Role of clinical criteria in the diagnosis of HNPCC: results of a multivariate analysis

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by early-onset colorectal tumors, primarily in the right colon, that are frequently associated with other cancers. In the absence of a reliable biomarker, clinical criteria for diagnosing HNPCC have been proposed by the international collaborative group on HNPCC (ICG-HNPCC). However, these criteria are often too restrictive for application in small families. We analyzed 6 clinical/pathological features suggestive of genetic colon-cancer risk in 970 colorectal-cancer patients defined according to the ICG criteria as HNPCC (96) or non-HNPCC (874). Logistic regression analysis was used to determine their relative potentials for predicting the diagnosis of HNPCC. The most predictive were then used to estimate HNPCC risk levels within the non-HNPCC group. Multivariate analysis showed the following associations with HNPCC diagnosis: vertically transmitted cancer (´´highly predictive´´), early-onset (<50 years) colorectal cancer, aggregation of tumors in the nuclear pedigree and proximal-colon tumors (the last 3 considered ´´predictive´´). Re-evaluation of all families revealed that 76 non-HNPCC families (8.9% of the whole series) satisfied our highly predictive vertical-transmission criterion plus at least one of the other ´´predictive´´ criteria. The presence of 2 consecutive generations affected by colorectal cancer or early primaries seems to be a major risk indicator of hereditary colorectal cancer. Using this approach we identified a large group of families that require further evaluation, although they do not currently meet the ICG-HNPCC criteria for HNPCC.