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 Morey 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

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)573-582
Number of pages10
JournalFamilial Cancer
Volume13
Issue number4
DOIs
StatePublished - 2014

Fingerprint

DNA Mismatch Repair
Colonic Neoplasms
Registries
Prostatic Neoplasms
Mutation
Genes
Neoplasms
Confidence Intervals
Tumor-Infiltrating Lymphocytes
Hereditary Nonpolyposis Colorectal Neoplasms
Turcot syndrome
Microsatellite Instability
Germ-Line Mutation
Ontario

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Oncology
  • Genetics(clinical)

Cite this

High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. / Rosty, Christophe; Walsh, Michael D.; Lindor, Noralane Morey; Thibodeau, Stephen N; Mundt, Erin; Gallinger, Steven; Aronson, Melyssa; Pollett, Aaron; Baron, John A.; Pearson, Sally; Clendenning, Mark; Walters, Rhiannon J.; Nagler, Belinda N.; Crawford, William J.; Young, Joanne P.; Winship, Ingrid; Win, Aung Ko; Hopper, John L.; Jenkins, Mark A.; Buchanan, Daniel D.

In: Familial Cancer, Vol. 13, No. 4, 2014, p. 573-582.

Research output: Contribution to journalArticle

Rosty, C, Walsh, MD, Lindor, NM, Thibodeau, SN, Mundt, E, Gallinger, S, Aronson, M, Pollett, A, Baron, JA, Pearson, S, Clendenning, M, Walters, RJ, Nagler, BN, Crawford, WJ, Young, JP, Winship, I, Win, AK, Hopper, JL, Jenkins, MA & Buchanan, DD 2014, 'High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry', Familial Cancer, vol. 13, no. 4, pp. 573-582. https://doi.org/10.1007/s10689-014-9744-1
Rosty, Christophe ; Walsh, Michael D. ; Lindor, Noralane Morey ; Thibodeau, Stephen N ; Mundt, Erin ; Gallinger, Steven ; Aronson, Melyssa ; Pollett, Aaron ; Baron, John A. ; Pearson, Sally ; Clendenning, Mark ; Walters, Rhiannon J. ; Nagler, Belinda N. ; Crawford, William J. ; Young, Joanne P. ; Winship, Ingrid ; Win, Aung Ko ; Hopper, John L. ; Jenkins, Mark A. ; Buchanan, Daniel D. / High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. In: Familial Cancer. 2014 ; Vol. 13, No. 4. pp. 573-582.
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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.",
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AU - Rosty, Christophe

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AU - Mundt, Erin

AU - Gallinger, Steven

AU - Aronson, Melyssa

AU - Pollett, Aaron

AU - Baron, John A.

AU - Pearson, Sally

AU - Clendenning, Mark

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AU - Crawford, William J.

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AU - Win, Aung Ko

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N2 - 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.

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