TY - JOUR
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
N1 - Funding Information:
We are indebted to Trausti Valdimarsson for his assistance with this study. This study was funded by the Ohio State University (OSU) Comprehensive Cancer Center P30 CA16058 grant (shared resource), the OSU R01-67941 grant, the OSU Colorectal Cancer Research fund, the Obrine-Weaver Fund, the Pelotonia Fellowship Award and deCODE genetics.
Publisher Copyright:
© The Author(s) 2017.
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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U2 - 10.1038/ncomms14755
DO - 10.1038/ncomms14755
M3 - Article
C2 - 28466842
AN - SCOPUS:85035134936
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
M1 - 14755
ER -