A cohort analysis of men with a family history of BRCA1/2 and Lynch mutations for prostate cancer

Abstract

BackgroundProstate cancer (PC) is a major health concern for men worldwide, with an estimated lifetime risk of ~14 %. A recent comprehensive analysis of mutational processes revealed ageing and mismatch repair as the only altered processes in PC. We wish to test if a cohort of men with inherited risk of mismatch repair defect through BRCA1/2 or Lynch Syndrome mutations represents a target population for prostate cancer testing.MethodsFifty-eight men (aged 40–69 years) from families with a history of BRCA1/2 or HNPCC/Lynch mutations were invited to take part. Men with PSA >3.0 ng/ml were recommended to have transrectal ultrasound-guided prostatic biopsies.ResultsOverall 1 of 7 (14 %) and 1 of 20 (5 %) men with BRCA1/2 mutations were positive for a diagnosis of prostate cancer. In men with Lynch syndrome, 1 of 4 (25 %) was diagnosed to have prostate cancer. The index case with Lynch syndrome harbours a heterozygous mutation in the mismatch repair MSH6 gene. Near to complete loss of MSH6 immunoreactivity in the prostate tumour supports silencing of the remaining MSH6 allele during prostate carcinogenesis.ConclusionThe finding of near-to-complete loss of MSH6 expression in affected men with a family history of Lynch Syndrome supports its mechanistic involvement during prostate carcinogenesis. This work therefore contributes to the argument that, in certain male populations, Lynch Syndrome mutations are biologically implicated in men with prostate cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2573-x) contains supplementary material, which is available to authorized users.

Sigmoid Colon Adenocarcinoma with Isolated Loss of PMS2 Presenting in a Patient with Synchronous Prostate Cancer with Intact MMR: Diagnosis and Analysis of the Family Pedigree

“…The index case with Lynch syndrome harbors a heterozygous mutation in the mismatch repair MSH6 gene. Near to complete loss of MSH6 immunoreactivity in the prostate cancer supports silencing of the remaining MSH6 allele during prostate carcinogenesis (12). In our case, MSH6 immunoreactivity was intact.…”

“…Prostate cancer present in Lynch patients is not commonly reported (11). However, a recent study by Kerr et al showed that in men with Lynch syndrome, 1 of 4 (25%) was diagnosed to have prostate cancer (12). The index case with Lynch syndrome harbors a heterozygous mutation in the mismatch repair MSH6 gene.…”

Recent Insights on Genetic Testing in Primary Prostate Cancer

“…One of four such patients was diagnosed with a GS 6 PCa and underwent radical prostatectomy. Genetic testing confirmed a family mutation of the MSH6 gene [ 29 ].…”

“…We identified three relevant studies on this topic, which we now discuss in detail. Kerr et al [29] performed a subcohort analysis of the IMPACT trial that included mainly patients with a FH of LS. One of four such patients was diagnosed with a GS 6 PCa and underwent radical prostatectomy.…”

“…Subsequently, a subset analysis of 47 men with an FH of BRCA1/2 mutations was published and showed that one in seven (14%) BRCA1 and one in 20 (5%) BRCA2 mutation carriers were diagnosed with PCa [29]. Interestingly, no single case of PCa was found among the non-carrier patients who underwent biopsy (no BRCA1/2) [29]. Recently, the interim data of the large IMPACT study in 3027 patients with verified BRCA1/2 mutations and nonmutation carriers (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, 497 BRCA2 non-carriers) who underwent PSA screening over 3 years was published [32].…”