DESCRIPTION: (Adapted from investigator's abstract) 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 is 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.
Error Notice
The database may currently be offline for maintenance and should be operational soon. If not, we have been notified of this error and will be reviewing it shortly.
We apologize for the inconvenience.
- The DCCPS Team.
