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

Mev Dominguez-Valentin; Julian R. Sampson; Toni T. Seppälä; Sanne W. ten Broeke; John Paul Plazzer; Sigve Nakken; Christoph Engel; Stefan Aretz; Mark A. Jenkins; Lone Sunde; Inge Bernstein; Gabriel Capella; Francesc Balaguer; Huw Thomas; D. Gareth Evans; John Burn; Marc Greenblatt; Eivind Hovig; Wouter H. de Vos tot Nederveen Cappel; Rolf H. Sijmons; Lucio Bertario; Maria Grazia Tibiletti; Giulia Martina Cavestro; Annika Lindblom; Adriana Della Valle; Francisco Lopez-Köstner; Nathan Gluck; Lior H. Katz; Karl Heinimann; Carlos A. Vaccaro; Reinhard Büttner; Heike Görgens; Elke Holinski-Feder; Monika Morak; Stefanie Holzapfel; Robert Hüneburg; Magnus von Knebel Doeberitz; Markus Loeffler; Nils Rahner; Hans K. Schackert; Verena Steinke-Lange; Wolff Schmiegel; Deepak Vangala; Kirsi Pylvänäinen; Laura Renkonen-Sinisalo; John L. Hopper; Aung Ko Win; Robert W. Haile; Noralane M. Lindor; Steven Gallinger; Loïc Le Marchand; Polly A. Newcomb; Jane C. Figueiredo; Stephen N. Thibodeau; Karin Wadt; Christina Therkildsen; Henrik Okkels; Zohreh Ketabi; Leticia Moreira; Ariadna Sánchez; Miquel Serra-Burriel; Marta Pineda; Matilde Navarro; Ignacio Blanco; Kate Green; Fiona Lalloo; Emma J. Crosbie; James Hill; Oliver G. Denton; Ian M. Frayling; Einar Andreas Rødland; Hans Vasen; Miriam Mints; Florencia Neffa; Patricia Esperon; Karin Alvarez; Revital Kariv; Guy Rosner; Tamara Alejandra Pinero; María Laura Gonzalez; Pablo Kalfayan; Douglas Tjandra; Ingrid M. Winship; Finlay Macrae; Gabriela Möslein; Jukka Pekka Mecklin; Maartje Nielsen; Pål Møller

doi:10.1038/s41436-019-0596-9

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

Mev Dominguez-Valentin^*
, Julian R. Sampson
, Toni T. Seppälä
, Sanne W. ten Broeke
, John Paul Plazzer
, Sigve Nakken
, Christoph Engel
, Stefan Aretz
, Mark A. Jenkins
, Lone Sunde
, Inge Bernstein
, Gabriel Capella
, Francesc Balaguer
, Huw Thomas
, D. Gareth Evans
, John Burn
, Marc Greenblatt
, Eivind Hovig
, Wouter H. de Vos tot Nederveen Cappel
, Rolf H. Sijmons

Lucio Bertario, Maria Grazia Tibiletti, Giulia Martina Cavestro, Annika Lindblom, Adriana Della Valle, Francisco Lopez-Köstner, Nathan Gluck, Lior H. Katz, Karl Heinimann, Carlos A. Vaccaro, Reinhard Büttner, Heike Görgens, Elke Holinski-Feder, Monika Morak, Stefanie Holzapfel, Robert Hüneburg, Magnus von Knebel Doeberitz, Markus Loeffler, Nils Rahner, Hans K. Schackert, Verena Steinke-Lange, Wolff Schmiegel, Deepak Vangala, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, John L. Hopper, Aung Ko Win, Robert W. Haile, Noralane M. Lindor, Steven Gallinger, Loïc Le Marchand, Polly A. Newcomb, Jane C. Figueiredo, Stephen N. Thibodeau, Karin Wadt, Christina Therkildsen, Henrik Okkels, Zohreh Ketabi, Leticia Moreira, Ariadna Sánchez, Miquel Serra-Burriel, Marta Pineda, Matilde Navarro, Ignacio Blanco, Kate Green, Fiona Lalloo, Emma J. Crosbie, James Hill, Oliver G. Denton, Ian M. Frayling, Einar Andreas Rødland, Hans Vasen, Miriam Mints, Florencia Neffa, Patricia Esperon, Karin Alvarez, Revital Kariv, Guy Rosner, Tamara Alejandra Pinero, María Laura Gonzalez, Pablo Kalfayan, Douglas Tjandra, Ingrid M. Winship, Finlay Macrae, Gabriela Möslein, Jukka Pekka Mecklin, Maartje Nielsen, Pål Møller

^*Corresponding author for this work

Internal Medicine

Research output: Contribution to journal › Article › peer-review

492 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	15-25
Number of pages	11
Journal	Genetics in Medicine
Volume	22
Issue number	1
DOIs	https://doi.org/10.1038/s41436-019-0596-9
State	Published - 1 Jan 2020

