||5R01CA085759-04 Interpret this number
||Dana-Farber Cancer Inst
||Inherited Msh6 Mutations in Diverse Colorectal Cancers
Germline mutations in mismatch repair genes are the most common
cause of hereditary colon cancer. Mutations in four mismatch repair genes
(MSH2, MLH1, PMS1 and PMS2) have been identified primarily in families with
hereditary nonpolyposis colorectal cancer (HNPCC) featuring high penetrance,
early age at diagnosis, and right colon predominance. These patients tend to
show replication errors (microsatellite instability (MSI) in DNA repeat
sequences of their neoplastic cells. Recently, inherited mutations in a fifth
mismatch repair gene, MSH6, have been identified in colorectal cancer patients.
Concurrently, our preliminary studies have found a total of 9 germline MSH6
mutations in 198 patients with colorectal cancer and diverse family histories.
Surprisingly, none of our MSH6 carriers have family histories that fulfill the
classic Amsterdam criteria for HNPCC; instead, they generally have only one
first- or second degree relative with cancer. In addition, the MSH6 carriers
have a median age of diagnosis of colorectal cancer of 62.5 years, similar to
that of sporadic cases. Family members are affected by a variety of other
cancers, including breast, endometrial and ovarian tumors. To pursue these
unexpected observations, we propose to analyze the MSH6 gene in 700 CRC cases
with family histories that do no fulfill classic criteria for HNPCC. Cases will
be stratified by age at diagnosis. Cases with germline MSH6 mutations and an
equal number of controls of colorectal cancer cases without MSH6 mutations will
be analyzed for MSI. Additionally, family members of MSH6 carriers will be
evaluated for the germline mutation, and their available tumor blocks will be
examined for MSI. Results will be analyzed to determine 1. the frequency and
clinical manifestations of germline MSH6 mutations in all 700 colorectal cancer
patients; 2. types and frequencies of MSI in the corresponding tumor tissues of
MSH6 carriers as compared with a matched series of non-carriers; and 3. MSH6
status of affected and unaffected relatives of MSH6 carriers, as well as MSI in
tumors of affected family members. Our preliminary data suggest that MSH6 may
be responsible for more colorectal cancer cases than MSH2, MLH1, PMS1 and PMS2
combined. Evidence that MSH6 is a moderately penetrant, later-onset hereditary
colorectal cancer gene would imply the existence of similar genes for other
common cancers that await discovery.
Comprehensive molecular analysis of mismatch repair gene defects in suspected Lynch syndrome (hereditary nonpolyposis colorectal cancer) cases.
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