Cancer Risks for PMS2-Associated Lynch Syndrome

Sanne W Ten Broeke¹, Heleen M van der Klift¹, Carli M J Tops¹, Stefan Aretz¹, Inge Bernstein¹, Daniel D Buchanan¹, Albert de la Chapelle¹, Gabriel Capella¹, Mark Clendenning¹, Christoph Engel¹, Steven Gallinger¹, Encarna Gomez Garcia¹, Jane C Figueiredo¹, Robert Haile¹, Heather L Hampel¹, John L Hopper¹, Nicoline Hoogerbrugge¹, Magnus von Knebel Doeberitz¹, Loic Le Marchand¹, Tom G W Letteboer¹, Mark A Jenkins¹, Annika Lindblom¹, Noralane M Lindor¹, Arjen R Mensenkamp¹, Pål Møller¹, Polly A Newcomb¹, Theo A M van Os¹, Rachel Pearlman¹, Marta Pineda¹, Nils Rahner¹, Egbert J W Redeker¹, Maran J W Olderode-Berends¹, Christophe Rosty¹, Hans K Schackert¹, Rodney Scott¹, Leigha Senter¹, Liesbeth Spruijt¹, Verena Steinke-Lange¹, Manon Suerink¹, Stephen Thibodeau¹, Yvonne J Vos¹, Anja Wagner¹, Ingrid Winship¹, Frederik J Hes¹, Hans F A Vasen¹, Juul T Wijnen¹, Maartje Nielsen¹, Aung Ko Win¹

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¹ Sanne W. ten Broeke, Heleen M. van der Klift, Carli M.J. Tops, Manon Suerink, Frederik J. Hes, Hans F.A. Vasen, Juul T. Wijnen, and Maartje Nielsen, Leiden University Medical Center, Leiden; Encarna Gomez Garcia, Maastricht University Medical Center, Maastricht; Nicoline Hoogerbrugge, Arjen R. Mensenkamp, and Liesbeth Spruijt, Radboud University Medical Center, Nijmegen; Tom G.W. Letteboer, University Medical Center, Utrecht; Theo A.M. van Os and Egbert J.W. Redeker, Academic Medical Center, Amsterdam; Maran J.W. Olderode-Berends and Yvonne J. Vos, University of Groningen; University Medical Center Groningen, Groningen; Anja Wagner, Erasmus Medical Center, Rotterdam, the Netherlands; Stefan Aretz, University of Bonn; University Hospital Bonn, Bonn; Christoph Engel, Leipzig University; Medizinisch Genetisches Zentrum Bayerstr, Leipzig; Magnus von Knebel Doeberitz, University of Heidelberg; German Cancer Research Center, Heidelberg; Pål Møller, University of Witten-Herdecke, Wuppertal; Nils Rahner, Heinrich-Heine-University, Düsseldorf; Hans K. Schackert, Technische Universität Dresden, Dresden; Verena Steinke-Lange, Medizinische Klinik und Poliklinik IV Campus Innenstadt, Klinikum der Universität München, Munich, Germany; Pål Møller, The Norwegian Radium Hospital; Oslo University Hospital, Oslo, Norway; Inge Bernstein, Hvidovre Hospital, Hvidovre, and Aalborg University Hospital, Aalborg, Denmark; Daniel D. Buchanan, Mark Clendenning, John L. Hopper, Mark A. Jenkins, Christophe Rosty, Ingrid Winship, and Aung Ko Win, The University of Melbourne; Daniel D. Buchanan, Ingrid Winship, and Aung Ko Win, Royal Melbourne Hospital, Parkville, Melbourne, Victoria; Rodney Scott, University of Newcastle, Newcastle, New South Wales, Australia; Albert de la Chapelle, Heather L. Hampel, Rachel Pearlman, and Leigha Senter, The Ohio State University Comprehensive Cancer Center, Columbus, OH; Gabriel Capella and Marta Pineda, Institut d'Investigació Biomédica de Bellvitge, Barcelona, Spain; Steven Gallinger, Mount Sinai Hospital, Toronto, Ontario, Canada; Jane C. Figueiredo and Robert Haile, Cedars-Sinai Medical Center, Los Angeles, CA; Loic Le Marchand, University of Hawaii Cancer Center, Honolulu, HI; Annika Lindblom, Karolinska Institutet; Karolinska University Hospital, Stockholm, Sweden; Noralane M. Lindor, Mayo Clinic Arizona, Scottsdale, AZ; Polly A. Newcomb, Fred Hutchinson Cancer Research Center; University of Washington, Seattle, WA; and Stephen Thibodeau, Mayo Clinic, Rochester, MN.

PMID: 30161022
PMCID: PMC6349460
DOI: 10.1200/JCO.2018.78.4777

Cancer Risks for PMS2-Associated Lynch Syndrome

Sanne W Ten Broeke et al. J Clin Oncol. 2018.

. 2018 Oct 10;36(29):2961-2968.

doi: 10.1200/JCO.2018.78.4777. Epub 2018 Aug 30.

