Cancer Risks for PMS2-associated lynch syndrom

Sanne W.Ten Broeke, Heleen M.Vander Klift, Carli M.J. Tops, Stefan Aretz, Inge Bernstein, Daniel D. Buchanan, Albert Dela Chapelle, Gabriel Capella, Mark Clendenning, Christoph Engel, Steven Gallinger, Encarna Gomez Garcia, Jane C. Figueiredo, Robert Haile, Heather L. Hampel, John L. Hopper, Nicoline Hoogerbrugge, Magnus Von Knebel Doeberitz, Loic Le Marchand, Tom G.W. Letteboer & 28 others Mark A. Jenkins, Annika Lindblom, Noralane Morey Lindor, Arjen R. Mensenkamp, Pal Møller, Polly A. Newcomb, Theo A.M. Van Os, Rachel Pearlman, Marta Pineda, Nils Rahner, Egbert J.W. Redeker, Maran J.W. Olderode-Berends, Christophe Rosty, Hans K. Schackert, Rodney Scott, Leigha Senter, Liesbeth Spruijt, Verena Steinke-Lange, Manon Suerink, Stephen N Thibodeau, Yvonne J. Vos, Anja Wagner, Ingrid Winship, J. Frederik Hes, Hans F.A. Vasen, Juul T. Wijnen, Maartje Nielsen, Aung Ko Win

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants. Methods A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance. Results In total, 284 families consisting of 4,878 first- A nd second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer. Conclusion Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.

Original languageEnglish (US)
Pages (from-to)2961-2968
Number of pages8
JournalJournal of Clinical Oncology
Volume36
Issue number29
DOIs
StatePublished - Oct 10 2018
Externally publishedYes

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Hereditary Nonpolyposis Colorectal Neoplasms
Penetrance
Endometrial Neoplasms
Colorectal Neoplasms
Neoplasms
Mutation
Intestinal Neoplasms
DNA Mismatch Repair
Ovariectomy
Colonoscopy
Hysterectomy
Population
Prostate
Stomach
Urinary Bladder
Breast
Kidney
Brain
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Broeke, S. W. T., Klift, H. M. V., Tops, C. M. J., Aretz, S., Bernstein, I., Buchanan, D. D., ... Win, A. K. (2018). Cancer Risks for PMS2-associated lynch syndrom. Journal of Clinical Oncology, 36(29), 2961-2968. https://doi.org/10.1200/JCO.2018.78.4777

Cancer Risks for PMS2-associated lynch syndrom. / Broeke, Sanne W.Ten; Klift, Heleen M.Vander; Tops, Carli M.J.; Aretz, Stefan; Bernstein, Inge; Buchanan, Daniel D.; Chapelle, Albert Dela; Capella, Gabriel; Clendenning, Mark; Engel, Christoph; Gallinger, Steven; Garcia, Encarna Gomez; Figueiredo, Jane C.; Haile, Robert; Hampel, Heather L.; Hopper, John L.; Hoogerbrugge, Nicoline; Doeberitz, Magnus Von Knebel; Marchand, Loic Le; Letteboer, Tom G.W.; Jenkins, Mark A.; Lindblom, Annika; Lindor, Noralane Morey; Mensenkamp, Arjen R.; Møller, Pal; Newcomb, Polly A.; Van Os, Theo A.M.; Pearlman, Rachel; Pineda, Marta; Rahner, Nils; Redeker, Egbert J.W.; Olderode-Berends, Maran J.W.; Rosty, Christophe; Schackert, Hans K.; Scott, Rodney; Senter, Leigha; Spruijt, Liesbeth; Steinke-Lange, Verena; Suerink, Manon; Thibodeau, Stephen N; Vos, Yvonne J.; Wagner, Anja; Winship, Ingrid; Hes, J. Frederik; Vasen, Hans F.A.; Wijnen, Juul T.; Nielsen, Maartje; Win, Aung Ko.

