This study proposes to use the large registries of colorectal cancer
(CRC) families accumulated by the John Hopkins University (JHU) and
University of Utah research groups to systematically evaluate the
phenotypic and genetic heterogeneity of hereditary non-polyposis colon
cancer (HNPCC), familial adenomatous polyposis (FAP), and multiplex
colorectal cancer kindreds. These studies are crucial to our
understanding of gene-environment interactions in colon cancer etiology.
Our aims are outlined below. Using our combined CRC (hereditary and
sporadic) registry resources we propose to:
1. Evaluate the rate of occurrence of the newly-described replication
error (RER) molecular phenotype in CRCs of 200 incident sporadic CRC
patients seen at JHU, 50 patients (JHU and Utah) from unrelated families
which fulfill diagnostic criteria of HNPCC, and 50 patients (JHU and
Utah) from unrelated multiplex CRC kindreds which do not meet the
criteria for HNPCC.
2. Test for differences between RER phenotype and clinical/epidemiologic
data on the patients tested in Specific Aim 1. These data include age
at diagnosis, cancer site, multiplicity of cancers in the patient, family
history of CRC, and p53, DCC, and RAS gene changes in the CRCs.
3. Determine concordance of RER phenotype in CRCs of relatives from
multiplex families and 20 CRC kindreds). This analysis will stratify
the families based on evidence of linkage or non-linkage to chromosome
Using the John Hopkins FAP registry resource, we propose to:
4. Characterize mutations in the FAP-causing gene (APC) in 250 unrelated
FAP patients, and test for differences between mutations in different APC
domains and clinical/epidemiologic data (age at onset, presence of
extracolonic tumors, number of polyps, etc.).
5. Compare clinical/epidemiologic characteristics of affected
individuals in FAP families that are and are not linked to the APC gene.
6. Test for the effect of dietary factors on the age of onset of colonic
polyps in a cohort of 100 at-risk individuals known by genetic testing
to have inherited mutant APC genes.
To achieve these aims, concurrently submitted proposals will perform
linkage studies (M. Skolnick, PI) and P53 and RAS gene studies (S.
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