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

被引：94

作者：

Haraldsdottir, Sigurdis ^{[1
,2
,3
]}

Rafnar, Thorunn ^{[4
]}

Frankel, Wendy L. ^{[5
]}

Einarsdottir, Sylvia ^{[6
,7
]}

Sigurdsson, Asgeir ^{[4
]}

Hampel, Heather ^{[2
]}

Snaebjornsson, Petur ^{[8
]}

Masson, Gisli ^{[4
]}

Weng, Daniel ^{[2
]}

Arngrimsson, Reynir ^{[3
,6
]}

Kehr, Birte ^{[4
]}

Yilmaz, Ahmet ^{[2
]}

Haraldsson, Stefan ^{[6
,9
]}

Sulem, Patrick ^{[4
]}

Stefansson, Tryggvi ^{[6
]}

Shields, Peter G. ^{[2
]}

Sigurdsson, Fridbjorn ^{[6
]}

Bekaii-Saab, Tanios ^{[10
]}

Moller, Pall H. ^{[6
]}

Steinarsdottir, Margret ^{[6
]}

Alexiusdottir, Kristin

Hitchins, Megan ^{[1
]}

Pritchard, Colin C. ^{[12
]}

de la Chapelle, Albert ^{[2
]}

Jonasson, Jon G. ^{[3
,6
,11
]}

Goldberg, Richard M. ^{[13
]}

Stefansson, Kari ^{[3
,4
]}

机构：

[1] Stanford Canc Ctr, Dept Internal Med, 875 Blake Wilbur Dr, Stanford, CA 94305 USA

[2] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, 460West 10th Ave, Columbus, OH 43210 USA

[3] Univ Iceland, Saemundargata 2, IS-101 Reykjavik, Iceland

[4] DeCODE Genet Amgen, Sturlugata 8, IS-101 Reykjavik, Iceland

[5] Ohio State Univ, Dept Pathol, Ctr Comprehens Canc, 460 West 10th Ave, Columbus, OH 43210 USA

[6] Landspitali Univ Hosp, IS-101 Reykjavik, Iceland

[7] Aalborg Univ Hosp, DK-9000 Aalborg, Denmark

[8] Netherlands Canc Inst Antoni van Leeuwenhoek NKI, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands

[9] Hvidovre Univ Hosp, Kettegard Alle 30, DK-2650 Hvidovre, Denmark

[10] Mayo Clin, Dept Internal Med, 5881 E Mayo Blvd, Phoenix, AZ 85054 USA

[11] Iceland Canc Registry, Skogarhlio 8, IS-105 Reykjavik, Iceland

[12] Univ Washington, 1959 NE Pacific St, Seattle, WA 98195 USA

[13] West Virginia Univ, Inst Canc, Dept Internal Med, 1805 Hlth Sci Ctr South Morgantown, Morgantown, WV 26506 USA

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

关键词：

NONPOLYPOSIS COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; GERMLINE; COLON; GUIDELINES; IMMUNOHISTOCHEMISTRY; MANAGEMENT; ORIGIN; HMLH1; MLH1;

D O I：

10.1038/ncomms14755

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 immuno-histochemistry. 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.

引用

页数：11

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