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, 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

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.

Conflict of interest statement

All authors from deCODE are employees of the biotechnology company deCODE genetics, a subsidiary of AMGEN. Ms Heather Hampel has received research support from Myriad Genetic Laboratories and is on the clinical advisory board for Invitae Genetics. The remaining authors declare no competing financial interests.

Figures

Figure 1. Novel MLH1 translocation.
Figure 1. Novel MLH1 translocation.
(a) The top half of the figure displays enlarged GRCh38 reference sequences from within MLH1 on chromosome 3 (blue) and from the reverse complement of chromosome 5 within ZCCHC10 (red) in a patient with CRC with MLH1/PMS2 absent on IHC. The bottom shows the translocation breakpoints observed in the sequencing data. The translocation connects an intron of MLH1 with an intron of ZCCHC10 in sense of the genes' orientations. At the breakpoint, a 3-bp duplication is present on both translocation haplotypes (dark blue), a 5-bp deletion is missing from both translocation haplotypes (dark red), and a 10-bp motif from nearby got inserted in reverse complemented orientation into one of the translocation haplotypes (yellow). (b) FISH, chromosome 3 (red CY3), chromosome 5 (green fitc). Chromosomes 3 and 5 are marked with white arrows. The scale shown is 5 μm. (c) Family tree with cancers and age at diagnosis. Proband is indicated with an arrow.
Figure 2. Study design.
Figure 2. Study design.
CRC, colorectal cancer; IHC, immunohistochemistry; LS, Lynch syndrome; WGS, whole-genome sequencing.

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