In: Journal of Clinical Oncology, Vol. 36, No. 29, 10.10.2018, p. 2961-2968.

Research output: Contribution to journalArticle

Broeke, SWT, Klift, HMV, Tops, CMJ, Aretz, S, Bernstein, I, Buchanan, DD, Chapelle, AD, Capella, G, Clendenning, M, Engel, C, Gallinger, S, Garcia, EG, Figueiredo, JC, Haile, R, Hampel, HL, Hopper, JL, Hoogerbrugge, N, Doeberitz, MVK, Marchand, LL, Letteboer, TGW, Jenkins, MA, Lindblom, A, Lindor, NM, Mensenkamp, AR, Møller, P, Newcomb, PA, Van Os, TAM, Pearlman, R, Pineda, M, Rahner, N, Redeker, EJW, Olderode-Berends, MJW, Rosty, C, Schackert, HK, Scott, R, Senter, L, Spruijt, L, Steinke-Lange, V, Suerink, M, Thibodeau, SN, Vos, YJ, Wagner, A, Winship, I, Hes, JF, Vasen, HFA, Wijnen, JT, Nielsen, M & Win, AK 2018, 'Cancer Risks for PMS2-associated lynch syndrom', Journal of Clinical Oncology, vol. 36, no. 29, pp. 2961-2968. https://doi.org/10.1200/JCO.2018.78.4777
Broeke SWT, Klift HMV, Tops CMJ, Aretz S, Bernstein I, Buchanan DD et al. Cancer Risks for PMS2-associated lynch syndrom. Journal of Clinical Oncology. 2018 Oct 10;36(29):2961-2968. https://doi.org/10.1200/JCO.2018.78.4777
Broeke, Sanne W.Ten ; Klift, Heleen M.Vander ; Tops, Carli M.J. ; Aretz, Stefan ; Bernstein, Inge ; Buchanan, Daniel D. ; Chapelle, Albert Dela ; Capella, Gabriel ; Clendenning, Mark ; Engel, Christoph ; Gallinger, Steven ; Garcia, Encarna Gomez ; Figueiredo, Jane C. ; Haile, Robert ; Hampel, Heather L. ; Hopper, John L. ; Hoogerbrugge, Nicoline ; Doeberitz, Magnus Von Knebel ; Marchand, Loic Le ; Letteboer, Tom G.W. ; Jenkins, Mark A. ; Lindblom, Annika ; Lindor, Noralane Morey ; Mensenkamp, Arjen R. ; Møller, Pal ; Newcomb, Polly A. ; Van Os, Theo A.M. ; Pearlman, Rachel ; Pineda, Marta ; Rahner, Nils ; Redeker, Egbert J.W. ; Olderode-Berends, Maran J.W. ; Rosty, Christophe ; Schackert, Hans K. ; Scott, Rodney ; Senter, Leigha ; Spruijt, Liesbeth ; Steinke-Lange, Verena ; Suerink, Manon ; Thibodeau, Stephen N ; Vos, Yvonne J. ; Wagner, Anja ; Winship, Ingrid ; Hes, J. Frederik ; Vasen, Hans F.A. ; Wijnen, Juul T. ; Nielsen, Maartje ; Win, Aung Ko. / Cancer Risks for PMS2-associated lynch syndrom. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 29. pp. 2961-2968.
@article{6ac9e6353eb44e98b647266bee83dd8e,
title = "Cancer Risks for PMS2-associated lynch syndrom",
abstract = "Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants. Methods A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95{\%} CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance. Results In total, 284 families consisting of 4,878 first- A nd second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13{\%} [95{\%} CI, 7.9{\%} to 22{\%}] for males and 12{\%} [95{\%} CI, 6.7{\%} to 21{\%}] for females) and endometrial cancer (13{\%} [95{\%} CI, 7.0{\%}-24{\%}]), compared with the general population (6.6{\%}, 4.7{\%}, and 2.4{\%}, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer. Conclusion Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.",
author = "Broeke, {Sanne W.Ten} and Klift, {Heleen M.Vander} and Tops, {Carli M.J.} and Stefan Aretz and Inge Bernstein and Buchanan, {Daniel D.} and Chapelle, {Albert Dela} and Gabriel Capella and Mark Clendenning and Christoph Engel and Steven Gallinger and Garcia, {Encarna Gomez} and Figueiredo, {Jane C.} and Robert Haile and Hampel, {Heather L.} and Hopper, {John L.} and Nicoline Hoogerbrugge and Doeberitz, {Magnus Von Knebel} and Marchand, {Loic Le} and Letteboer, {Tom G.W.} and Jenkins, {Mark A.} and Annika Lindblom and Lindor, {Noralane Morey} and Mensenkamp, {Arjen R.} and Pal M{\o}ller and Newcomb, {Polly A.} and {Van Os}, {Theo A.M.} and Rachel Pearlman and Marta Pineda and Nils Rahner and Redeker, {Egbert J.W.} and Olderode-Berends, {Maran J.W.} and Christophe Rosty and Schackert, {Hans K.} and Rodney Scott and Leigha Senter and Liesbeth Spruijt and Verena Steinke-Lange and Manon Suerink and Thibodeau, {Stephen N} and Vos, {Yvonne J.} and Anja Wagner and Ingrid Winship and Hes, {J. Frederik} and Vasen, {Hans F.A.} and Wijnen, {Juul T.} and Maartje Nielsen and Win, {Aung Ko}",
year = "2018",
month = "10",
day = "10",
doi = "10.1200/JCO.2018.78.4777",
language = "English (US)",
volume = "36",
pages = "2961--2968",
journal = "Journal of Clinical Oncology",
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TY - JOUR

