<i>MSH6</i> Mutations in Hereditary Nonpolyposis Colon Cancer: Another Slice of the Pie
Authors: Kenneth Offit
Journal: Journal of Clinical Oncology (2004)

The identification of individuals at hereditary risk for cancer is now an established aspect of the practice of clinical oncology. Documentation of a family history of cancer offers a critical opportunity for the prevention or early detection of hereditary malignancies. One such preventive strategy is endoscopic and extracolonic surveillance in kindreds with hereditary nonpolyposis colon cancer (HNPCC) (Table 1). In HNPCC, also known as Lynch syndrome, cancers of the colon and other sites (endometrium, ovary, stomach, genitourinary tract, and skin) occur and appear at an early age (average age, 45 years). Approximately 3% to 5% of all patients with colon cancer can be diagnosed as HNPCC by the clinician who is aware of this syndrome. Just as oncologists have finally memorized the “3 to 2-1” Amsterdam rule for the diagnosis of HNPCC (three cases of colon cancer in two successive generations with at least one diagnosed before age 50 years), revisions to testing guidelines throughout the years have sought to broaden clinical criteria to capture a greater number of families carrying the genetic hallmarks of HNPCC. The latest revision, published earlier this year, is presented in Table 2. Central to the diagnosis of HNPCC is the identification of mutations in one of a class of genes whose products are involved in the fundamental biologic process of DNA mismatch repair (MMR). Defects of one of these MMR genes (MSH2, MLH1, and MSH6) underlie most cases of HNPCC. As detailed in the article by Plaschke et al in this issue of the Journal of Clinical Oncology, the “slice” of the “HNPCC pie” associated with MSH6 mutations in families with colon cancer is somewhat larger than previously believed. Moreover, these authors show that MSH6 mutations require the same stringent level of surveillance as for any other HNPCC kindred. In the recently released American Society of Clinical Oncology curriculum on cancer genetics, we depict MMR gene mutations in HNPCC as a pie chart, with the MSH6 fraction shown as a very small slice. The 15% frequency of MSH6 mutations among all mutations of MMR genes in the report by Plaschke et al is the highest yet reported. Can we assume that this frequency of MSH6 mutations observed in a German consortium will be relevant to other geographical settings? While a 12% frequency of MSH6 mutations (among all MMR mutations noted) was initially reported by the Dutch consortium, we recently observed a 7% frequency in a single center in North America. However, as emphasized in a recent review, data on MSH6 mutations in families remain relatively sparse; therefore, MSH6 sequence analysis should be performed in HNPCC families when other MMR genes are not mutated. The report by Plaschke et al also reinforces the limitations of the classical criteria for HNPCC. Almost two-thirds of families carrying MSH6 mutations in this report would have been missed by the “Amsterdam” criteria. Recent reports have confirmed a high risk of cancer (60% lifetime risk) and altered tumor spectrum in MSH6 mutation carriers. In seven families with MSH6 mutations, the proband was identified solely on the basis of endometrial cancers demonstrating a high pattern of microsatellite instability (MSI)—the hallmark of mutations in MMR genes. In four of the seven families in that report, the tumor spectrum and age of diagnosis fell outside even the broadest definitions of the revised Bethesda criteria.