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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

Lookup NU author(s): Professor Sir John BurnORCiD, Dr Fiona Douglas


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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). © 2006 American Association for Cancer Research.

Publication metadata

Author(s): Park J-G, Kim D-W, Hong CW, Nam B-H, Shin Y-K, Hong S-H, Kim I-J, Lim S-B, Aronson M, Bisgaard ML, Brown GJ, Burn J, Chow E, Conrad P, Douglas F, Dunlop M, Ford J, Greenblatt MS, Heikki J, Heinimann K, Lynch EL, Macrae F, McKinnon WC, Moeslein G, Rossi BM, Rozen P, Schofield L, Vaccaro C, Vasen H, Velthuizen M, Viel A, Wijnen J

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2006

Volume: 12

Issue: 11

Pages: 3389-3393

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association for Cancer Research


DOI: 10.1158/1078-0432.CCR-05-2452

PubMed id: 16740762


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Funder referenceFunder name
G0100496Medical Research Council
MC_U127527198Medical Research Council