<p> Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death in the United States. Twin cohort studies indicate that inherited susceptibility accounts for approximately 35% of all CRC cases, but only 5-6% of CRC cases can be attributed to known functional mutations. We were the first to identify a germline mutation in Transforming Growth Factor Beta Receptor 1 (<i>TGFBR1</i>) that is also somatically acquired in tumors, a 9 bp in frame deletion within exon 1 (rs11466445), which results in a receptor with decreased TGF-β signaling properties. The observed association between this hypomorphic variant and cancer risk led us to hypothesize that constitutively decreased TGF-β signaling may contribute to the development of CRC. </p><p> In this dissertation, we developed a novel mouse model of <i>Tgfbr1 </i> haploinsufficiency (<i>Tgfbr1</i><sup>+/−</sup>) and found that <i>Tgfbr1</i><sup>+/−</sup> mice were twice as likely as <i>Tgfbr1</i><sup>+/+</sup> mice to develop CRC. We subsequently identified two human haplotypes associated with constitutively decreased <i>TGFBR1</i> expression and CRC risk and found that decreased <i> TGFBR1</i> expression is strongly associated with three SNPs: rs7034462, rs11466445 and rs11568785. Further examination of <i>TGFBR1</i> haplotype tagging SNPs suggests that the <i>TGFBR1</i> rs7034462-TT is a novel moderate penetrance risk genotype, which has high penetrance among African Americans, the ethnic group with the highest risk for CRC. Our results provide strong support for the novel notion that rs7034462-TT is a potentially clinically relevant CRC susceptibility genotype that may identify individuals at high risk of dying from CRC.</p>
| Identifer | oai:union.ndltd.org:PROQUEST/oai:pqdtoai.proquest.com:3741319 |
| Date | 23 December 2015 |
| Creators | Pennison, Michael James |
| Publisher | Northwestern University |
| Source Sets | ProQuest.com |
| Language | English |
| Detected Language | English |
| Type | thesis |
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