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dc.contributor.authorDominguez-Valentin, Mev
dc.contributor.authorSampson, Julian R.
dc.contributor.authorSeppälä, Toni T.
dc.contributor.authorten Broeke, Sanne W.
dc.contributor.authorPlazzer, John-Paul
dc.contributor.authorNakken, Sigve
dc.contributor.authorEngel, Christoph
dc.contributor.authorAretz, Stefan
dc.contributor.authorJenkins, Mark A.
dc.contributor.authorSunde, Lone
dc.contributor.authorBernstein, Inge
dc.contributor.authorCapella, Gabriel
dc.contributor.authorBalaguer, Francesc
dc.contributor.authorThomas, Huw
dc.contributor.authorEvans, D. Gareth
dc.contributor.authorBurn, John
dc.contributor.authorGreenblatt, Marc
dc.contributor.authorHovig, Eivind
dc.contributor.authorde Vos tot Nederveen Cappel, Wouter H.
dc.contributor.authorSijmons, Rolf H.
dc.contributor.authorBertario, Lucio
dc.contributor.authorTibiletti, Maria Grazia
dc.contributor.authorCavestro, Giulia Martina
dc.contributor.authorLindblom, Annika
dc.contributor.authorDella Valle, Adriana
dc.contributor.authorLopez-Köstner, Francisco
dc.contributor.authorGluck, Nathan
dc.contributor.authorKatz, Lior H.
dc.contributor.authorHeinimann, Karl
dc.contributor.authorVaccaro, Carlos A.
dc.contributor.authorBüttner, Reinhard
dc.contributor.authorGörgens, Heike
dc.contributor.authorHolinski-Feder, Elke
dc.contributor.authorMorak, Monika
dc.contributor.authorHolzapfel, Stefanie
dc.contributor.authorHüneburg, Robert
dc.contributor.authorKnebel Doeberitz, Magnus von
dc.contributor.authorLoeffler, Markus
dc.contributor.authorRahner, Nils
dc.contributor.authorSchackert, Hans K.
dc.contributor.authorSteinke-Lange, Verena
dc.contributor.authorSchmiegel, Wolff
dc.contributor.authorVangala, Deepak
dc.contributor.authorPylvänäinen, Kirsi
dc.contributor.authorRenkonen-Sinisalo, Laura
dc.contributor.authorHopper, John L.
dc.contributor.authorWin, Aung Ko
dc.contributor.authorHaile, Robert W.
dc.contributor.authorLindor, Noralane M.
dc.contributor.authorGallinger, Steven
dc.contributor.authorLe Marchand, Loïc
dc.contributor.authorNewcomb, Polly A.
dc.contributor.authorFigueiredo, Jane C.
dc.contributor.authorThibodeau, Stephen N.
dc.contributor.authorWadt, Karin
dc.contributor.authorTherkildsen, Christina
dc.contributor.authorOkkels, Henrik
dc.contributor.authorKetabi, Zohreh
dc.contributor.authorMoreira, Leticia
dc.contributor.authorSánchez, Ariadna
dc.contributor.authorSerra-Burriel, Miquel
dc.contributor.authorPineda, Marta
dc.contributor.authorNavarro, Matilde
dc.contributor.authorBlanco, Ignacio
dc.contributor.authorGreen, Kate
dc.contributor.authorLalloo, Fiona
dc.contributor.authorCrosbie, Emma J.
dc.contributor.authorHill, James
dc.contributor.authorDenton, Oliver G.
dc.contributor.authorFrayling, Ian M.
dc.contributor.authorRødland, Einar Andreas
dc.contributor.authorVasen, Hans
dc.contributor.authorMints, Miriam
dc.contributor.authorNeffa, Florencia
dc.contributor.authorEsperon, Patricia
dc.contributor.authorAlvarez, Karin
dc.contributor.authorKariv, Revital
dc.contributor.authorRosner, Guy
dc.contributor.authorPinero, Tamara Alejandra
dc.contributor.authorGonzalez, María Laura
dc.contributor.authorKalfayan, Pablo
dc.contributor.authorTjandra, Douglas
dc.contributor.authorWinship, Ingrid M.
dc.contributor.authorMacrae, Finlay
dc.contributor.authorMöslein, Gabriela
dc.contributor.authorMecklin, Jukka-Pekka
dc.contributor.authorNielsen, Maartje
dc.contributor.authorMøller, Pål
dc.identifier.citationDominguez-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. <i>Genetics in Medicine</i>, <i>22</i>(1), 15-25. <a href="" target="_blank"></a>
dc.description.abstractPURPOSE: 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.en
dc.publisherNature Publishing Group
dc.relation.ispartofseriesGenetics in Medicine
dc.rightsCC BY-NC-SA 4.0
dc.subject.otherLynch syndrome
dc.titleCancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants : findings from the Prospective Lynch Syndrome Database
dc.contributor.laitosLiikuntatieteellinen tiedekuntafi
dc.contributor.laitosFaculty of Sport and Health Sciencesen
dc.rights.copyright© The Author(s) 2019
dc.subject.ysoLynchin oireyhtymä
dc.subject.ysogeneettiset tekijät
jyx.fundinginformationWe also thank the Finnish Cancer Foundation, Jane and Aatos Erkko Foundation, and the Norwegian Cancer Society, contract 194751–2017 for funding. D.G.E. and E.J.C are supported by the all Manchester National Institute for Health Research (NIHR) Biomedical Research Centre (IS-BRC-1215–20007). Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number UM1CA167551 and through cooperative agreements with the following Colorectal Cancer Family Registry (CCFR) centers: Australasian Colorectal Cancer Family Registry (National Cancer Institute/National Institutes of Health [NCI/NIH] U01 CA074778 and U01/U24 CA097735), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH U01/U24 CA074794), University of Hawaii Colorectal Cancer Family Registry (NCI/NIH U01/U24 CA074806 and R01 CA104132 to L.L.M.), University of Southern California (USC) Consortium Colorectal Cancer Family Registry (NCI/NIH U01/U24 CA074799). GC, MP and MN work was funded by the Spanish Ministry of Economy and Competitiveness and cofunded by FEDER funds -a way to build Europe- (grant SAF2015-68016-R), CIBERONC and the Government of Catalonia (grants 2017SGR1282 and PERIS SLT002/16/0037). The German Consortium for Familial Intestinal Cancer has been supported by grants from the German Cancer Aid. Data collection in Bonn was facilitated by the Center for Hereditary Tumor Syndromes, University of Bonn. F.B. is supported by grants from the Instituto de Salud Carlos III (PI13/00719; PI16/00766) and from the Asociación Española de Gastroenterología (AEG). Data collection from Wales, UK was supported by the Wales Gene Park. This work was cofunded by the European Regional Development Fund (ERDF).

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