Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

被引：412

作者：

Dominguez-Valentin, Mev ^{[1
]}

Sampson, Julian R. ^{[2
]}

Seppala, Toni T. ^{[3
,4
]}

ten Broeke, Sanne W. ^{[5
]}

Plazzer, John-Paul ^{[6
]}

Nakken, Sigve ^{[1
]}

Engel, Christoph ^{[7
]}

Aretz, Stefan ^{[8
]}

Jenkins, Mark A. ^{[9
]}

Sunde, Lone ^{[10
,11
]}

Bernstein, Inge ^{[12
]}

Capella, Gabriel ^{[13
]}

Balaguer, Francesc ^{[14
]}

Thomas, Huw ^{[15
]}

Evans, D. Gareth ^{[16
,17
]}

Burn, John ^{[18
]}

Greenblatt, Marc ^{[19
]}

Hovig, Eivind ^{[1
,20
]}

de Vos Tot Nederveen Cappel, Wouter H. ^{[21
]}

Sijmons, Rolf H. ^{[22
]}

Bertario, Lucio ^{[23
,24
]}

Tibiletti, Maria Grazia ^{[25
]}

Cavestro, Giulia Martina ^{[26
]}

Lindblom, Annika ^{[27
,28
,29
]}

Della Valle, Adriana ^{[30
]}

Lopez-Kostner, Francisco ^{[31
]}

Gluck, Nathan ^{[32
,33
]}

Katz, Lior H. ^{[34
]}

Heinimann, Karl ^{[35
]}

Vaccaro, Carlos A. ^{[36
,37
]}

Buettner, Reinhard ^{[38
]}

Goergens, Heike ^{[39
]}

Holinski-Feder, Elke ^{[40
,41
]}

Morak, Monika ^{[40
,41
]}

Holzapfel, Stefanie ^{[8
]}

Hueneburg, Robert ^{[42
]}

von Knebel Doeberitz, Magnus ^{[43
,44
]}

Loeffler, Markus ^{[7
]}

Rahner, Nils ^{[45
]}

Schackert, Hans K. ^{[39
]}

Steinke-Lange, Verena ^{[40
,41
]}

Schmiegel, Wolff ^{[46
]}

Vangala, Deepak ^{[46
]}

Pylvanainen, Kirsi ^{[47
]}

Renkonen-Sinisalo, Laura ^{[3
,48
]}

Hopper, John L. ^{[9
]}

Win, Aung Ko ^{[9
]}

Haile, Robert W. ^{[49
]}

Lindor, Noralane M. ^{[50
]}

Gallinger, Steven ^{[51
]}

机构：

[1] Oslo Univ Hosp, Inst Canc Res, Norwegian Radium Hosp, Dept Tumor Biol, Oslo, Norway

[2] Cardiff Univ, Sch Med, Inst Med Genet, Div Canc & Genet, Cardiff, Wales

[3] Univ Helsinki, Dept Gastrointestinal Surg, Cent Hosp, Helsinki, Finland

[4] Univ Helsinki, Clin, Helsinki, Finland

[5] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands

[6] Royal Melbourne Hosp, Colorectal Med & Genet, Melbourne, Vic, Australia

[7] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany

[8] Univ Bonn, Inst Human Genet, Bonn, Germany

[9] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Parkville, Vic, Australia

[10] Aarhus Univ Hosp, Dept Clin Genet, Aarhus, Denmark

[11] Aarhus Univ, Dept Biomed, Aarhus, Denmark

[12] Aalborg Univ Hosp, Dept Surg Gastroenterol, Aalborg, Denmark

[13] Inst Catal Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain

[14] Univ Barcelona, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Gastroenterol Dept,Hosp Clin Barcelona, Barcelona, Spain

[15] Imperial Coll London, St Marks Hosp, Dept Surg & Canc, London, England

[16] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Ctr Genom Med, Manchester, Lancs, England

[17] Univ Manchester, Manchester Ctr Genom Med, Manchester, Lancs, England

[18] Newcastle Univ, Inst Genet Med, Newcastle Upon Tyne, Tyne & Wear, England

[19] Univ Vermont, Coll Med, Burlington, VT USA

[20] Oslo Univ Hosp, Inst Canc Genet & Informat, Norwegian Radium Hosp, Oslo, Norway

[21] Isala Clin, Dept Gastroenterol & Hepatol, Zwolle, Netherlands

[22] Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[23] IRCCS Ist Nazl Tumori, Unit Hereditary Digest Tract Tumors, Milan, Italy

[24] European Inst Oncol, Div Canc Prevent & Genet, Milan, Italy

[25] Univ Insubria, Osped Circolo ASST Settelaghi, Ctr Ric Tumori Eredofamiliari, Varese, Italy

[26] Univ Vita Salute San Raffaele, Gastroenterol & Gastrointestinal Endoscopy Unit, San Raffaele Sci Inst, Milan, Italy

[27] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[28] Karolinska Inst, Dept Clin Genet, Stockholm, Sweden

[29] Univ Hosp, Stockholm, Sweden

[30] Hosp Fuerzas Armadas, Grp Colaborat Uruguayo, Invest Afecc Oncol Hereditarias GCU, Montevideo, Uruguay

[31] Clin Las Condes, Lab Oncol & Genet Mol, Unidad Coloproctol, Santiago, Chile

[32] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Gastroenterol, Tel Aviv, Israel

[33] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel

[34] Sheba Med Ctr, High Risk & GI Canc Prevent Clin, Gastrooncol Unit, Dept Gastroenterol, Ramat Gan, Israel

[35] Univ Hosp Basel, Inst Med Genet & Pathol, Basel, Switzerland

[36] Hosp Italiano Buenos Aires, Hereditary Canc Program PROCANHE, Buenos Aires, DF, Argentina

[37] Hosp Italiano Buenos Aires, IMTIB, CONICET IU, Buenos Aires, DF, Argentina

[38] Univ Cologne, Inst Pathol, Cologne, Germany

[39] Tech Univ Dresden, Dept Surg Res, Dresden, Germany

[40] Klinikum Univ Munchen, Med Klin & Poliklin 4, Campus Innenstadt, Munich, Germany

[41] Ctr Med Genet, Munich, Germany

[42] Univ Hosp Bonn, Dept Internal Med, Bonn, Germany

[43] Univ Hosp Heidelberg, Dept Appl Tumour Biol, Inst Pathol, Heidelberg, Germany

[44] German Canc Res Ctr, Cooperat Unit Appl Tumour Biol, Heidelberg, Germany

[45] Heinrich Heine Univ, Inst Human Genet, Sch Med, Dusseldorf, Germany

[46] Ruhr Univ Bochum, Dept Med, Knappschaftskrankenhaus, Bochum, Germany

[47] Cent Finland Hlth Care Dist, Dept Educ & Sci, Jyvaskyla, Finland

[48] Univ Helsinki, Appl Tumour Genom Res Program, Helsinki, Finland

[49] Stanford Univ, Dept Med, Div Oncol, Stanford Canc Inst, Palo Alto, CA 94304 USA

[50] Mayo Clin Arizona, Dept Hlth Sci Res, Phoenix, AZ USA

来源：

GENETICS IN MEDICINE | 2020年 / 22卷 / 01期

基金：

美国国家卫生研究院;

关键词：

Lynch syndrome; MLH1; MSH2; MSH6; PMS2; MUTATION CARRIERS; MLH1; MSH2;

D O I：

10.1038/s41436-019-0596-9

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：15 / 25

页数：11

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