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. SijmonsLucio 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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 languageEnglish (US)
JournalGenetics in Medicine
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Hereditary Nonpolyposis Colorectal Neoplasms
DNA Mismatch Repair
Neoplasm Genes
Databases
Endometrial Neoplasms
Neoplasms
Ovarian Neoplasms
Colorectal Neoplasms
Urologic Neoplasms
Upper Gastrointestinal Tract
Penetrance
Colonic Neoplasms
Genes
Observational Studies
Prostate
Prospective Studies
Guidelines
Brain

Keywords

  • Lynch syndrome
  • MLH1
  • MSH2
  • MSH6
  • PMS2

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

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

In: Genetics in Medicine, 01.01.2019.

Research output: Contribution to journalArticle

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 2019, '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. https://doi.org/10.1038/s41436-019-0596-9
Dominguez-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 ; Bernstein, Inge ; Capella, Gabriel ; Balaguer, Francesc ; Thomas, Huw ; Evans, D. Gareth ; Burn, John ; Greenblatt, Marc ; Hovig, Eivind ; de Vos tot Nederveen Cappel, Wouter H. ; Sijmons, Rolf H. ; Bertario, Lucio ; Tibiletti, Maria Grazia ; Cavestro, Giulia Martina ; Lindblom, Annika ; Della Valle, Adriana ; Lopez-Köstner, Francisco ; Gluck, Nathan ; Katz, Lior H. ; Heinimann, Karl ; Vaccaro, Carlos A. ; Büttner, Reinhard ; Görgens, Heike ; Holinski-Feder, Elke ; Morak, Monika ; Holzapfel, Stefanie ; Hüneburg, Robert ; Knebel Doeberitz, Magnus von ; Loeffler, Markus ; Rahner, Nils ; Schackert, Hans K. ; Steinke-Lange, Verena ; Schmiegel, Wolff ; Vangala, Deepak ; Pylvänäinen, Kirsi ; Renkonen-Sinisalo, Laura ; Hopper, John L. ; Win, Aung Ko ; Haile, Robert W. ; Lindor, Noralane M. ; Gallinger, Steven ; Le Marchand, Loïc ; Newcomb, Polly A. ; Figueiredo, Jane C. ; Thibodeau, Stephen N. ; Wadt, Karin ; Therkildsen, Christina ; Okkels, Henrik ; Ketabi, Zohreh ; Moreira, Leticia ; Sánchez, Ariadna ; Serra-Burriel, Miquel ; Pineda, Marta ; Navarro, Matilde ; Blanco, Ignacio ; Green, Kate ; Lalloo, Fiona ; Crosbie, Emma J. ; Hill, James ; Denton, Oliver G. ; Frayling, Ian M. ; Rødland, Einar Andreas ; Vasen, Hans ; Mints, Miriam ; Neffa, Florencia ; Esperon, Patricia ; Alvarez, Karin ; Kariv, Revital ; Rosner, Guy ; Pinero, Tamara Alejandra ; Gonzalez, María Laura ; Kalfayan, Pablo ; Tjandra, Douglas ; Winship, Ingrid M. ; Macrae, Finlay ; Möslein, Gabriela ; Mecklin, Jukka Pekka ; Nielsen, Maartje ; Møller, Pål. / Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants : findings from the Prospective Lynch Syndrome Database. In: Genetics in Medicine. 2019.
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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",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41436-019-0596-9",
language = "English (US)",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Lippincott Williams and Wilkins",

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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 - 2019/1/1

Y1 - 2019/1/1

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

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JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

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