The goal of this proposal is to identify and characterize susceptibility
loci for common colorectal cancer. In order to accomplish this task we
will: 1) ascertain and collect DNA samples from large colorectal cancer
kindreds, 2) test each kindred for linkage to candidate regions for
colorectal cancer susceptibility loci, 3) perform a genomic search for
colorectal cancer susceptibility loci, 4) create a fine structure map
around the susceptibility loci identified, and 5) characterize the
abnormal phenotype in carriers of the inherited susceptibility. The
unique characteristics of the Utah population for genetic analysis will
be an essential asset. We currently have the most informative set of
breast cancer kindreds (in terms of LOD score) in the genetic
epidemiology community. We also have the most informative set of
melanoma susceptibility kindreds, which identified the 9p melanoma
susceptibility locus (Cannon-Albright et al., 1992). We will ascertain
large Utah kindreds likely to carry colorectal cancer susceptibility
loci, and study those kindreds which are not linked to the chromosome 2
or chromosome 5 loci previously identified. These Utah kindreds will be
pooled with unmapped kindreds available from our Johns Hopkins University
(JHU) collaborators. All kindreds will be analyzed for linkage first
with candidate loci and known genes (APC, chromosome 2 HNPCC, p53, DCC
and ras). Then, in a genomic linkage search, they will be screened with
a series of short tandem repeat markers (STRs). When a new colorectal
cancer susceptibility locus is identified, we will identify key
recombinants in these large kindreds and use them to create fine
structure map around the susceptibility locus. New STR markers will be
developed to aid in this effort. Haplotypes will be constructed around
a susceptibility locus to identify gene carriers. We will characterize
the phenotypic effect of each identified colorectal cancer susceptibility
locus. This proposal is one of three submitted by an interdisciplinary
collaborative group of investigators committed to understanding the
etiology of colorectal cancer through genetic epidemiologic approaches.
Our proposals are best described by the unifying theme, "Beyond
identification of colon cancer genes." The other two proposals will
examine the genetic epidemiology of the hereditary colorectal cancers (G.
Petersen, P.I.). and diet and genetic alterations in colorectal neoplasia
(S. Hamilton, P.I.). Genetic epidemiology provides a framework to study
these questions in families and populations, and to develop new
methodologies for analyzing these data.
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