Increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population.
Adult
Black or African American
/ genetics
BRCA1 Protein
/ genetics
BRCA2 Protein
/ genetics
Case-Control Studies
DNA Mutational Analysis
Disease Progression
Follow-Up Studies
Germ-Line Mutation
Humans
Male
Middle Aged
Neoplasm Grading
Neoplasm Recurrence, Local
/ genetics
Neoplasm Staging
Prostate
/ pathology
Prostatectomy
Prostatic Neoplasms
/ genetics
Time Factors
White People
/ genetics
Journal
Prostate cancer and prostatic diseases
ISSN: 1476-5608
Titre abrégé: Prostate Cancer Prostatic Dis
Pays: England
ID NLM: 9815755
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
11
07
2018
accepted:
12
09
2018
revised:
17
08
2018
pubmed:
14
12
2018
medline:
3
4
2020
entrez:
14
12
2018
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 30542053
doi: 10.1038/s41391-018-0114-1
pii: 10.1038/s41391-018-0114-1
pmc: PMC6760554
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
BRCA2 Protein
0
BRCA2 protein, human
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
406-410Références
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