Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland

Abstract

In designing national strategies for genetic testing, it is important to define the full spectrum of pathogenic mutations in prostate cancer (PCa) susceptibility genes. To investigate the frequency of mutations in PCa susceptibility genes in Polish familial PCa cases and to estimate gene-related PCa risks and probability of aggressive disease, we analyzed the coding regions of 14 genes by exome sequencing in 390 men with familial prostate cancer and 308 cancer-free controls. We compared the mutation frequencies between PCa cases and controls. We also compared clinical characteristics of prostate cancers between mutation carriers and noncarriers. Of the 390 PCa cases, 76 men (19.5%) carried a mutation in BRCA1, BRCA2, NBN, ATM, CHEK2, HOXB13, MSH2 or MSH6 genes. No mutations were found in BRIP1, PTEN, TP53, MLH1, PMS2 and SPOP. Significant associations with familial PCa risk were observed for CHEK2, NBN, ATM, and HOXB13. High-grade (Gleason 8-10) tumors

A Case-Based Clinical Approach to the Investigation, Management and Screening of Families with BRCA2 Related Prostate Cancer

“…When compared with non-BRCA2 carriers, BRCA2 carriers had a significantly higher PPV of PSA >3.0 ng/mL (31% vs 18%; p=0.025), a higher PC incidence rate per 1000 person years (19.4 vs 12.0; p=0.03), a significantly higher frequency of intermediate-high risk PC (p=0.011) and were significantly younger at the time of PC diagnosis (p=0.044), with the youngest age of onset being recorded in a 41-year-old BRCA2 carrier. Overall, the results so far from the ongoing IMPACT study further substantiate the earlier age of onset and more aggressive PC phenotype seen in BRCA2 carriers which has been widely reported throughout the literature, 11,[31][32][33][34]36,87 and also highlights the efficacy of using PSA testing in this patient subgroup.…”

“…In addition, a higher proportion of BRCA2+ve tumours have T3/T4 staging (41% (BRCA2+ve) vs 29% (BRCA2-ve), (p<0.001)) and higher rates of metastatic disease at diagnosis (26% (BRCA2+ve) vs 8% (BRCA2-ve), (p<0.001)). A study by Wokołorczyk et al 32 found that PC with Gleason scores >8 were more likely in men carrying germline BRCA2 variants than in non-carriers (75% (BRCA2+ve) vs 22% (BRCA2-ve), (p<0.05)). This group stipulated that BRCA2 carriers had a lower mean age than non- BRCA2 carriers at the time of their PC diagnosis (57 years (BRCA2+ve) vs 61 years (BRCA2-ve), p=0.3).…”

BRCA1 and BRCA2 pathogenic variants and prostate cancer risk: systematic review and meta-analysis

“…Controls: patients with non-prostate cancers from the same biobank. Not stated Not stated Covariate adjustment for age and genetic ancestry BRCA1 Any pathogenic variant 3/409 (0.73%) Not stated (total: 7711 non-PCa patients) 2.20 (0.62–7.83) Wokolorczyk [ 25 ] Poland 2000–2017 Cases vs controls from the same population Cases: men with PCa who had a family history of PCa in first- or second-degree relatives (three or more relatives with PCa, or two affected relatives of whom at least one was diagnosed before age 60). Controls: participants in an unrelated population-based study.…”

“…One case–control study included only cases with a family history of PCa and an unselected control group, and did not adjust for this family history-based ascertainment [ 25 ]. This is likely to lead to higher RR estimates compared to RRs based on case–control studies of unselected cases, because of likely enrichment of PCa PVs in subjects from PCa families.…”

Identification of miRNA-Mediated Subpathways as Prostate Cancer Biomarkers Based on Topological Inference in a Machine Learning Process Using Integrated Gene and miRNA Expression Data

“…The ATM-CHEK2-p53 axis acts as a backbone for the DNA damage response (DDR) and is hypothesized to act as a barrier to cancer initiation (Stolarova et al, 2020). Significant associations with familial prostate cancer risk have been reported for both CHEK2 and ATM (Wokolorczyk et al, 2020).…”