Germline characterization of early-aged onset of hereditary non-polyposis colorectal cancer

Abstract

Objectives: Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by the early onset of colorectal cancer (~40 years). Adolescent colorectal cancer is unusual in HNPCC families. We speculated that some DNA mismatch repair germline mutations might be associated with early onset of disease. Study design: Genomic DNA was extracted from members of a kindred with virulent HNPCC fitting the Amsterdam Criteria for HNPCC and sequenced for 2 DNA mismatch repair genes, hMSH2 and hMLH1. A sigmoid adenocarcinoma from the 14-year-old proband was analyzed for highfrequency microsatellite instability and immunostained for DNA mismatch repair gene expression. Results: A germline mutation was identified at nucleotide 676 (codon 226) of the hMLH1 gene. The C to T transition created a nonsense mutation, truncating the hMLH1 protein. This mutation also alters the splice donor sequence, because nucleotide 676 is 2 base pairs from the 3′ end of the exon 8. The proband’s tumor demonstrated high-frequency microsatellite instability and displayed loss of hMLH1 expression, indicating bi-allelic inactivation of hMLH1. Conclusions: A complex mutation of hMLH1 at codon 226 is associated with adolescent onset of colorectal cancer in an HNPCC family. Genetic screening of other suspected HNPCC families with unusually young members with cancer might reveal certain genotypes with particularly virulent forms of this disease. (J Pediatr 2001;138:629-35)