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

Abstract

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. On November 11 and 12, 1996, the Early Detection Branch of the National Cancer Institute convened an international workshop in Bethesda, MD, entitled “The Intersection of Pathology and Genetics in the Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome.” The purpose of the workshop was to clarify the role of genetics in the pathology of HNPCC. Discussions centered on genomic instability, multistep carcinogenesis and the role of mismatch repair genes in HNPCC, histopathology of HNPCCs and possible relationships to molecular genetic changes, markers of cell proliferation and their relationship to HNPCC as well as their potential use in early diagnosis and prognosis, and, lastly, clinicopathologic criteria that could lead to the identification of additional HNPCC patients. The keynote speaker was Dr. Alfred Knudson (Fox Chase Cancer Center, Philadelphia), who discussed the tumor spectrum of the HNPCC syndrome. Issues that arose during the workshop are discussed below. Genomic instability is a fundamental property of tumor cells. One form of genomic instability results from the malfunction of the DNA mismatch repair system. This instability results in the accumulation of mutations, particularly at simple repetitive sequences called microsatellites, and leads to a phenotype that has been termed the replication error (RER) phenotype or microsatellite instability (MIN). What is the relationship between MIN and colorectal cancer as it applies to HNPCC? Dr. Manuel Perucho (The Burnhan Institute, La Jolla, CA) discussed the following two pathways for colorectal carcinogenesis: 1) the suppressor pathway, where mutational inactivation of two alleles of tumor suppressor genes is required; and 2) the mutator phenotype pathway, or the microsatellite mutator pathway, which involves the mutational inactivation of two alleles of the same gene that is not a suppressor gene but is a mutator gene, (e.g., a member of the mismatch repair gene family). These two pathways are different, i.e., they result from mutations in different cancer genes. For example, in colon cancer, p53 and K-ras are mutated in the suppressor pathway, whereas TGF-β receptor and BAX genes are mutated in the mutator pathway. The former pathway leads to a tumor that is generally aneuploid and does not have MIN, whereas the latter pathway results in a tumor that is diploid and has MIN. The cell containing the inactivated tumor suppressor gene has a territorial and growth advantage over the neighboring cells, whereas the cell that contains inactivated mutator alleles does not have any territorial advantage. These mutator genes increase the mutation rate and, therefore, increase the probability of mutations occurring from mutations in the suppressor genes or other cancer genes (e.g., TGF-β-RII or BAX) that have a negative role in cell growth and survival, as well as from mutator genes themselves (e.g., MSH3 and MSH6). Tumors of the microsatellite mutator pathway accumulate hundreds of thousands of somatic mutations (insertions and deletions of one nucleotide or a few nucleotides) in simple repeated sequences or microsatellites. The workshop participants also discussed how to differentiate “true” MIN from clonality. The former underlies the mutator pathway, whereas the latter underlies the suppressor pathway. The distinction between MIN and clonality is even more interesting, be