Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 May 3:8:14755.
doi: 10.1038/ncomms14755.

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

Sigurdis Haraldsdottir  1   2   3 , Thorunn Rafnar  4 , Wendy L Frankel  5 , Sylvia Einarsdottir  6   7 , Asgeir Sigurdsson  4 , Heather Hampel  2 , Petur Snaebjornsson  8 , Gisli Masson  4 , Daniel Weng  2 , Reynir Arngrimsson  3   6 , Birte Kehr  4 , Ahmet Yilmaz  2 , Stefan Haraldsson  6   9 , Patrick Sulem  4 , Tryggvi Stefansson  6 , Peter G Shields  2 , Fridbjorn Sigurdsson  6 , Tanios Bekaii-Saab  10 , Pall H Moller  6 , Margret Steinarsdottir  6 , Kristin Alexiusdottir  11 , Megan Hitchins  1 , Colin C Pritchard  12 , Albert de la Chapelle  2 , Jon G Jonasson  3   6   11 , Richard M Goldberg  13 , Kari Stefansson  3   4
Affiliations

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

Sigurdis Haraldsdottir et al. Nat Commun. .

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.

PubMed Disclaimer

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
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
Figure 2. Study design.
CRC, colorectal cancer; IHC, immunohistochemistry; LS, Lynch syndrome; WGS, whole-genome sequencing.
See this image and copyright information in PMC

References

    1. Hampel H. & de la Chapelle A. How do we approach the goal of identifying everybody with Lynch Syndrome? Fam. Cancer 12, 313–317 (2013). - PMC - PubMed
    1. Watson P. & Lynch H. T. The tumor spectrum in HNPCC. Anticancer Res. 14, 1635–1639 (1994). - PubMed
    1. Bonadona V. et al. Cancer risks associated with germline mutations in mlh1, msh2, and msh6 genes in lynch syndrome. JAMA 305, 2304–2310 (2011). - PubMed
    1. ten Broeke S. W. et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J. Clin. Oncol. 33, 319–325 (2015). - PubMed
    1. The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012). - PMC - PubMed

Publication types

Substances