This proposal seeks to identify cancer specific gene mutations that are linked with important clinical and epidemiological characteristics of colon cancer (CC). 'Driver'gene mutations are directly related to clinical behavior in virtually all cancers. However, mutations that drive CC progression, from the eady curable disease to late stage incurable disease, are yet to be identified. Recent studies by our group and our collaborators have identified 140 candidate cancer genes (CAN genes) in CC. We also found that virtually all the CAN gene mutations found in metastatic CCs are also found in the antecedent primary cancer. This surprising result gives us an opportunity to explore CAN gene mutations in multiple clinical settings. To enable these studies, we have constructed a large biorepository containing CCs from patients treated at a large medical center over the last 20 years. The majority of these specimens are formalin-fixed paraffin embedded [FFPE]. We have developed sophisticated approaches to enhance the utility of DNA extracted from FFPE materials. These include reliable extraction of large DNA fragments. We also developed the technologies and processes to 'DNA capture'targeted exonal fragments and identify mutations from FFPE material using a 'next generation'sequencer. We have developed an infrastructure and knowledge base to support high throughput tissue processing and sequencing. We propose to use these methods to identify CAN gene mutations which appear only in late stage CCs. Also we will functionally dissect the role of these genes using cell line and xenograft mouse models. As CC is one of the cancers with significant disparities attributed to race and gender associated etiologic factors, we will compare CC CAN gene mutations between African American and white patients and between females and male patients, of similar cancer stage and outcome. The former studies will be facilitated by our use of an Ancestry Informative Marker- SNP classification of patients which will be incorporated directly into the DNA sequencing analyses. Our proposals have the potential to significantly advance the understanding of the biological basis for cancer metastasis and to gain insights into racial/gender based differences in etiology and outcomes among CC patients.

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Case Western Reserve University
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Chak, Amitabh; Buttar, Navtej S; Foster, Nathan R et al. (2015) Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's esophagus. Clin Gastroenterol Hepatol 13:665-72.e1-4
Sanchis-Gomar, Fabian; Lucia, Alejandro; Yvert, Thomas et al. (2015) Physical inactivity and low fitness deserve more attention to alter cancer risk and prognosis. Cancer Prev Res (Phila) 8:105-10
Luo, Yanxin; Wong, Chao-Jen; Kaz, Andrew M et al. (2014) Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer. Gastroenterology 147:418-29.e8
Fink, Stephen P; Yamauchi, Mai; Nishihara, Reiko et al. (2014) Aspirin and the risk of colorectal cancer in relation to the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD). Sci Transl Med 6:233re2
Koon, Henry B; Krown, Susan E; Lee, Jeannette Y et al. (2014) Phase II trial of imatinib in AIDS-associated Kaposi's sarcoma: AIDS Malignancy Consortium Protocol 042. J Clin Oncol 32:402-8
Corradin, Olivia; Saiakhova, Alina; Akhtar-Zaidi, Batool et al. (2014) Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits. Genome Res 24:1-13
Hao, Yujun; Zhao, Shuliang; Wang, Zhenghe (2014) Targeting the protein-protein interaction between IRS1 and mutant p110* for cancer therapy. Toxicol Pathol 42:140-7
Cummings 3rd, Kenneth C; Patel, Meatal; Htoo, Phyo Than et al. (2014) A comparison of the effects of epidural analgesia versus traditional pain management on outcomes after gastric cancer resection: a population-based study. Reg Anesth Pain Med 39:200-7
Alashkar, Bronia; Faulx, Ashley L; Hepner, Ashley et al. (2014) Development of a program to train physician extenders to perform transnasal esophagoscopy and screen for Barrett's esophagus. Clin Gastroenterol Hepatol 12:785-92
Scott, Anthony; Song, Jing; Ewing, Rob et al. (2014) Regulation of protein stability of DNA methyltransferase 1 by post-translational modifications. Acta Biochim Biophys Sin (Shanghai) 46:199-203

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