Mueller-Koch Y et al. (2005) Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut 54: 1733–1740

Early studies describing the cancer now known as hereditary nonpolyposis colorectal cancer suggested that this cancer type is genetically transmitted and could be molecularly defined. Further work showed, however, that a subgroup of patients who met the AMSTERDAM CRITERIA had neither the instability in their MICROSATELLITE SEQUENCES nor the germline mutations in particular DNA-repair genes to lead to that suggestion. To better define this subgroup, Mueller-Koch and co-workers compared the clinical features of patients whose tumors did or did not have DNA-repair gene mutations and high levels of microsatellite instability.

Of the 41 families studied, 25 (106 patients) had truncating mutations in DNA-repair genes ('positive'), and 16 (71 patients) had no mutations in these genes and no identified instability, but fulfilled the Amsterdam criteria ('negative'). The median age of cancer onset was earlier in positive families for both all tumors and colorectal tumors. The positive group had a higher incidence of extracolorectal tumors and a greater proportion of colorectal tumors that were near the splenic flexure. Adenomas were less common than carcinomas in the positive group, suggesting that progression to malignant tumors is faster in these patients.

These findings have implications for surveillance programs generally and for the frequency of monitoring. Cancer research should focus on defining the germline mutations that are associated with the development of this cancer type in the negative subset of patients.