Increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population

Abstract

Background:Germline mutations in BRCA2 have been linked to a higher risk of prostate cancer (PCa), and high frequency of BRCA1 and BRCA2 (BRCA1/2) gene alterations was recently reported in metastatic castration-resistant PCa specimens. Mutations in BRCA2 vary in racial and ethnic groups including African-American (AA) and Caucasian-American (CA) populations.Methods:BRCA1 and BRCA2 genes were sequenced (Ion AmpliSeq targeted sequencing) in archived blood DNA specimens in 1240 PCa patients, including 30% AA patients, in three different cohorts: localized early stage (T2) PCa (N = 935); advanced PCa (50% T3–4) (N = 189); and metastatic PCa (N = 116). The sequences were analyzed for known and novel mutations in BRCA1/2. Statistical analyses were performed to determine associations of the mutations with clinico-pathological parameters.Results:BRCA2 mutations with known pathogenic annotation were significantly more prevalent in men with advanced and metastatic PCa (3.1%) compared to patients with an organ-confined disease (0.7%). AA patients carried more frequently BRCA1/2 variants of unknown significance (VUS) when compared to Caucasian Americans (4.6 vs. 1.6%, respectively). Significantly, pathogenic BRCA2 mutations in men with localized early stage PCa increased the risk of distant metastasis.Conclusions:Germline variants of unknown significance in BRCA1/2 are more frequent in AA than CA PCa patients; however, the prevalence of pathogenic mutations were similar across the races. Patients carrying BRCA2 pathogenic mutations are more likely to progress to metastasis.

Role of the DNA damage response in prostate cancer formation, progression and treatment

“…Loss-of-function DDR gene mutations can contribute to a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis [5, [49][50][51]. This aggressive phenotype was also reported in patients harboring BRCA1/2 and ATM combined mutations [52] and NBS1 mutations alone [6].…”

Genetisch onderzoek bij prostaatkanker: nieuwe ontwikkelingen

“…Na deze studie van Pritchard et al zijn meerdere studies gepubliceerd met resultaten van onderzoek naar kiembaanmutaties bij patiënten met gemetastaseerde prostaatkanker (tab. 1; [8][9][10][11]). In deze studies is bij grote groepen patiënten een wisselend aantal genen onderzocht, variërend van alleen het BRCA1en BRCA2-gen [10] tot 28 [9], 30 [11] of 76 verschillende kankerpredispositiegenen [8].…”

“…1; [8][9][10][11]). In deze studies is bij grote groepen patiënten een wisselend aantal genen onderzocht, variërend van alleen het BRCA1en BRCA2-gen [10] tot 28 [9], 30 [11] of 76 verschillende kankerpredispositiegenen [8]. De mutatiedetectie varieert van 3,1% [10] (alleen onderzoek BRCA1en BRCA2-gen) tot 19% [8] indien ook andere kankerpredispositiegenen worden onderzocht.…”

“…In deze studies is bij grote groepen patiënten een wisselend aantal genen onderzocht, variërend van alleen het BRCA1en BRCA2-gen [10] tot 28 [9], 30 [11] of 76 verschillende kankerpredispositiegenen [8]. De mutatiedetectie varieert van 3,1% [10] (alleen onderzoek BRCA1en BRCA2-gen) tot 19% [8] indien ook andere kankerpredispositiegenen worden onderzocht. Verreweg de meeste mutaties worden gevonden in het BRCA2gen, gevolgd door het ATM-gen en het CHEK2-gen. Er lijkt geen relatie te zijn met de familieanamnese (voor prostaatkanker, of andere vormen van kanker) of leeftijd [11].…”

Single Nucleotide Polymorphisms Associated With Prostate Cancer Development in Saudi Males

“…No single gene is responsible for PC, but some studies have demonstrated that BRCA1 and BRCA2 mutations, which are associated with ovarian and breast cancers in women, are also risk factors for PC. Men with positive BRCA2 mutations are vefold more likely to have PC than negative individuals (10,11). A group of studies have demonstrated that single nucleotide polymorphisms (SNPs) are risk factors for PC (12)(13)(14)(15).…”