A1 Journal article (refereed)
Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants : findings from the Prospective Lynch Syndrome Database (2020)

Dominguez-Valentin, M., Sampson, J. R., Seppälä, T. T., ten Broeke, S. W., Plazzer, J.-P., Nakken, S., Engel, C., Aretz, S., Jenkins, M. A., Sunde, L., Bernstein, I., Capella, G., Balaguer, F., Thomas, H., Evans, D. G., Burn, J., Greenblatt, M., Hovig, E., de Vos tot Nederveen Cappel, W. H., . . . Møller, P. (2020). Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants : findings from the Prospective Lynch Syndrome Database. Genetics in Medicine, 22(1), 15-25. https://doi.org/10.1038/s41436-019-0596-9

JYU authors or editors

Publication details

All authors or editorsDominguez-Valentin, Mev; Sampson, Julian R.; Seppälä, Toni T.; ten Broeke, Sanne W.; Plazzer, John-Paul; Nakken, Sigve; Engel, Christoph; Aretz, Stefan; Jenkins, Mark A.; Sunde, Lone; et al.

Journal or seriesGenetics in Medicine



Publication year2020


Issue number1

Pages range15-25

PublisherNature Publishing Group

Publication countryUnited Kingdom

Publication languageEnglish


Publication open accessOpenly available

Publication channel open accessPartially open access channel

Publication is parallel published (JYX)https://jyx.jyu.fi/handle/123456789/67156

Additional informationNote: A Correction to this article was published on 20 July 2020; http://dx.doi.org/10.1038/s41436-020-0892-4



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.


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.


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.


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.

Keywordsbowel cancerLynch syndromeoncogenesgenetic factorsgenderage

Free keywordsLynch syndrome; MLH1; MSH2; MSH6; PMS2

Contributing organizations

Ministry reportingYes

Reporting Year2020

JUFO rating2

Last updated on 2024-22-04 at 13:30