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Genome-wide Approaches for Discovery of Novel Genetic and Epigenetic Events in Gastrointestinal Cancer

Fecteau, Ryan E
http://rave.ohiolink.edu/etdc/view?acc_num=case1436549464

Abstract Details

2015, Doctor of Philosophy, Case Western Reserve University, Pathology.
Cancer is a disease caused by the sequential acquisition of genetic and epigenetic changes that transform a normal cell into an ungovernable malignancy. Advances in technologies to interrogate these changes on a genome-wide scale have reshaped our understanding of this disease and rapidly expanded the field of cancer genomics. The objective of the projects described herein was to adapt high-throughput methods to discover and characterize novel genetic and epigenetic events in gastrointestinal cancers with the intention of translational application. Three primary studies comprise the body of this thesis. In the first, we identify recurrent mutations in the oncogene GNAS found by sequencing of the colorectal cancer genome. Targeted pyrosequencing of GNAS in a colon cancer tumor cohort established a mutation frequency in colorectal cancer of around 2%. By comparing GNAS mutation status with clinical and pathologic data, we found that GNAS mutations associate with a distinct class of colon cancers that are characterized by concomitant KRAS or BRAF mutations, by location in the proximal colon, and by a unique association with a villous morphology. The second study applied a targeted next generation sequencing approach, whole exome sequencing, to identify a germ-line susceptibility variant in a familial syndrome of Barrett’s esophagus and esophageal adenocarcinoma. Sequencing revealed a private variant in the uncharacterized gene VSIG10L that segregated with disease in a large familial Barrett’s esophagus family and functional studies suggested the discovered variant disrupted maturation of the normal esophageal epithelium. Lastly, we describe using reduced representation bisulfite sequencing to examine the colon cancer methylome for candidate methylated biomarker loci. Preliminary data from this work has identified 3 candidate methylated DNA biomarkers for potential use in detection of colorectal cancer in patient plasma. Cumulatively, these studies have identified a rare mutation in colon cancer associated with a unique molecular phenotype, a private germ-line variant predisposing to familial Barrett’s esophagus and adenocarcinoma, and candidate methylated biomarkers for detection and monitoring of colon cancer, all of which are of potential clinical importance.
Sanford Markowitz, MD, PhD (Advisor)
136 p.
Genetics; Oncology; Pathology
Gastrointestinal cancer; translational; next generation sequencing; colon cancer; Barretts esophagus; esophageal adenocarcinoma

Recommended Citations

Citations

  • Fecteau, R. E. (2015). Genome-wide Approaches for Discovery of Novel Genetic and Epigenetic Events in Gastrointestinal Cancer [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1436549464

    APA Style (7th edition)

  • Fecteau, Ryan. Genome-wide Approaches for Discovery of Novel Genetic and Epigenetic Events in Gastrointestinal Cancer. 2015. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1436549464.

    MLA Style (8th edition)

  • Fecteau, Ryan. "Genome-wide Approaches for Discovery of Novel Genetic and Epigenetic Events in Gastrointestinal Cancer." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1436549464

    Chicago Manual of Style (17th edition)

case1436549464
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© 2015, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.