FAMILIAL AND EARLY ONSET COLORECTAL CANCER ABSTRACT Colorectal cancer (CRC) is a common and potentially lethal disease that usually occurs in older people, and is a sporadic process principally related to dietary and other environmental influences. However, about 4% of CRC can be attributed to specific genetic syndromes such as Lynch Syndrome, familial adenomatous polyposis, and a few other rare diseases. Another 20-30% of patients with CRC have a first degree relative with CRC, but it is not known how much of this familiality is due to shared genes rather than shared environmental factors. In any event, we have few methods of identifying these high-risk people. CRC is particularly suited to preventive strategies because of the availability of multiple effective screening modalities, but we cannot screen everyone frequently, and these resources would be more effective if they were used more intensively in those people at greatest risk for the disease, and more sparingly in those individuals at ordinary or lower risk. Also, about 5-10% of CRC occurs in people who are relatively young, <50 years old, and even ambitious screening recommendations are inadequate for these individuals. The goals of this project are to study individuals who are at increased risk for CRC on a familial basis, or for non-familial early-onset CRC, so that they might be offered appropriately intensive screening to mitigate their risk of dying of cancer. The focus of the application will be on alterations of the DNA mismatch repair (MMR) genes. We have used collaborations to accumulate a large number of routine and unique CRC specimens to look for a number of previously unexplored possibilities. Methylation-induced silencing of the MLH1 gene occurs because of a CpG island in its promoter, and accounts for about 12% of CRCs. We have developed a unique model to study the regulation of methylation of the MLH1 gene in vitro and in vivo. We will test the hypothesis that a unique demethylating agent discovered in our laboratory can reverse this process in vitro and in vivo. We will also look for evidence of methylation-induced silencing of the MSH2 and MSH6 genes, which also have CpG islands in their promoters, and should be susceptible to the same perturbation. We will look for mechanisms responsible for early-onset CRC in patients who do not appear to have a family history of this by testing a new panel of microsatellite markers for microsatellite instability (MSI), by looking for the promoter methylator phenotype in these tumors, and by using novel methods to look for low-level MSI. Finally, we will test the hypothesis that low-level MSI is caused by the down-regulation of the MSH3 gene, and that this process facilitates the generation of highly metastatic clones within a growing tumor mass. The broad aim of this application is to develop additional tools that increase our ability to more precisely categorize CRCs, to develop more accurate interpretations of the mutational signatures in CRCs, which will permit us to deliver more highly personalized treatment to CRC patients, particularly those who are young or have positive family histories of this disease.
FAMILIAL AND EARLY-ONSET COLORECTAL CANCER PROJECT NARRATIVE Colorectal cancer is a common disease, and many cases occur due to familial factors, only some of which are currently understood. This project is aimed toward finding the genetic or epigenetic basis of familial clusters of colorectal cancer, and the genetic or epigenetic factors that affect people who develop this disease before age 50, which is the age at which routine screening begins. We also plan to test a strategy to correct epigenetic abnormalities that might be involved in the risk for early-onset cancer.
|Yoshida, Kazuhiro; Toden, Shusuke; Ravindranathan, Preethi et al. (2017) Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression. Carcinogenesis 38:1036-1046|
|Pichler, Martin; Stiegelbauer, Verena; Vychytilova-Faltejskova, Petra et al. (2017) Genome-Wide miRNA Analysis Identifies miR-188-3p as a Novel Prognostic Marker and Molecular Factor Involved in Colorectal Carcinogenesis. Clin Cancer Res 23:1323-1333|
|Ozawa, T; Matsuyama, T; Toiyama, Y et al. (2017) CCAT1 and CCAT2 long noncoding RNAs, located within the 8q.24.21 'gene desert', serve as important prognostic biomarkers in colorectal cancer. Ann Oncol 28:1882-1888|
|Toden, Shusuke; Theiss, Arianne L; Wang, Xuan et al. (2017) Essential turmeric oils enhance anti-inflammatory efficacy of curcumin in dextran sulfate sodium-induced colitis. Sci Rep 7:814|
|Shigeyasu, Kunitoshi; Toden, Shusuke; Zumwalt, Timothy J et al. (2017) Emerging Role of MicroRNAs as Liquid Biopsy Biomarkers in Gastrointestinal Cancers. Clin Cancer Res 23:2391-2399|
|Toiyama, Yuji; Okugawa, Yoshinaga; Tanaka, Koji et al. (2017) A Panel of Methylated MicroRNA Biomarkers for Identifying High-Risk Patients With Ulcerative Colitis-Associated Colorectal Cancer. Gastroenterology 153:1634-1646.e8|
|Okugawa, Yoshinaga; Toiyama, Yuji; Toden, Shusuke et al. (2017) Clinical significance of SNORA42 as an oncogene and a prognostic biomarker in colorectal cancer. Gut 66:107-117|
|Ozawa, Tsuyoshi; Kandimalla, Raju; Gao, Feng et al. (2017) A microRNA Signature Associated With Metastasis of T1 Colorectal Tumors to Lymph Nodes. Gastroenterology :|
|Shigeyasu, Kunitoshi; Okugawa, Yoshinaga; Toden, Shusuke et al. (2017) Exportin-5 Functions as an Oncogene and a Potential Therapeutic Target in Colorectal Cancer. Clin Cancer Res 23:1312-1322|
|Hur, Keun; Toiyama, Yuji; Okugawa, Yoshinaga et al. (2017) Circulating microRNA-203 predicts prognosis and metastasis in human colorectal cancer. Gut 66:654-665|
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