Cancer Risk in Hereditary Nonpolyposis Colorectal Cancer Syndrome: Later Age of Onset

Background & Aims: Mutations in the mismatch repair genes cause hereditary nonpolyposis colorectal cancer (HNPCC) syndrome and convey high lifetime cancer risks for colorectal (CRC) and endometrial cancer. Currently, cancer risks for individuals with HNPCC are based on data from clinically ascertained families. The purpose of this study was to re-examine the penetrance in HNPCC using a comprehensive dataset from a geographically defined region. Methods: A combined dataset of 70 HNPCC families ascertained by traditional high-risk criteria and by molecular screening comprising 88 probands and 373 mutation-positive family members was used. Statistical methods were modified survival analysis techniques. Results: In mutation-positive relatives (excluding probands), the median age at diagnosis of CRC was 61.2 years (confidence interval [CI], 56.3–68.0 y). The lifetime risk for CRC was 68.7% (CI, 58.6%–78.9%) for men and 52.2% (CI, 37.6%–66.9%) for women. Considering only probands, the median age at diagnosis of CRC was 44.0 years (CI, 41.0–46.3 y). Median age of onset of EC was 62.0 years (CI, 55.9 y to an upper limit too high to calculate) with a lifetime cancer risk of 54% (CI, 41.9%–66.1%). Conclusions: A markedly later age of onset for CRC at 61 y than previously reported (∼44 y) is suggested, resulting mainly from a more rigorous method of analysis in which all gene-positive individuals (both affected and unaffected with cancer) are considered. Lifetime cancer risks may be lower for CRC and endometrial cancer than presently assumed. If confirmed, these data suggest a need to alter counseling practices, and to consider HNPCC in older individuals than before.

Abbreviations used in this paper:  CRC, colorectal cancer , HNPCC, hereditary nonpolyposis colorectal cancer , LTR, lifetime risk