Susceptibility to hereditary nonpolyposis colon cancer (HNPCC) is associated with germline mutations in five genes with DNA mismatch repair function. Previous studies have shown that these genes account for two-thirds of HNPCC kindreds meeting the international diagnostic criteria for the disorder and displaying microsatellite instability as a characteristic abnormality in tumors. The basis for cancer susceptibility is unknown in the remaining one-third of kindreds with microsatellite instability and in most families without this abnormality. Furthermore, in kindreds with detectable mutations and even with shared predispositions, the clinical phenotype varies a lot between and within individual families, the reasons for which are largely unknown. The broad objective of the present study is to identify genes and mechanisms associated with cancer susceptibility and phenotype determination in non-polypotic colon cancer. The detection of such genes is of prime importance given the fact that half the Western population is estimated to develop a colon tumor during their lifetime. Importantly, the progression of those lesions to cancer can be prevented by early intervention, and genetic markers of increased cancer risk are needed to define the cohorts who would be the first to benefit from such preventive measures.
The Specific Aim 1 focuses on kindreds with non-polyposis colon cancer in which mutations in the presently known HNPCC-associated DNA mismatch repair genes have been ruled out by sequencing. A genome-wide search is applied with the goal to identify novel genes associated with cancer predisposition in these kindreds.
The Specific Aim 2 focuses on a unique series of families with shared predisposing mutations. The observation of clinical variation in the setting shared predisposition suggests the existence of additional phenotype determinants.
The aim i s to identify genes that might modify the clinical phenotype of HNPCC, taking advantage of association and linkage-based approaches in these genetically homogeneous subsets of HNPCC patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082282-02
Application #
6173601
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Seminara, Daniela
Project Start
1999-08-17
Project End
2002-07-31
Budget Start
2000-09-15
Budget End
2001-07-31
Support Year
2
Fiscal Year
2000
Total Cost
$238,218
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
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