Context Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch
syndrome, is caused by mutations in the mismatch repair genes and confers
an extraordinarily high risk of colorectal, endometrial, and other cancers.
However, while carriers of these mutations should be identified, counseled,
and offered clinical surveillance, at present the mutations are not tested
for in mutation analyses.
Objective To describe the prevalence of a large genomic deletion encompassing
exons 1 to 6 of the MSH2 gene that is widespread
in the US population as a result of a founder effect.
Design, Setting, and Patients Ongoing genealogical and historical study conducted to assess the origin
and spread of an MSH2 mutation previously identified
in 9 apparently unrelated families with putative HNPCC and living in widely
different geographic locations in the United States.
Main Outcome Measures Classification of family members as carriers or noncarriers of the MSH2 mutation; spread of the mutation across the continental
Results To date, 566 family members of the 9 probands have been identified to
be at risk and counseled; 137 of these have been tested, and 61 carry the
founder mutation. Three families have been genealogically shown to descend
from a German immigrant family that arrived and first settled in Pennsylvania
in the early 1700s. Movements of branches of the family from Pennsylvania
through North Carolina, Alabama, Kentucky, Missouri, Iowa, Nebraska, Utah,
Texas, and California have been documented, and carriers of the mutation have
already been diagnosed in 14 states. In contrast, the deletion was not found
among 407 European and Australian families with HNPCC.
Conclusion The postulated high frequency and continent-wide geographic distribution
of a cancer-predisposing founder mutation of the MSH2 gene
in a large, outbred (as opposed to genetically isolated) population, and the
ease with which the mutation can be detected, suggest that the routine testing
of individuals at risk for HNPCC in the United States should include an assay
for this mutation until more is learned about its occurrence.