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Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

Journal article
Authors K. Lagerstedt-Robinson
Anna Rohlin
C. Aravidis
B. Melin
Margareta Nordling
M. Stenmark-Askmalm
A. Lindblom
M. E. F. Nilbert
Published in Oncology Reports
Volume 36
Issue 5
Pages 2823-2835
ISSN 1021-335X
Publication year 2016
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Pages 2823-2835
Language en
Links dx.doi.org/10.3892/or.2016.5060
Keywords HNPCC, MLH1, MSH2, MSH6, EPCAM, hereditary colorectal cancer, Lynch syndrome, NONPOLYPOSIS COLORECTAL-CANCER, ASHKENAZI JEWISH POPULATION, AMERICAN, FOUNDER MUTATION, HEREDITARY COLON-CANCER, MSH6 MUTATIONS, PMS2, MUTATIONS, MLH1, REARRANGEMENTS, DELETIONS, RISK
Subject categories Molecular medicine (genetics and pathology), Cancer and Oncology

Abstract

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.

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