Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

Kristina Lagerstedt-Robinson; Anna Rohlin; Christos Aravidis; Beatrice Melin; Margareta Nordling; Marie Stenmark-Askmalm; Annika Lindblom; Mef Nilbert

doi:10.3892/or.2016.5060

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

Kristina Lagerstedt-Robinson^*, Anna Rohlin, Christos Aravidis, Beatrice Melin, Margareta Nordling, Marie Stenmark-Askmalm, Annika Lindblom, Mef Nilbert

^*Corresponding author for this work

19 Citations (Scopus)

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.

Original language	English
Journal	Oncology Reports
Volume	36
Issue number	5
Pages (from-to)	2823-2835
Number of pages	13
ISSN	1021-335X
DOIs	https://doi.org/10.3892/or.2016.5060
Publication status	Published - 1 Nov 2016
Externally published	Yes

Keywords

EPCAM
Hereditary colorectal cancer
HNPCC
Lynch syndrome
MLH1
MSH2
MSH6

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3892/or.2016.5060

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title = "Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population",

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.",

keywords = "EPCAM, Hereditary colorectal cancer, HNPCC, Lynch syndrome, MLH1, MSH2, MSH6",

author = "Kristina Lagerstedt-Robinson and Anna Rohlin and Christos Aravidis and Beatrice Melin and Margareta Nordling and Marie Stenmark-Askmalm and Annika Lindblom and Mef Nilbert",

year = "2016",

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doi = "10.3892/or.2016.5060",

language = "English",

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pages = "2823--2835",

journal = "Oncology Reports",

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T1 - Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

AU - Lagerstedt-Robinson, Kristina

AU - Rohlin, Anna

AU - Aravidis, Christos

AU - Melin, Beatrice

AU - Nordling, Margareta

AU - Stenmark-Askmalm, Marie

AU - Lindblom, Annika

AU - Nilbert, Mef

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

KW - EPCAM

KW - Hereditary colorectal cancer

KW - HNPCC

KW - Lynch syndrome

KW - MLH1

KW - MSH2

KW - MSH6

U2 - 10.3892/or.2016.5060

DO - 10.3892/or.2016.5060

M3 - Journal article

C2 - 27601186

AN - SCOPUS:84989967242

SN - 1021-335X

VL - 36

SP - 2823

EP - 2835

JO - Oncology Reports

JF - Oncology Reports

IS - 5

ER -

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

Abstract

Keywords

UN SDGs

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