Colorectal cancer (CRC) is estimated to affect over 1 million people and to cause over 528 000 deaths worldwide each year (Globocan, 2002). In the USA, the cumulative lifetime risks of CRC and death from CRC are approximately 5–6% and 2.5%, respectively.¹ Most colon cancers occur in individuals over the age of 50 years and are believed to develop as a consequence of environmental carcinogen exposure and genetic factors.^2,3 However, approximately 3–5% of all colon cancers occur as a direct consequence of highly penetrant germline mutations which cause hereditary colon cancer syndromes, such as familial adenomatous polyposis (FAP), hereditary non-polyposis colon cancer (HNPCC), juvenile polyposis syndrome, and Peutz-Jeghers syndrome.^4–6

HNPCC is the most common hereditary CRC syndrome and the subject of a study by Mueller-Koch and colleagues⁷ in this issue of Gut that characterises the cancer risks of families that meet the clinical definition for HNPCC but who do not have any of the molecular features that have come to define this syndrome (see page 1733). The study by Mueller-Koch and colleagues⁷ is remarkable because it demonstrates the progress that has been made in our understanding of the molecular basis of familial CRC syndromes. In fact, since the discovery of APC germline mutations as the major cause of FAP and of MLH1 and MSH2 germline mutations as the cause of most cases of HNPCC, it has become increasingly recognised that the clinical presentation of these families with hereditary …