysis of mutation allele fractions suggests that several of the polyps studied are multi-clonal in nature. Excluding the known genes <em>APC</em> and <em>KRAS,</em> 50 candidate genes were identified that are putatively involved in the early development of CRC. These genes could play a role in future chemoprevention strategies. Most of these genes have been previously associated with CRC. In addition, a gene fusion in <em>PTEN</em> was detected and a novel, recurrent <em>REG3A</em> fusion was identified in duodenum polyps. The WNT signaling pathway, aberrant in 92% of CRCs, was recurrently altered in 80% of polyps.</p> <p>We identified colon and duodenum gene expression signatures of FAP patients and screened them against drug-induced signatures using our <em>Cancer in-silico Drug Discovery</em> (CiDD) software. CiDD identified Celecoxib, a COX-2 inhibitor that has already been clinically tested as a chemopreventive drug, providing validity to our drug development approach. CiDD also identified a novel candidate compound, TTNPB, which targets the Retinoid pathway as a potential drug for chemopreventive treatment of FAP patients.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2014

Author dc:creator

• San Lucas, Francis A

Contributors dc:contributor

• Paul Scheet, Ph.D.
• Eduardo Vilar, M.D., Ph.D.
• James Hixson, Ph.D.

• hereditary colon cancer
• cancer genomics
• drug discovery
• bioinformatics
• TCGA
• Computational Biology
• Genomics
• Integrative Biology
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/501

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1539