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Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Diagnostics
Affiliations of authors: Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden (KLR, TL, JV, AL); Department of Oncology–Pathology, Karolinska Institute, Stockholm, Sweden (TL); Department of Pathology, Lund University Hospital, Lund, Sweden (BH); Department of Pathology, Helsingborg Hospital, Helsingborg, Sweden (BH); Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (MC); Department of Genetics, Rouen University Hospital, Rouen, France (TF); Howard Hughes Medical Institute and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD (NP, KWK, BV); Department of Medical Genetics, University of Helsinki, Helsinki, Finland (PP); Ludwig Institute for Cancer Research, University of California, San Diego, School of Medicine, La Jolla, CA (RDK); Department of Oncology, Lund University, Lund, Sweden (MN)
Correspondence to: Annika Lindblom, MD, PhD, Department of Clinical Genetics, Karolinska University Hospital, S-17176 Stockholm, Sweden (e-mail: annika.lindblom{at}ki.se).
Background: Preventive programs for individuals who have high lifetime risks of colorectal cancer may reduce disease morbidity and mortality. Thus, it is important to identify the factors that are associated with hereditary colorectal cancer and to monitor the effects of tailored surveillance. In particular, patients with Lynch syndrome, hereditary nonpolyposis colorectal cancer (HNPCC), have an increased risk to develop colorectal cancer at an early age. The syndrome is explained by germline mutations in DNA mismatch repair (MMR) genes, and there is a need for diagnostic tools to preselect patients for genetic testing to diagnose those with HNPCC.
Methods: Patients (n = 112) from 285 families who were counseled between 1990 and 2005 at a clinic for patients at high risk for HNPCC were selected for screening to detect mutations in MMR genes MLH1, MSH2, MSH6, and PMS2 based on family history, microsatellite instability (MSI), and immunohistochemical analysis of MMR protein expression. Tumors were also screened for BRAF V600E mutations; patients with the mutation were considered as non-HNPCC.
Results: Among the 112 patients who were selected for screening, 69 had germline MMR mutations (58 pathogenic and 11 of unknown biologic relevance). Sixteen of the 69 mutations (23%) were missense mutations. Among patients with MSI-positive tumors, pathogenic MMR mutations were found in 38 of 43 (88%) of patients in families who met Amsterdam criteria and in 13 of 22 (59%) of patients in families who did not. Among patients with MSI-negative tumors, pathogenic MMR mutations were found in 5 of 17 (29%) of families meeting Amsterdam criteria and in 1 of 30 (3%) of non-Amsterdam families with one patient younger than age 50 years. In three patients with MSI-negative tumors who had pathogenic mutations in MLH1 or MSH6, immunohistochemistry showed loss of the mutated protein.
Conclusion: Our findings suggest that missense MMR gene mutations are common in HNPCC and that germline MMR mutations are also found in patients with MSI-negative tumors.
| CONTEXT AND CAVEATS Prior knowledge Lynch syndrome, or HNPCC, is currently diagnosed by the detection of germline mutations in MMR genes. Study design A new protocol to select patients for screening for germline mutations in MMR genes was tested on family members who had undergone counseling for being at high risk for HNPCC. Contribution Overall, mutations in MMR genes were found in more than half of the patients who were screened for mutations, including some who would not have been screened using current protocols. Implications More true HNPCC cases were identified using the new protocol than the previous protocol. Study limitations It is possible that some patients who were not selected for mutation screening also had tumors with germline mutations in MMR genes.
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Manuscript received August 14, 2006; revised October 18, 2006; accepted December 28, 2006.
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J Natl Cancer Inst 2007 99: 261-263.
J Natl Cancer Inst 2007 99: 257.
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