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Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

Lagerstedt-Robinson, Kristina; Rohlin, Anna; Aravidis, Christos; Melin, Beatrice; Nordling, Margareta; Stenmark-Askmalm, Marie; Lindblom, Annika and Nilbert, Mef LU (2016) In Oncology Reports 36(5). p.2823-2835
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... (More)

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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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
EPCAM, Hereditary colorectal cancer, HNPCC, Lynch syndrome, MLH1, MSH2, MSH6
in
Oncology Reports
volume
36
issue
5
pages
13 pages
publisher
D.A. Spandidos
external identifiers
  • scopus:84989967242
  • wos:000385992700047
ISSN
1021-335X
DOI
10.3892/or.2016.5060
language
English
LU publication?
yes
id
674217d6-c5c2-4a0d-9210-c1b7df773da1
date added to LUP
2016-10-28 10:23:30
date last changed
2017-11-19 04:34:18
@article{674217d6-c5c2-4a0d-9210-c1b7df773da1,
  abstract     = {<p>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.</p>},
  author       = {Lagerstedt-Robinson, Kristina and Rohlin, Anna and Aravidis, Christos and Melin, Beatrice and Nordling, Margareta and Stenmark-Askmalm, Marie and Lindblom, Annika and Nilbert, Mef},
  issn         = {1021-335X},
  keyword      = {EPCAM,Hereditary colorectal cancer,HNPCC,Lynch syndrome,MLH1,MSH2,MSH6},
  language     = {eng},
  month        = {11},
  number       = {5},
  pages        = {2823--2835},
  publisher    = {D.A. Spandidos},
  series       = {Oncology Reports},
  title        = {Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population},
  url          = {http://dx.doi.org/10.3892/or.2016.5060},
  volume       = {36},
  year         = {2016},
}