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

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.

Risk of Prostate Cancer in Lynch Syndrome: A Systematic Review and Meta-analysis

“…Of the six molecular studies, two were single case reports (16,17) and four were case series (18)(19)(20)(21) in which prostate cancer tumors of MMR gene mutation carriers were analyzed for MMR deficiency by MSI and/or immunohistochemistry (Table 1). When all case series were combined, 32 of 44 (73%, 95% CI, 57%-85%) prostate cancers in mutation carriers were MMR deficient.…”

“…Except for the study of Rosty and colleagues (20), most studies have been underpowered to observe any differences in prostate cancer risk by specific MMR gene mutations. Large cohorts will be required to measure separate prostate cancer risks for specific MMR gene mutation carriers.…”

“…Both cases were male and had prior cancers. Four studies did provide both MSI/IHC phenotype and MMR mutation genotype (18)(19)(20)(21). Overall, 73% of prostate cancers observed in MMR gene mutation carriers were MMR deficient, and absence of MMR protein expression was completely concordant with that of the underlying germline mutation in all cases.…”

“…Overall, 73% of prostate cancers observed in MMR gene mutation carriers were MMR deficient, and absence of MMR protein expression was completely concordant with that of the underlying germline mutation in all cases. Furthermore, the largest case series (20) showed that tumors from MSH2 mutation carriers had a higher proportion of MMR deficiency (83%, 95% CI, 61%-95%) compared with MLH1 (40%, 95% CI, 5%-85%) and MSH6 (25%, 95% CI, 1%-81%) mutation carriers (P ¼ 0.01). They also observed that MMR-deficient prostate cancer tumors had increased levels of tumor-infiltrating lymphocytes compared with MMR-proficient tumors, which is commonly observed in other Lynch syndrome tumors (45,46).…”

“…The majority of this evidence is from studies of prostate cancers in men known or suspected to be carriers of an MMR gene mutation, in which they have shown absence of MMR protein expression in prostate tumors by immunohistochemical (IHC) analysis, and the presence of a substantial change (contractions or expansions) in the length of short repetitive DNA sequences in tumor compared with normal tissue (microsatellite instability; MSI) in prostate tumors by PCR-based analysis (16)(17)(18)(19)(20)(21). However, because the proportion of prostate tumors exhibiting MMR deficiency is inconsistent across studies, and MMR deficiency alone does not constitute proof that the tumor was caused by the germline mutation, MMR germline mutation testing in men diagnosed with prostate cancer is not currently recommended.…”