A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: Meeting Highlights and Bethesda Guidelines

Extract

Hereditary nonpolyposis colorectal cancer (HNPCC) is a distinct autosomal dominant syndrome accounting for approximately 5%–6% of the total colorectal cancer burden with clinical and pathologic features caused by defective mismatch repair genes ( 1 ). Germline mutations in hMSH2, hMLH1, hPMS1, hPMS2, and MSH6/GTBP have been identified in affected individuals ( 2 , 3 ). HNPCC is characterized by early-onset colorectal cancer (median age at diagnosis 45 years); right-sided predominance; excess synchronous and metachronous colorectal neoplasms; and an increased incidence of extracolonic neoplasms, including endometrial, small-bowel, gastric, renal pelvis and ureter, and ovarian tumors and skin lesions, such as sebaceous adenomas, carcinomas, and keratoacanthomas ( 4–10 ).

In 1991, the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer ( 11 ) established minimal clinical criteria for recruiting HNPCC patients for collaborative studies. These criteria, also known as the Amsterdam Criteria, include the following: 1) at least three relatives with histologically verified colorectal cancer, one of them a first-degree relative of the other two (familial adenomatous polyposis excluded); 2) at least two successive generations affected; and 3) in one of the individuals, diagnosis of colorectal cancer before the age of 50. These criteria were pivotal in identifying kindreds that eventually led to the association of the HNPCC syndrome with germline mismatch repair gene mutations (MMR). However, the criteria do not account for extracolonic cancers or for small kindreds.