Funding

Funders	Funder number
Australasian Colorectal Cancer Family Registry
CCFR
Colorectal Cancer Family Registry
Finnish Cancer Foundation
National Cancer Institute/National Institutes of Health	U01 CA074778, U01/U24 CA097735
Ontario Familial Colorectal Cancer Registry	U01/U24 CA074783
Seattle Colorectal Cancer Family Registry	U01/U24 CA074794
Spanish Ministry of Economy and Competitiveness
University of Hawaii Colorectal Cancer Family Registry	R01 CA104132, U01/U24 CA074806
Wales Gene Park
National Institutes of Health
National Cancer Institute	UM1CA167551, U01CA074806
Mayo Clinic	NCI/NIH U01/U24 CA074800
University of Southern California	NCI/NIH U01/U24 CA074799
Kreftforeningen	194751–2017
NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research	IS-BRC-1215–20007
Asociación Española de Coloproctología
National Institute for Health Research
Generalitat de Catalunya	2017SGR1282, SLT002/16/0037
Jane ja Aatos Erkon Säätiö
Instituto de Salud Carlos III	PI13/00719, PI16/00766
Deutsche Krebshilfe
European Regional Development Fund	SAF2015-68016-R
Centro de Investigación Biomédica en Red de Cáncer

Keywords

Lynch syndrome
MLH1
MSH2
MSH6
PMS2

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41436-019-0596-9

Cite this

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

@article{e822b0ab8c2246a7bfc558e278dd5673,

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

abstract = "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.",

keywords = "Lynch syndrome, MLH1, MSH2, MSH6, PMS2",

author = "Mev Dominguez-Valentin and Sampson, \{Julian R.\} and Sepp{\"a}l{\"a}, \{Toni T.\} and \{ten Broeke\}, \{Sanne W.\} and Plazzer, \{John Paul\} and Sigve Nakken and Christoph Engel and Stefan Aretz and Jenkins, \{Mark A.\} and Lone Sunde and Inge Bernstein and Gabriel Capella and Francesc Balaguer and Huw Thomas and Evans, \{D. Gareth\} and John Burn and Marc Greenblatt and Eivind Hovig and \{de Vos tot Nederveen Cappel\}, \{Wouter H.\} and Sijmons, \{Rolf H.\} and Lucio Bertario and Tibiletti, \{Maria Grazia\} and Cavestro, \{Giulia Martina\} and Annika Lindblom and \{Della Valle\}, Adriana and Francisco Lopez-K{\"o}stner and Nathan Gluck and Katz, \{Lior H.\} and Karl Heinimann and Vaccaro, \{Carlos A.\} and Reinhard B{\"u}ttner and Heike G{\"o}rgens and Elke Holinski-Feder and Monika Morak and Stefanie Holzapfel and Robert H{\"u}neburg and \{Knebel Doeberitz\}, \{Magnus von\} and Markus Loeffler and Nils Rahner and Schackert, \{Hans K.\} and Verena Steinke-Lange and Wolff Schmiegel and Deepak Vangala and Kirsi Pylv{\"a}n{\"a}inen and Laura Renkonen-Sinisalo and Hopper, \{John L.\} and Win, \{Aung Ko\} and Haile, \{Robert W.\} and Lindor, \{Noralane M.\} and Steven Gallinger and \{Le Marchand\}, Lo{\"i}c and Newcomb, \{Polly A.\} and Figueiredo, \{Jane C.\} and Thibodeau, \{Stephen N.\} and Karin Wadt and Christina Therkildsen and Henrik Okkels and Zohreh Ketabi and Leticia Moreira and Ariadna S{\'a}nchez and Miquel Serra-Burriel and Marta Pineda and Matilde Navarro and Ignacio Blanco and Kate Green and Fiona Lalloo and Crosbie, \{Emma J.\} and James Hill and Denton, \{Oliver G.\} and Frayling, \{Ian M.\} and R{\o}dland, \{Einar Andreas\} and Hans Vasen and Miriam Mints and Florencia Neffa and Patricia Esperon and Karin Alvarez and Revital Kariv and Guy Rosner and Pinero, \{Tamara Alejandra\} and Gonzalez, \{Mar{\'i}a Laura\} and Pablo Kalfayan and Douglas Tjandra and Winship, \{Ingrid M.\} and Finlay Macrae and Gabriela M{\"o}slein and Mecklin, \{Jukka Pekka\} and Maartje Nielsen and P{\aa}l M{\o}ller",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2020",