T1 - Cancer Risks for PMS2-associated lynch syndrom

AU - Broeke, Sanne W.Ten

AU - Klift, Heleen M.Vander

AU - Tops, Carli M.J.

AU - Aretz, Stefan

AU - Bernstein, Inge

AU - Buchanan, Daniel D.

AU - Chapelle, Albert Dela

AU - Capella, Gabriel

AU - Clendenning, Mark

AU - Engel, Christoph

AU - Gallinger, Steven

AU - Garcia, Encarna Gomez

AU - Figueiredo, Jane C.

AU - Haile, Robert

AU - Hampel, Heather L.

AU - Hopper, John L.

AU - Hoogerbrugge, Nicoline

AU - Doeberitz, Magnus Von Knebel

AU - Marchand, Loic Le

AU - Letteboer, Tom G.W.

AU - Jenkins, Mark A.

AU - Lindblom, Annika

AU - Lindor, Noralane Morey

AU - Mensenkamp, Arjen R.

AU - Møller, Pal

AU - Newcomb, Polly A.

AU - Van Os, Theo A.M.

AU - Pearlman, Rachel

AU - Pineda, Marta

AU - Rahner, Nils

AU - Redeker, Egbert J.W.

AU - Olderode-Berends, Maran J.W.

AU - Rosty, Christophe

AU - Schackert, Hans K.

AU - Scott, Rodney

AU - Senter, Leigha

AU - Spruijt, Liesbeth

AU - Steinke-Lange, Verena

AU - Suerink, Manon

AU - Thibodeau, Stephen N

AU - Vos, Yvonne J.

AU - Wagner, Anja

AU - Winship, Ingrid

AU - Hes, J. Frederik

AU - Vasen, Hans F.A.

AU - Wijnen, Juul T.

AU - Nielsen, Maartje

AU - Win, Aung Ko

PY - 2018/10/10

Y1 - 2018/10/10

N2 - Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants. Methods A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance. Results In total, 284 families consisting of 4,878 first- A nd second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer. Conclusion Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.

AB - Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants. Methods A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance. Results In total, 284 families consisting of 4,878 first- A nd second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer. Conclusion Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.

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