TY - JOUR

T1 - Frequent mismatch-repair defects link prostate cancer to Lynch syndrome

AU - Dominguez-Valentin, Mev

AU - Joost, Patrick

AU - Therkildsen, Christina

AU - Jonsson, Mats

AU - Rambech, Eva

AU - Nilbert, Mef Christina

PY - 2016/3/24

Y1 - 2016/3/24

N2 - BACKGROUND: 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.METHODS: We 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.RESULTS: In 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).CONCLUSION: We 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.

AB - BACKGROUND: 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.METHODS: We 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.RESULTS: In 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).CONCLUSION: We 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.

KW - Adaptor Proteins, Signal Transducing

KW - Adenocarcinoma

KW - Aged

KW - Aged, 80 and over

KW - Colorectal Neoplasms, Hereditary Nonpolyposis

KW - DNA Mismatch Repair

KW - DNA-Binding Proteins

KW - Denmark

KW - Germ-Line Mutation

KW - Humans

KW - Immunohistochemistry

KW - Male

KW - Microsatellite Instability

KW - Middle Aged

KW - MutL Protein Homolog 1

KW - MutS Homolog 2 Protein

KW - Mutation

KW - Nuclear Proteins

KW - Prostatic Neoplasms

KW - Registries

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1186/s12894-016-0130-1

DO - 10.1186/s12894-016-0130-1

M3 - Journal article

C2 - 27013479

VL - 16

SP - 1

EP - 7

JO - BMC Urology

JF - BMC Urology

SN - 1471-2490

IS - 15

M1 - 15

ER -