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

The IMPACT study is a large-scale study looking at the relative risk of men with a history of hereditary BRCA mutations in developing prostate cancer at a population level. This report case cohort contributes to the overall IMPACT study cases. However, none of the prostate cancer identified within the IMPACT study would have undergone investigations to test if the mutated gene was in fact functionally altered in relation to the development of prostate cancer. In our report, we carried out molecular investigation to confirm the presence of mutations in the affected individuals as well as characterised the expression levels of the implicated gene (MSH6). We found that there was evidence of loss of expression for this mismatch repair gene for Lynch Syndrome at the protein level, which provides indirect mechanistic evidence to support the presence of molecular event that results in the lost of gene expression at protein level, in addition to the presence of an inherited mutation in the mismatch repair enzyme gene. A single mutation in a heterozygous manner would not typically affect the gene expression as drastic as what we have observed. In addition, within the recent published IMPACT series [7], patients with a history of Lynch Syndrome were not included for analysis. Hence, it remains highly debated whether men affected by Lynch Syndrome are at risk of developing prostate cancer. Our report, albeit small, contributes to the literature in this field. Important publications arguing for an increased risk for prostate cancer with Lynch Syndrome are appropriately cited in our report.

Besides changes in genetic profile associated with ageing, a recent comprehensive analysis of mutational processes in human cancer has revealed mismatch repair mutations to be the only genetic signature implicated in PC [8]. Among the mismatch match repair (MMR) genes, defects within the MSH2 and MSH6 genes have been previously reported in patients with PC [9]. In a prospective unbiased analysis of a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, MSH2, MSH6, and PMS2) and 1029 of their unaffected relatives, as part of a Colon Cancer Family Registry, MMR gene mutation was found to confer increased cancer risks in a number of tumour types recognised to be associated with Lynch Syndrome (colorectal, endometrial, ovarian, renal, gastric, and urinary bladder), breast cancer and pancreatic cancer [10]. Importantly, the non-carrier relatives of family-specific MMR gene mutations did not have increased risks of colorectal or other cancers, including PC. Bratt et al. identified a two fold increased risk of PC associated with MSH2 mutation [11]. MMR mutation carriers were found to be nearly 6 times more likely to develop PC [12]: PC occurred at an earlier age than expected (60.4 years compared with 66.6 years) and tumours were significantly more aggressive (Gleason 8–10).

BRCA1 and BRCA2 are implicated in homologous-recombination based DNA double-strand break repair. BRCA1 is also implicated in mismatch repair, interacting with the DNA mismatch repair protein MSH2 [13, 14]. In addition to the genomic structural instability conferred by defective double-strand break repair, a base substitution mutational signature in keeping with microsatellite instability, was also associated with BRCA1/2 deficiency [8].

The cumulative lifetime risk of PC among carriers with mutations in MMR-related genes has been suggested to be as high as 30 %, compared with ~18 % in the general population [9]. Our patient cohort is included in the recently published data on the initial screening round of the IMPACT [15] (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls; www.impact-study.co.uk) Study, supporting the notion that men with BRCA1/2 gene mutations are at increased risk of developing PC. Overall, from the 2481 recruited men within the IMPACT study [15], 199 men had PSA 3.0 ng/ml, and 162 men underwent prostatic biopsies. Among biopsied patients, 59 (or 36 % of) men were found to have PC. Similarly, in our cohort, 3 of 7 (or 43 %) have positive biopsies for PC. While 66 % of the PC patients within the overall IMPACT study have intermediate- or high-risk disease, all three patients with PC have relatively low-risk (Gleason 6) disease at diagnosis, although the single patient undergoing prostatectomy was found to have his disease upgraded to Gleason 7 tumour. This data contrast a recent report suggesting that BRCA mutations were associated with less favouable outcome following radical treatment [7].

Our study supports the notion that men with a family history of BRCA1/2 or Lynch Syndrome mutations may benefit from testing for PC, highlighting the role of MMR in prostate carcinogenesis. Specifically, our patient with documented MSH6 mutation and associated loss of its expression involves a less commonly implicated member of the MMR genes [16].