Familial Cancer

, Volume 13, Issue 4, pp 573–582 | Cite as

High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry

  • Christophe Rosty
  • Michael D. Walsh
  • Noralane M. Lindor
  • Stephen N. Thibodeau
  • Erin Mundt
  • Steven Gallinger
  • Melyssa Aronson
  • Aaron Pollett
  • John A. Baron
  • Sally Pearson
  • Mark Clendenning
  • Rhiannon J. Walters
  • Belinda N. Nagler
  • William J. Crawford
  • Joanne P. Young
  • Ingrid Winship
  • Aung Ko Win
  • John L. Hopper
  • Mark A. Jenkins
  • Daniel D. Buchanan
Original Article

Abstract

The question of whether prostate cancer is part of the Lynch syndrome spectrum of tumors is unresolved. We investigated the mismatch repair (MMR) status and pathologic features of prostate cancers diagnosed in MMR gene mutation carriers. Prostate cancers (mean age at diagnosis = 62 ± SD = 8 years) from 32 MMR mutation carriers (23 MSH2, 5 MLH1 and 4 MSH6) enrolled in the Australasian, Mayo Clinic and Ontario sites of the Colon Cancer Family Registry were examined for clinico-pathologic features and MMR-deficiency (immunohistochemical loss of MMR protein expression and high levels of microsatellite instability; MSI-H). Tumor MMR-deficiency was observed for 22 cases [69 %; 95 % confidence interval (CI) 50–83 %], with the highest prevalence of MMR-deficiency in tumors from MSH2 mutation carriers (19/23, 83 %) compared with MLH1 and MSH6 carriers combined (3/9, 33 %; p = 0.01). MMR-deficient tumors had increased levels of tumor infiltrating lymphocytes compared with tumors without MMR-deficiency (p = 0.04). Under the assumption that tumour MMR-deficiency occurred only because the cancer was caused by the germline mutation, mutation carriers are at 3.2-fold (95 % CI 2.0–6.3) increased risk of prostate cancer, and when assessed by gene, the relative risk was greatest for MSH2 carriers (5.8, 95 % CI 2.6–20.9). Prostate cancer was the first or only diagnosed tumor in 37 % of carriers. MMR gene mutation carriers have at least a twofold or greater increased risk of developing MMR-deficient prostate cancer where the risk is highest for MSH2 mutation carriers. MMR IHC screening of prostate cancers will aid in identifying MMR gene mutation carriers.

Keywords

Prostate cancer Lynch syndrome Mismatch repair deficiency Mismatch repair gene mutations Tumor infiltrating lymphocytes 

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Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Christophe Rosty
    • 1
    • 2
    • 3
    • 4
  • Michael D. Walsh
    • 1
    • 5
  • Noralane M. Lindor
    • 6
  • Stephen N. Thibodeau
    • 7
  • Erin Mundt
    • 8
  • Steven Gallinger
    • 9
    • 10
    • 11
  • Melyssa Aronson
    • 11
  • Aaron Pollett
    • 11
  • John A. Baron
    • 12
  • Sally Pearson
    • 2
  • Mark Clendenning
    • 1
    • 2
  • Rhiannon J. Walters
    • 2
  • Belinda N. Nagler
    • 2
  • William J. Crawford
    • 2
  • Joanne P. Young
    • 2
  • Ingrid Winship
    • 13
    • 14
  • Aung Ko Win
    • 15
  • John L. Hopper
    • 15
    • 16
  • Mark A. Jenkins
    • 15
  • Daniel D. Buchanan
    • 1
    • 2
    • 15
  1. 1.Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology and Centre for Epidemiology and BiostatisticsUniversity of MelbourneParkvilleAustralia
  2. 2.Cancer and Population Studies Group, Bancroft CentreQueensland Institute of Medical ResearchHerstonAustralia
  3. 3.Envoi Specialist PathologistsHerstonAustralia
  4. 4.School of MedicineUniversity of QueenslandHerstonAustralia
  5. 5.Department of HistopathologySullivan Nicolaides PathologyTaringaAustralia
  6. 6.Department of Health Science ResearchMayo Clinic ArizonaScottsdaleUSA
  7. 7.Department of Laboratory MedicineMayo ClinicRochesterUSA
  8. 8.Division of Human GeneticsCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  9. 9.Cancer Care OntarioTorontoCanada
  10. 10.Samuel Lunenfeld Research InstituteMount Sinai HospitalTorontoCanada
  11. 11.Zane Cohen Centre for Digestive DiseasesMount Sinai HospitalTorontoCanada
  12. 12.Department of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  13. 13.Department of MedicineThe University of MelbourneParkvilleAustralia
  14. 14.Genetic MedicineThe Royal Melbourne HospitalParkvilleAustralia
  15. 15.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global HealthThe University of MelbourneParkvilleAustralia
  16. 16.Seoul National UniversitySeoulKorea

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