Review ArticleDiagnosis and Management of Hereditary Non-Polyposis Colon Cancer
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History
The first description of a family with HNPCC was published almost 100 years ago. In 1895, Aldred Warthin's seamstress predicted she would die at an early age from cancer of her colon or female organs because “most of my family members die of these cancers,” an observation that led Warthin to publish a description of this family with a hereditary predisposition to GI and gynecologic cancer (Fig. 1A).11, 12, 13 However, the true significance of the extensive history of cancer of the colon, the
Causative Genes
As mentioned above, it is now appreciated that most cases of HNPCC result from the inactivation of the DNA MMR process caused by germline gene defects in the genes that encode key components of the MMR DNA repair complexes. The DNA mismatch repair system (also known as the mutation mismatch repair system) consists of a complex of proteins that recognize and repair base pair mismatches that occur during DNA replication. At least 8 genes, including 7 that encode proteins involved in the MMR
Clinical Features of HNPCC
The central clinical features that should suggest the diagnosis of HNPCC are the familial clustering of HNPCC-associated tumors (i.e., colorectal, gastric, endometrial, small bowel, renal, and ureteral cancers) and a young age at onset of these tumors. Hereditary non-polyposis colon cancer is inherited in an autosomal dominant fashion and is 80% penetrant. Thus, the lifetime risk for colon cancer is 80% by age 70 years.34, 45 The mean age of diagnosis of colon cancer in an HNPCC individual is
Clinical Diagnosis
The clinical diagnostic criteria that define HNPCC have evolved gradually since the first formal criteria, the Amsterdam criteria, were published in 1990.77 Clinical criteria for defining HNPCC are necessary because two other CFSs, attenuated FAP and common familial colon cancer, can be difficult to distinguish from HNPCC (Table 1).78 In 1990, the International Collaborative Group, composed of 30 experts from 8 different countries, outlined the minimal set of clinical features that define HNPCC
Overview
Genetic tests, or assays that can detect mutations in the genes responsible for most cases of HNPCC, are currently available for routine clinical use, which has created new opportunities, as well as challenges, for the practicing gastroenterologist. Challenges include not only identifying individuals who should be considered for genetic testing but also providing genetic counseling, identifying the type of genetic test to perform and the laboratory that will perform the test, and correctly
Genetic Testing and Its Affects on Surveillance Recommendations
The substantially increased lifetime risk of colon, small bowel, gastric, and genitourinary tract cancer has led to the use of cancer surveillance regimens in HNPCC family members (Table 4). There is some evidence to suggest that the type of germline mutation present in a family may predict the absolute risk for cancer in the family, as well as the spectrum of tumor types to which these family members are predisposed. Vasen et al.107 found that carriers of MSH2 mutations are at higher risk of
Conclusions
The management of HNPCC family members is both challenging and gratifying. Currently, the field of clinical cancer genetics and molecular genetics is in a state of rapid evolution, and HNPCC is one of the syndromes at the forefront of our understanding of CFSs arising from germline mutations in DNA caretaker genes. As could be predicted, the translation of the molecular genetics of HNPCC into the clinical management has been outpaced by our understanding of the molecular biology of the genes
Disclosure
This work was supported by the Damon-Runyon/Lilly Clinical Investigator Award, the Vanderbilt Physician-Scientist Development Award, the VA Advanced Research Career Development Award, the Mallinckrodt Scholar Award, and KO8 CA77676 to W.M.G.
Acknowledgments
The investigators thank Dr. Kay Washington for providing the photomicrograph of the HNPCC colon cancer and for her helpful comments on the histopathology of HNPCC tumors. The investigators also wish to apologize to the investigators of many important studies that were not cited in this review because of space limitations. Our understanding of the genetics of colon cancer has progressed rapidly as a result of the many talented investigators actively engaged in research in this area, and it is
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