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Colon cancer connections. Cancer syndrome meets molecular biology meets histopathology.

When E.M. Forster chose "Only connect..." as the epigraph for his novel Howard's End, he probably wasn't thinking about colon cancer. But if Forster had connections of a more philosophical nature in mind, he could also have been summarizing recent dramatic developments in colon cancer research, developments that connected disparate observations from diverse disciplines into a coherent model for a novel mechanism of carcinogenesis. In brief, hereditary nonpolyposis colorectal cancer (HNPCC), a colon cancer-prone syndrome long thought to be hereditary but dependent until now on family history and clinicopathological description for diagnosis, has been linked to sites on two different chromosomes, 2p and 3p.1 2 Most colon cancers arising in the HNPCC setting harbor many-fold more genetic mutations than other cancers; a subset of sporadic colon cancers have the same changes.3-5 Genes involved in repair of DNA replication errors (human mismatch repair genes) have been cloned and mapped to the regions of 2p and 3p that segregate with HNPCC.6 9 Mutations in the mismatch repair genes have been found in patients afflicted with HNPCC. In this issue of the American Journal of Pathology, Kim et all' take the research out of the basic science lab and into the realm of surgical pathology by providing a detailed clinicopathological description of sporadic colon cancers that carry the phenotypical marker of mutated mismatch repair genes, multiple replication errors. They confirm earlier intimations that such cancers are histologically similar to the colon cancers seen in HNPCC. Most of the excitement over mutated mismatch repair genes has focused, justifiably, on two areas: implications for carcinogenesis and prospects for a blood test that will identify carriers of the mutated genes, allowing early diagnosis of HNPCC and radically altering the management of affected patients. But the new information also provides a potentially powerful tool for surgical pathologists by implying that there is a genotype-specific pathology for a subset of colon cancers (and some extracolonic cancers as well). The prognostic implications of this genetic alteration will undoubtedly be the subject of many future studies. This commentary will review the features of HNPCC, summarize (for the moment anyway) the mismatch repair gene story, and discuss areas for future investigation.