Daniel C. Chung, MD; Anil K. Rustgi, MD
Acknowledgment: The authors thank Jonathan Terdiman for sharing his photographs of MSH2/MLH1 immunohistochemistry.
Grant Support: Elsevier Research Award/American Digestive Health Foundation, NIH R01 CA92594 (Dr. Chung) and National Colon Cancer Research Alliance/Entertainment Industry Foundation, Irving Hansen Foundation, NIH DK56645 (Dr. Rustgi).
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Daniel C. Chung, MD, Gastrointestinal Unit, GI Cancer Genetics Service, GRJ 825, Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02 114; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Chung: Gastrointestinal Unit, GI Cancer Genetics Service, GRJ 825, Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02114.
Dr. Rustgi: Division of Gastroenterology, Abramson Family Cancer Research Institute and Cancer Center, University of Pennsylvania Medical School, 415 Curie Boulevard, Philadelphia, PA 19104.
Basic studies of DNA replication and repair have provided surprising and pivotal insights into a novel pathway of tumorigenesis. Defects in the DNA mismatch repair process dramatically increase the risk for specific types of cancer because of instability in microsatellite DNA sequences. A germline mutation in either the hMSH2 or hMLH1 mismatch repair gene results in the hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch, syndrome. The lifetime risk for colon cancer is 80% in affected persons, and an aggressive cancer surveillance program is essential not only for these individuals but also for at-risk family members. The diagnosis of HNPCC can be made by fulfillment of the Amsterdam clinical criteria or through genetic testing for germline mutations in hMSH2 or hMLH1. Genetic testing is particularly useful in families with atypical clinical features and also for cancer risk assessment within an established HNPCC kindred. Microsatellite instability (MSI) of DNA is a hallmark feature of HNPCC-associated tumors, and as many as 15% of cases of sporadic colorectal cancer also display MSI. The biological behavior of colorectal tumors with MSI is distinctive; the most intriguing feature is their favorable natural history. The study of HNPCC has provided an example of the powerful interplay between molecular genetics and clinical care.
Chung DC, Rustgi AK. The Hereditary Nonpolyposis Colorectal Cancer Syndrome: Genetics and Clinical Implications. Ann Intern Med. 2003;138:560–570. doi: 10.7326/0003-4819-138-7-200304010-00012
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Published: Ann Intern Med. 2003;138(7):560-570.
Colorectal Cancer, Gastroenterology/Hepatology, Gastrointestinal Cancer, Hematology/Oncology.
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