Journal
GENETICS IN MEDICINE
Volume 22, Issue 1, Pages 15-25Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-019-0596-9
Keywords
Lynch syndrome; MLH1; MSH2; MSH6; PMS2
Categories
Funding
- Finnish Cancer Foundation
- Jane and Aatos Erkko Foundation
- Norwegian Cancer Society [194751-2017]
- Manchester National Institute for Health Research (NIHR) Biomedical Research Centre [IS-BRC-1215-20007]
- National Cancer Institute of the National Institutes of Health [UM1CA167551]
- Colorectal Cancer Family Registry (CCFR) center: Australasian Colorectal Cancer Family Registry (National Cancer Institute/National Institutes of Health [NCI/NIH]) [U01 CA074778, U01/U24 CA097735]
- Colorectal Cancer Family Registry (CCFR) center: Mayo Clinic Cooperative Family Registry for Colon Cancer Studies [NCI/NIH U01/U24 CA074800]
- Colorectal Cancer Family Registry (CCFR) center: Ontario Familial Colorectal Cancer Registry [NCI/NIH U01/U24 CA074783]
- Colorectal Cancer Family Registry (CCFR) center: Seattle Colorectal Cancer Family Registry [NCI/NIH U01/U24 CA074794]
- Colorectal Cancer Family Registry (CCFR) center: University of Hawaii Colorectal Cancer Family Registry [NCI/NIH U01/U24 CA074806, R01 CA104132]
- Colorectal Cancer Family Registry (CCFR) center: University of Southern California (USC) Consortium Colorectal Cancer Family Registry [NCI/NIH U01/U24 CA074799]
- Spanish Ministry of Economy and Competitiveness
- FEDER funds -a way to build Europe [SAF2015-68016-R]
- CIBERONC
- Government of Catalonia [2017SGR1282, PERIS SLT002/16/0037]
- German Cancer Aid
- Instituto de Salud Carlos III [PI13/00719, PI16/00766]
- Asociacion Espanola de Gastroenterologia (AEG)
- European Regional Development Fund (ERDF)
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Purpose Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. Methods We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. Results There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. Conclusion Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.
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