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Germ Line Mutations of Mismatch Repair Genes in Hereditary Nonpolyposis Colorectal Cancer Patients with Small Bowel Cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study

Authors' Affiliations: ¹ Korean Hereditary Tumor Registry, Laboratory of Cell Biology, Cancer Research Institute and Cancer Research Center, Seoul National University College of Medicine; ² Center for Colorectal Cancer and ³ Cancer Biostatistics Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea; ⁴ Familial Gastrointestinal Cancer Registry, Mt. Sinai Hospital, Ontario, Canada; ⁵ Medical Genetic Clinic, Copenhagen University, Copenhagen, Denmark; ⁶ Colorectal Medicine and Genetics and ⁷ Familial Cancer Centre, Royal Melbourne Hospital, Parkville, Australia; ⁸ Institute of Human Genetics, Newcastle University; ⁹ Northern Region Genetics Service, Centre for Life, Newcastle-upon-Tyne, United Kingdom; ¹⁰ University of California San Francisco Colorectal Cancer Prevention Program, University of California San Francisco, San Francisco, California; ¹¹ Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom; ¹² Cancer Genetics Clinic, Division of Oncology, Stanford University School of Medicine, Stanford, California; ¹³ Familial Cancer Program, University of Vermont College of Medicine, Burlington, Vermont; ¹⁴ Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland; ¹⁵ Research Group Human Genetics, Division of Medical Genetics, University of Basel, Basel, Switzerland; ¹⁶ Department of Surgery, St. Josefs-Hospital Bochum-Linden, Bochum-Linden, Germany; ¹⁷ Pelvic Surgery Department, Hospital do Cancer A.C. Camargo, Sao Paolo, Brazil; ¹⁸ Department of Gastroenterology, Tel Aviv Medical Center, Tel Aviv, Israel; ¹⁹ Western Australian Familial Cancer Registry, Genetic Services of Western Australia, Subiaco, Australia; ²⁰ Program of Hereditary Cancer, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; ²¹ Netherlands Foundation for the Detection of Hereditary Tumours; ²² Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands; and ²³ Oncologia Sperimentale 1, Centro Riferimento Oncologico, Aviano, Italy

Requests for reprints: Jae-Gahb Park, Korean Hereditary Tumor Registry, Laboratory of Cell Biology, Cancer Research Institute and Cancer Research Center, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, Korea. Phone: 82-2-2072-3380; Fax: 82-2-742-4727; E-mail: jgpark{at}plaza.snu.ac.kr.

Purpose: The aim of study was to determine the clinical characteristics and mutational profiles of the mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients with small bowel cancer (SBC).

Experimental Design: A questionnaire was mailed to 55 members of the International Society for Gastrointestinal Hereditary Tumours, requesting information regarding patients with HNPCC-associated SBC and germ line mismatch repair gene mutations.

Results: The study population consisted of 85 HNPCC patients with identified mismatch repair gene mutations and SBCs. SBC was the first HNPCC-associated malignancy in 14 of 41 (34.1%) patients for whom a personal history of HNPCC-associated cancers was available. The study population harbored 69 different germ line mismatch repair gene mutations, including 31 mutations in MLH1, 34 in MSH2, 3 in MSH6, and 1 in PMS2. We compared the distribution of the mismatch repair mutations in our study population with that in a control group, including all pathogenic mismatch repair mutations of the International Society for Gastrointestinal Hereditary Tumours database (excluding those in our study population). In patients with MSH2 mutations, patients with HNPCC-associated SBCs had fewer mutations in the MutL homologue interaction domain (2.9% versus 19.9%, P = 0.019) but an increased frequency of mutations in codons 626 to 733, a domain that has not previously been associated with a known function, versus the control group (26.5% versus 2.8%, P < 0.001).

Conclusions: In HNPCC patients, SBC can be the first and only cancer and may develop as soon as the early teens. The distribution of MSH2 mutations found in patients with HNPCC-associated SBCs significantly differed from that found in the control group (P < 0.001).

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