High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry
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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.
KeywordsProstate cancer Lynch syndrome Mismatch repair deficiency Mismatch repair gene mutations Tumor infiltrating lymphocytes
This work was supported by the National Cancer Institute, National Institutes of Health under RFA # CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and PIs of the Australasian Colorectal Cancer Family Registry (U01 CA097735), Familial Colorectal Neoplasia Collaborative Group (U01 CA074799) [USC], Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), Seattle Colorectal Cancer Family Registry (U01 CA074794), and University of Hawaii Colorectal Cancer Family Registry (U01 CA074806). The authors thank all study participants of the Colon Cancer Family Registry and staff for their contributions to this project. Prostate cancer tissue samples in this study were obtained from the Jeremy Jass Memorial Tissue Pathology Bank. The authors are grateful to the many pathology laboratories involved for supply of archived prostate tissue for analysis. Thanks are due to Judi Maskiell, Leanne Prior, Maggie Angelakos and Kelly Aujard, for data and pedigree retrieval. This work was supported by the National Cancer Institute, National Institutes of Health under RFA # CA-95-011 and through the Australasian Colorectal Cancer Family Registry (U01 CA097735), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800) and the Ontario Colon Cancer Family Registry (U01 CA074783) cooperative agreements. Christophe Rosty is the Jeremy Jass Pathology Fellow. John L. Hopper is an NHMRC Senior Principal Research Fellow and Distinguished Visiting Professor at Seoul National University, Korea. Mark A. Jenkins is an NHMRC Senior Research Fellow. Aung Ko Win is an NHMRC Early Career Fellow.
Conflict of interest
The authors declare they hold no conflict of interest with respect to this work.
Written informed consent was obtained from all study participants and the study protocol was approved by the QIMR HREC under protocol P628.
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