Background: The hereditary nonpolyposis colorectal carcinoma (HNPCC) syndrome is an autosomal dominant genetic disorder caused by the inheritance of a mutation in one of a family of genes encoding DNA mismatch repair (MMR) proteins. HNPCC manifests as genetic instability in linked tumors. Clinically, the syndrome is characterized by early onset malignancies, primarily of the colon and endometrium, with an increased incidence of tumors at other gastrointestinal sites, upper urologic tract, ovary, and pancreas as well. However, the inclusion of breast cancer as an integral tumor of this syndrome is controversial.
Methods: Mutation screening of MMR genes was carried out by single strand conformation polymorphism (SSCP) and sequencing analyses of genomic DNA prepared from normal lymphocytes. Expression analysis was performed by SSCP. Sequence analyses of cDNA was prepared from breast tumor tissue and normal lymphocytes. Genetic instability was assessed by comparing the electrophoretic mobility of polymerase chain reaction (PCR) products using multiple microsatellite markers.
Results: A 4-bp frameshift mutation in the hMLH1 gene was found to segregate with disease in the germlines of the affected members of a large kindred HNPCC. Expression of only the mutant allele was observed in the breast cancer tissue of one family member, however both alleles were observed in her normal tissue. This breast cancer exhibited widespread microsatellite instability, as did breast cancers obtained from several other HNPCC kindreds.
Conclusions: These data indicate that breast cancer may result from the inheritance of a mutant MMR gene, and that breast cancer may occur as an integral tumor in the HNPCC syndrome.