Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

Sigurdis Haraldsdottir; Thorunn Rafnar; Wendy L. Frankel; Sylvia Einarsdottir; Asgeir Sigurdsson; Heather Hampel; Petur Snaebjornsson; Gisli Masson; Daniel Weng; Reynir Arngrimsson; Birte Kehr; Ahmet Yilmaz; Stefan Haraldsson; Patrick Sulem; Tryggvi Stefansson; Peter G. Shields; Fridbjorn Sigurdsson; Tanios Bekaii-Saab; Pall H. Moller; Margret Steinarsdottir; Kristin Alexiusdottir; Megan Hitchins; Colin C. Pritchard; Albert De La Chapelle; Jon G. Jonasson; Richard M. Goldberg; Kari Stefansson

doi:10.1038/ncomms14755

Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

Sigurdis Haraldsdottir, Thorunn Rafnar, Wendy L. Frankel, Sylvia Einarsdottir, Asgeir Sigurdsson, Heather Hampel, Petur Snaebjornsson, Gisli Masson, Daniel Weng, Reynir Arngrimsson, Birte Kehr, Ahmet Yilmaz, Stefan Haraldsson, Patrick Sulem, Tryggvi Stefansson, Peter G. Shields, Fridbjorn Sigurdsson, Tanios Bekaii-Saab, Pall H. Moller, Margret SteinarsdottirKristin Alexiusdottir, Megan Hitchins, Colin C. Pritchard, Albert De La Chapelle, Jon G. Jonasson, Richard M. Goldberg, Kari Stefansson

Hematology/Oncology

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000-2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.

Original language	English (US)
Article number	14755
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14755
State	Published - 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Haraldsdottir, S., Rafnar, T., Frankel, W. L., Einarsdottir, S., Sigurdsson, A., Hampel, H., Snaebjornsson, P., Masson, G., Weng, D., Arngrimsson, R., Kehr, B., Yilmaz, A., Haraldsson, S., Sulem, P., Stefansson, T., Shields, P. G., Sigurdsson, F., Bekaii-Saab, T., Moller, P. H., ... Stefansson, K. (2017). Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. Nature communications, 8, Article 14755. https://doi.org/10.1038/ncomms14755

Haraldsdottir, S, Rafnar, T, Frankel, WL, Einarsdottir, S, Sigurdsson, A, Hampel, H, Snaebjornsson, P, Masson, G, Weng, D, Arngrimsson, R, Kehr, B, Yilmaz, A, Haraldsson, S, Sulem, P, Stefansson, T, Shields, PG, Sigurdsson, F, Bekaii-Saab, T, Moller, PH, Steinarsdottir, M, Alexiusdottir, K, Hitchins, M, Pritchard, CC, De La Chapelle, A, Jonasson, JG, Goldberg, RM & Stefansson, K 2017, 'Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2', Nature communications, vol. 8, 14755. https://doi.org/10.1038/ncomms14755

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title = "Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2",

abstract = "Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000-2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.",

author = "Sigurdis Haraldsdottir and Thorunn Rafnar and Frankel, {Wendy L.} and Sylvia Einarsdottir and Asgeir Sigurdsson and Heather Hampel and Petur Snaebjornsson and Gisli Masson and Daniel Weng and Reynir Arngrimsson and Birte Kehr and Ahmet Yilmaz and Stefan Haraldsson and Patrick Sulem and Tryggvi Stefansson and Shields, {Peter G.} and Fridbjorn Sigurdsson and Tanios Bekaii-Saab and Moller, {Pall H.} and Margret Steinarsdottir and Kristin Alexiusdottir and Megan Hitchins and Pritchard, {Colin C.} and {De La Chapelle}, Albert and Jonasson, {Jon G.} and Goldberg, {Richard M.} and Kari Stefansson",

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year = "2017",

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journal = "Nature communications",

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T1 - Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

AU - Haraldsdottir, Sigurdis

AU - Rafnar, Thorunn

AU - Frankel, Wendy L.

AU - Einarsdottir, Sylvia

AU - Sigurdsson, Asgeir

AU - Hampel, Heather

AU - Snaebjornsson, Petur

AU - Masson, Gisli

AU - Weng, Daniel

AU - Arngrimsson, Reynir

AU - Kehr, Birte

AU - Yilmaz, Ahmet

AU - Haraldsson, Stefan

AU - Sulem, Patrick

AU - Stefansson, Tryggvi

AU - Shields, Peter G.

AU - Sigurdsson, Fridbjorn

AU - Bekaii-Saab, Tanios

AU - Moller, Pall H.

AU - Steinarsdottir, Margret

AU - Alexiusdottir, Kristin

AU - Hitchins, Megan

AU - Pritchard, Colin C.

AU - De La Chapelle, Albert

AU - Jonasson, Jon G.

AU - Goldberg, Richard M.

AU - Stefansson, Kari

PY - 2017

Y1 - 2017

N2 - Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000-2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.

AB - Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000-2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.

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Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

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