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

• Published in: Nature Communications
• Main Authors: Haraldsdottir, Sigurdis, Rafnar, Thorunn, Frankel, Wendy L., Einarsdóttir, Sylvía, Sigurðsson, Ásgeir, Hampel, Heather, Snaebjornsson, Petur, Másson, Gísli, Weng, Daniel, Arngrimsson, Reynir, Kehr, Birte, Yilmaz, Ahmet, Haraldsson, Stefan, sulem, patrick, Stefansson, Tryggvi, Shields, Peter G., Sigurðsson, Fridbjörn, Bekaii-Saab, Tanios, Moller, Pall H., Steinarsdóttir, Margrét, Alexíusdóttir, Kristín, Hitchins, Megan, Pritchard, Colin C., de la Chapelle, Albert, Jónasson, Jón Gunnlaugur, Goldberg, Richard M., Stefansson, Kari
• Other Authors: Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland
• Format: Article in Journal/Newspaper
• Language: English
• Published: Springer Nature 2017
• Subjects: Cancer epidemiology; Cancer genetics; Cancer genomics; Krabbamein; Krabbameinsrannsóknir; Arfgengi; Erfðagreining; Lynch; Weaver; Iceland
• Online Access: https://hdl.handle.net/20.500.11815/374; https://doi.org/10.1038/ncomms14755

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. 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. Peer Reviewed