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. Seppala; 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-Kostner; Nathan Gluck; Lior H. Katz; Karl Heinimann; Carlos A. Vaccaro; Reinhard Buettner; Heike Goergens; Elke Holinski-Feder; Monika Morak; Stefanie Holzapfel; Robert Hueneburg; Magnus von Knebel Doeberitz; Markus Loeffler; Nils Rahner; Hans K. Schackert; Verena Steinke-Lange; Wolff Schmiegel; Deepak Vangala; Kirsi Pylvanainen; Laura Renkonen-Sinisalo; John L. Hopper; Aung Ko Win; Robert W. Haile; Noralane M. Lindor; Steven Gallinger

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. Seppala, 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-Kostner, Nathan Gluck, Lior H. Katz, Karl Heinimann, Carlos A. Vaccaro, Reinhard Buettner, Heike Goergens, Elke Holinski-Feder, Monika Morak, Stefanie Holzapfel, Robert Hueneburg, Magnus von Knebel Doeberitz, Markus Loeffler, Nils Rahner, Hans K. Schackert, Verena Steinke-Lange, Wolff Schmiegel, Deepak Vangala, Kirsi Pylvanainen, Laura Renkonen-Sinisalo, John L. Hopper, Aung Ko Win, Robert W. Haile, Noralane M. Lindor, Steven Gallinger

^*Corresponding author for this work

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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
Publication status	Published - Jan-2020

Keywords

Lynch syndrome
MLH1
MSH2
MSH6
PMS2
MUTATION CARRIERS

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Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variantsFinal publisher's version, 1.16 MBLicence: CC BY-NC

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Dominguez-Valentin, M., Sampson, J. R., Seppala, 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., ... Gallinger, S. (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{1e3e4c1d209b436ba70b364e8018be7c,

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, MUTATION CARRIERS",

author = "Mev Dominguez-Valentin and Sampson, {Julian R.} and Seppala, {Toni T.} and {ten Broeke}, {Sanne W.} and John-Paul Plazzer 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-Kostner and Nathan Gluck and Katz, {Lior H.} and Karl Heinimann and Vaccaro, {Carlos A.} and Reinhard Buettner and Heike Goergens and Elke Holinski-Feder and Monika Morak and Stefanie Holzapfel and Robert Hueneburg and {von Knebel Doeberitz}, Magnus and Markus Loeffler and Nils Rahner and Schackert, {Hans K.} and Verena Steinke-Lange and Wolff Schmiegel and Deepak Vangala and Kirsi Pylvanainen and Laura Renkonen-Sinisalo and Hopper, {John L.} and Win, {Aung Ko} and Haile, {Robert W.} and Lindor, {Noralane M.} and Steven Gallinger",

year = "2020",

month = jan,

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

language = "English",

volume = "22",

pages = "15--25",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Nature Publishing Group",

number = "1",

}

Dominguez-Valentin, M, Sampson, JR, Seppala, TT, ten Broeke, SW, Plazzer, J-P, 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-Kostner, F, Gluck, N, Katz, LH, Heinimann, K, Vaccaro, CA, Buettner, R, Goergens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Hueneburg, R, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schackert, HK, Steinke-Lange, V, Schmiegel, W, Vangala, D, Pylvanainen, K, Renkonen-Sinisalo, L, Hopper, JL, Win, AK, Haile, RW, Lindor, NM & Gallinger, S 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 - Seppala, 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-Kostner, Francisco

AU - Gluck, Nathan

AU - Katz, Lior H.

AU - Heinimann, Karl

AU - Vaccaro, Carlos A.

AU - Buettner, Reinhard

AU - Goergens, Heike

AU - Holinski-Feder, Elke

AU - Morak, Monika

AU - Holzapfel, Stefanie

AU - Hueneburg, Robert

AU - von Knebel Doeberitz, Magnus

AU - Loeffler, Markus

AU - Rahner, Nils

AU - Schackert, Hans K.

AU - Steinke-Lange, Verena

AU - Schmiegel, Wolff

AU - Vangala, Deepak

AU - Pylvanainen, Kirsi

AU - Renkonen-Sinisalo, Laura

AU - Hopper, John L.

AU - Win, Aung Ko

AU - Haile, Robert W.

AU - Lindor, Noralane M.

AU - Gallinger, Steven

PY - 2020/1

Y1 - 2020/1

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

KW - MUTATION CARRIERS

U2 - 10.1038/s41436-019-0596-9

DO - 10.1038/s41436-019-0596-9

M3 - Article

C2 - 31337882

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

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Keywords

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