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Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population
Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, L5 03, SE-17176 Stockholm, Sweden..
Sahlgrens Univ Hosp, Dept Clin Pathol & Genet, SE-41345 Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Clin Genet, SE-40530 Gothenburg, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
Umea Univ, Div Oncol, Dept Radiat Sci, SE-90187 Umea, Sweden..
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2016 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 36, no 5, 2823-2835 p.Article in journal (Refereed) Published
Abstract [en]

Lynch syndrome caused by constitutional mismatch-repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2. After 20 years of genetic counseling and genetic testing for Lynch syndrome, we have compiled the mutation spectrum in Sweden with the aim to provide a population-based perspective on the contribution from the different MMR genes, the various types of mutations and the influence from founder mutations. Mutation data were collected on a national basis from all laboratories involved in genetic testing. Mutation analyses were performed using mainly Sanger sequencing and multiplex ligation-dependent probe amplification. A total of 201 unique disease-predisposing MMR gene mutations were identified in 369 Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6. Large deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder mutation that accounted for 15% of the families with mutations in MLH1. In conclusion, the Swedish Lynch syndrome mutation spectrum is diverse with private MMR gene mutations in two-thirds of the families, has a significant contribution from internationally recognized mutations and a limited effect from founder mutations.

Place, publisher, year, edition, pages
2016. Vol. 36, no 5, 2823-2835 p.
Keyword [en]
HNPCC, MLH1, MSH2, MSH6, EPCAM, hereditary colorectal cancer, Lynch syndrome
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-308633DOI: 10.3892/or.2016.5060ISI: 000385992700047PubMedID: 27601186OAI: oai:DiVA.org:uu-308633DiVA: diva2:1050837
Funder
Swedish Cancer Society
Available from: 2016-11-30 Created: 2016-11-29 Last updated: 2016-11-30Bibliographically approved

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