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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA072851-17
Application #
8249110
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Thurin, Magdalena
Project Start
1996-05-10
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
17
Fiscal Year
2012
Total Cost
$332,512
Indirect Cost
$119,363
Name
Baylor Research Institute
Department
Type
DUNS #
145745022
City
Dallas
State
TX
Country
United States
Zip Code
75204
Yamada, Atsushi; Minamiguchi, Sachiko; Sakai, Yoshiharu et al. (2014) Colorectal advanced neoplasms occur through dual carcinogenesis pathways in individuals with coexisting serrated polyps. PLoS One 9:e98059
Okugawa, Yoshinaga; Toiyama, Yuji; Goel, Ajay (2014) An update on microRNAs as colorectal cancer biomarkers: where are we and what's next? Expert Rev Mol Diagn 14:999-1021
Hur, Keun; Cejas, Paloma; Feliu, Jaime et al. (2014) Hypomethylation of long interspersed nuclear element-1 (LINE-1) leads to activation of proto-oncogenes in human colorectal cancer metastasis. Gut 63:635-46
Perez-Carbonell, Lucia; Balaguer, Francesc; Toiyama, Yuji et al. (2014) IGFBP3 methylation is a novel diagnostic and predictive biomarker in colorectal cancer. PLoS One 9:e104285
Rhees, Jennifer; Arnold, Mildred; Boland, C Richard (2014) Inversion of exons 1-7 of the MSH2 gene is a frequent cause of unexplained Lynch syndrome in one local population. Fam Cancer 13:219-25
Toiyama, Yuji; Okugawa, Yoshinaga; Goel, Ajay (2014) DNA methylation and microRNA biomarkers for noninvasive detection of gastric and colorectal cancer. Biochem Biophys Res Commun 455:43-57
Toiyama, Yuji; Hur, Keun; Tanaka, Koji et al. (2014) Serum miR-200c is a novel prognostic and metastasis-predictive biomarker in patients with colorectal cancer. Ann Surg 259:735-43
Toiyama, Yuji; Takahashi, Masanobu; Hur, Keun et al. (2013) Serum miR-21 as a diagnostic and prognostic biomarker in colorectal cancer. J Natl Cancer Inst 105:849-59
Boland, C Richard; Lynch, Henry T (2013) The history of Lynch syndrome. Fam Cancer 12:145-57
Komarova, Natalia L; Boland, C Richard (2013) Cancer: calculated treatment. Nature 499:291-2

Showing the most recent 10 out of 98 publications