Authors

Affiliation

¹ Sanne W. ten Broeke, Heleen M. van der Klift, Carli M.J. Tops, Manon Suerink, Frederik J. Hes, Hans F.A. Vasen, Juul T. Wijnen, and Maartje Nielsen, Leiden University Medical Center, Leiden; Encarna Gomez Garcia, Maastricht University Medical Center, Maastricht; Nicoline Hoogerbrugge, Arjen R. Mensenkamp, and Liesbeth Spruijt, Radboud University Medical Center, Nijmegen; Tom G.W. Letteboer, University Medical Center, Utrecht; Theo A.M. van Os and Egbert J.W. Redeker, Academic Medical Center, Amsterdam; Maran J.W. Olderode-Berends and Yvonne J. Vos, University of Groningen; University Medical Center Groningen, Groningen; Anja Wagner, Erasmus Medical Center, Rotterdam, the Netherlands; Stefan Aretz, University of Bonn; University Hospital Bonn, Bonn; Christoph Engel, Leipzig University; Medizinisch Genetisches Zentrum Bayerstr, Leipzig; Magnus von Knebel Doeberitz, University of Heidelberg; German Cancer Research Center, Heidelberg; Pål Møller, University of Witten-Herdecke, Wuppertal; Nils Rahner, Heinrich-Heine-University, Düsseldorf; Hans K. Schackert, Technische Universität Dresden, Dresden; Verena Steinke-Lange, Medizinische Klinik und Poliklinik IV Campus Innenstadt, Klinikum der Universität München, Munich, Germany; Pål Møller, The Norwegian Radium Hospital; Oslo University Hospital, Oslo, Norway; Inge Bernstein, Hvidovre Hospital, Hvidovre, and Aalborg University Hospital, Aalborg, Denmark; Daniel D. Buchanan, Mark Clendenning, John L. Hopper, Mark A. Jenkins, Christophe Rosty, Ingrid Winship, and Aung Ko Win, The University of Melbourne; Daniel D. Buchanan, Ingrid Winship, and Aung Ko Win, Royal Melbourne Hospital, Parkville, Melbourne, Victoria; Rodney Scott, University of Newcastle, Newcastle, New South Wales, Australia; Albert de la Chapelle, Heather L. Hampel, Rachel Pearlman, and Leigha Senter, The Ohio State University Comprehensive Cancer Center, Columbus, OH; Gabriel Capella and Marta Pineda, Institut d'Investigació Biomédica de Bellvitge, Barcelona, Spain; Steven Gallinger, Mount Sinai Hospital, Toronto, Ontario, Canada; Jane C. Figueiredo and Robert Haile, Cedars-Sinai Medical Center, Los Angeles, CA; Loic Le Marchand, University of Hawaii Cancer Center, Honolulu, HI; Annika Lindblom, Karolinska Institutet; Karolinska University Hospital, Stockholm, Sweden; Noralane M. Lindor, Mayo Clinic Arizona, Scottsdale, AZ; Polly A. Newcomb, Fred Hutchinson Cancer Research Center; University of Washington, Seattle, WA; and Stephen Thibodeau, Mayo Clinic, Rochester, MN.

PMID: 30161022
PMCID: PMC6349460
DOI: 10.1200/JCO.2018.78.4777

Erratum in

Errata.
[No authors listed] [No authors listed] J Clin Oncol. 2019 Mar 20;37(9):761. doi: 10.1200/JCO.19.00316. J Clin Oncol. 2019. PMID: 30875485 Free PMC article. No abstract available.

Abstract

Purpose: 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- and 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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Figures

**Fig 1.**
Cumulative risks (solid lines) and corresponding 95% CIs (dotted lines) of (A) colorectal cancer, and (B) endometrial cancer for heterozygous *PMS2* mutation carriers, and for the US general population (dashed lines). Blue and gold represent males and females, respectively.

**Fig 2.**
Hazard ratios (HRs) and corresponding 95% CIs of extracolonic cancers for *PMS2* mutation carriers.

See this image and copyright information in PMC

References

1. Lynch HT, Snyder CL, Shaw TG, et al. : Milestones of Lynch syndrome: 1895-2015. Nat Rev Cancer 15:181-194, 2015 - PubMed
1. Umar A, Boland CR, Terdiman JP, et al. : Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261-268, 2004 - PMC - PubMed
1. Barrow E, Hill J, Evans DG: Cancer risk in Lynch syndrome. Fam Cancer 12:229-240, 2013 - PubMed
1. Harkness EF, Barrow E, Newton K, et al. : Lynch syndrome caused by MLH1 mutations is associated with an increased risk of breast cancer: A cohort study. J Med Genet 52:553-556, 2015 - PubMed
1. Win AK, Lindor NM, Young JP, et al. : Risks of primary extracolonic cancers following colorectal cancer in Lynch syndrome. J Natl Cancer Inst 104:1363-1372, 2012 - PMC - PubMed

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Cancer Risks for PMS2-Associated Lynch Syndrome

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Cancer Risks for PMS2-Associated Lynch Syndrome

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