month = jan,

day = "1",

doi = "10.1038/s41436-019-0596-9",

language = "אנגלית",

volume = "22",

pages = "15--25",

journal = "Genetics in Medicine",

issn = "1098-3600",

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Dominguez-Valentin, M, Sampson, JR, Seppälä, TT, ten Broeke, SW, Plazzer, JP, Nakken, S, Engel, C, Aretz, S, Jenkins, MA, Sunde, L, Bernstein, I, Capella, G, Balaguer, F, Thomas, H, Evans, DG, Burn, J, Greenblatt, M, Hovig, E, de Vos tot Nederveen Cappel, WH, Sijmons, RH, Bertario, L, Tibiletti, MG, Cavestro, GM, Lindblom, A, Della Valle, A, Lopez-Köstner, F, Gluck, N , Katz, LH, Heinimann, K, Vaccaro, CA, Büttner, R, Görgens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Hüneburg, R, Knebel Doeberitz, MV, Loeffler, M, Rahner, N, Schackert, HK, Steinke-Lange, V, Schmiegel, W, Vangala, D, Pylvänäinen, K, Renkonen-Sinisalo, L, Hopper, JL, Win, AK, Haile, RW, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Wadt, K, Therkildsen, C, Okkels, H, Ketabi, Z, Moreira, L, Sánchez, A, Serra-Burriel, M, Pineda, M, Navarro, M, Blanco, I, Green, K, Lalloo, F, Crosbie, EJ, Hill, J, Denton, OG, Frayling, IM, Rødland, EA, Vasen, H, Mints, M, Neffa, F, Esperon, P, Alvarez, K, Kariv, R , Rosner, G, Pinero, TA, Gonzalez, ML, Kalfayan, P, Tjandra, D, Winship, IM, Macrae, F, Möslein, G, Mecklin, JP, Nielsen, M & 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, vol. 22, no. 1, pp. 15-25. https://doi.org/10.1038/s41436-019-0596-9

TY - JOUR

T1 - Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants

T2 - findings from the Prospective Lynch Syndrome Database

AU - Dominguez-Valentin, Mev

AU - Sampson, Julian R.

AU - Seppälä, Toni T.

AU - ten Broeke, Sanne W.

AU - Plazzer, John Paul

AU - Nakken, Sigve

AU - Engel, Christoph

AU - Aretz, Stefan

AU - Jenkins, Mark A.

AU - Sunde, Lone

AU - Bernstein, Inge

AU - Capella, Gabriel

AU - Balaguer, Francesc

AU - Thomas, Huw

AU - Evans, D. Gareth

AU - Burn, John

AU - Greenblatt, Marc

AU - Hovig, Eivind

AU - de Vos tot Nederveen Cappel, Wouter H.

AU - Sijmons, Rolf H.

AU - Bertario, Lucio

AU - Tibiletti, Maria Grazia

AU - Cavestro, Giulia Martina

AU - Lindblom, Annika

AU - Della Valle, Adriana

AU - Lopez-Köstner, Francisco

AU - Gluck, Nathan

AU - Katz, Lior H.

AU - Heinimann, Karl

AU - Vaccaro, Carlos A.

AU - Büttner, Reinhard

AU - Görgens, Heike

AU - Holinski-Feder, Elke

AU - Morak, Monika

AU - Holzapfel, Stefanie

AU - Hüneburg, Robert

AU - Knebel Doeberitz, Magnus von

AU - Loeffler, Markus

AU - Rahner, Nils

AU - Schackert, Hans K.

AU - Steinke-Lange, Verena

AU - Schmiegel, Wolff

AU - Vangala, Deepak

AU - Pylvänäinen, Kirsi

AU - Renkonen-Sinisalo, Laura

AU - Hopper, John L.

AU - Win, Aung Ko

AU - Haile, Robert W.

AU - Lindor, Noralane M.

AU - Gallinger, Steven

AU - Le Marchand, Loïc

AU - Newcomb, Polly A.

AU - Figueiredo, Jane C.

AU - Thibodeau, Stephen N.

AU - Wadt, Karin

AU - Therkildsen, Christina

AU - Okkels, Henrik

AU - Ketabi, Zohreh

AU - Moreira, Leticia

AU - Sánchez, Ariadna

AU - Serra-Burriel, Miquel

AU - Pineda, Marta

AU - Navarro, Matilde

AU - Blanco, Ignacio

AU - Green, Kate

AU - Lalloo, Fiona

AU - Crosbie, Emma J.

AU - Hill, James

AU - Denton, Oliver G.

AU - Frayling, Ian M.

AU - Rødland, Einar Andreas

AU - Vasen, Hans

AU - Mints, Miriam

AU - Neffa, Florencia

AU - Esperon, Patricia

AU - Alvarez, Karin

AU - Kariv, Revital

AU - Rosner, Guy

AU - Pinero, Tamara Alejandra

AU - Gonzalez, María Laura

AU - Kalfayan, Pablo

AU - Tjandra, Douglas

AU - Winship, Ingrid M.

AU - Macrae, Finlay

AU - Möslein, Gabriela

AU - Mecklin, Jukka Pekka

AU - Nielsen, Maartje

AU - Møller, Pål

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

AB - 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.

KW - Lynch syndrome

KW - MLH1

KW - MSH2

KW - MSH6

KW - PMS2

UR - https://www.scopus.com/pages/publications/85069746674

U2 - 10.1038/s41436-019-0596-9

DO - 10.1038/s41436-019-0596-9

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 31337882

AN - SCOPUS:85069746674

SN - 1098-3600

VL - 22

SP - 15

EP - 25

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 1

ER -

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

Abstract

Funding

Keywords

UN SDGs

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