Abstract

BackgroundA possible role for prostate cancer in Lynch syndrome has been debated based on observations of mismatch-repair defective tumors and reports of an increased risk of prostate cancer in mutation carriers. Potential inclusion of prostate cancer in the Lynch syndrome tumor spectrum is relevant for family classification, risk estimates and surveillance recommendations in mutation carriers.MethodsWe used the population-based Danish HNPCC-register to identify all prostate cancers that developed in mutation carriers and in their first-degree relatives from 288 Lynch syndrome families. The tumors were evaluated for clinicopathologic features and mismatch-repair status, and the cumulative risk of prostate cancer was determined.ResultsIn total, 28 prostate cancers developed in 16 mutation carriers and in 12 first-degree relatives at a median age of 63 years. The majority of the tumors were high-grade tumors with Gleason scores 8–10. Prostate cancer was associated with mutations in MSH2, MLH1 and MSH6 with loss of the respective mismatch repair protein in 69 % of the tumors, though a MSI-high phenotype was restricted to 13 % of the tumors. The cumulative risk of prostate cancer at age 70 was 3.7 % (95 % CI: 2.3–4.9).ConclusionWe provide evidence to link prostate cancer to Lynch syndrome through demonstration of MMR defective tumors and an increased risk of the disease, which suggests that prostate cancer should be considered in the diagnostic work-up of Lynch syndrome.

Highlights

  • A possible role for prostate cancer in Lynch syndrome has been debated based on observations of mismatch-repair defective tumors and reports of an increased risk of prostate cancer in mutation carriers

  • In total, 288 Lynch syndrome families with diseasepredisposing germline mutations in MLH1, MSH2, MSH6 or PMS2 were identified in the Danish Hereditary Non-Polyposis Colorectal Cancer (HNPCC) register

  • The tumors were linked to diseasepredisposing mutations in MSH2 (n = 14), MLH1 (n = 8) and MSH6 (n = 6) (Table 1)

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Summary

Introduction

A possible role for prostate cancer in Lynch syndrome has been debated based on observations of mismatch-repair defective tumors and reports of an increased risk of prostate cancer in mutation carriers. Potential inclusion of prostate cancer in the Lynch syndrome tumor spectrum is relevant for family classification, risk estimates and surveillance recommendations in mutation carriers. Other tumor types assumed to represent sporadic tumors in families with hereditary cancer, e.g. breast cancer, pancreatic cancer and sarcoma may develop as part of the syndrome. This is suggested based on identification of mismatch repair (MMR) defective tumors of these subtypes and demonstration of an increased risk of these tumor types in mutation carriers [3,4,5,6,7,8,9,10].

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