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Cancer Risks for PMS2-Associated Lynch Syndrome
Sanne W Ten Broeke1, Heleen M van der Klift1, Carli M J Tops1
1Sanne 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.
Individuals with pathogenic variants in the PMS2 gene have a slightly increased risk for colorectal and endometrial cancers. Screening protocols for PMS2-associated Lynch syndrome can focus on colonoscopies.
Area of Science:
- Genetics and Genomics
- Cancer Biology
- Epidemiology
Background:
- Lynch syndrome is linked to DNA mismatch repair gene variants (MLH1, MSH2, MSH6), primarily causing colorectal and endometrial cancers.
- Extracolonic cancers are known in Lynch syndrome, but cancer risks for PMS2 variants are not well-defined.
Purpose of the Study:
- To determine accurate cancer penetrance measures for individuals with heterozygous pathogenic PMS2 variants.
- To clarify the age-specific cumulative risk of cancers in PMS2-associated Lynch syndrome.
Main Methods:
- Modified segregation analysis incorporating genotyped and nongenotyped relatives.
- Ascertainment conditioning for bias-corrected estimates.
- Estimation of hazard ratios and penetrance for various cancer sites compared to the general population.
Main Results:
- Analysis included 284 families (4,878 individuals).
- PMS2 carriers showed increased colorectal cancer risk (13% males, 12% females by age 80) and endometrial cancer risk (13%).
- No significant increased risk was observed for ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancers.
Conclusions:
- Heterozygous PMS2 pathogenic variant carriers have a small increased risk for colorectal and endometrial cancers.
- PMS2-specific screening may be limited to colonoscopies.
- The necessity of risk-reducing surgeries like hysterectomy and oophorectomy for PMS2 carriers requires further investigation.
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