Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene.
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ABSTRACT:
SUBMITTER: Edwards SM
PROVIDER: S-EPMC420008 | biostudies-literature | 2003 Jan
REPOSITORIES: biostudies-literature
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Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene.
Edwards Stephen M SM Kote-Jarai Zsofia Z Meitz Julia J Hamoudi Rifat R Hope Questa Q Osin Peter P Jackson Rachel R Southgate Christine C Singh Rashmi R Falconer Alison A Dearnaley David P DP Ardern-Jones Audrey A Murkin Annette A Dowe Anna A Kelly Jo J Williams Sue S Oram Richard R Stevens Margaret M Teare Dawn M DM Ponder Bruce A J BA Gayther Simon A SA Easton Doug F DF Eeles Rosalind A RA
American journal of human genetics 20021209 1
Studies of families with breast cancer have indicated that male carriers of BRCA2 mutations are at increased risk of prostate cancer, particularly at an early age. To evaluate the contribution of BRCA2 mutations to early-onset prostate cancer, we screened the complete coding sequence of BRCA2 for germline mutations, in 263 men with diagnoses of prostate cancer who were </=55 years of age. Protein-truncating mutations were found in six men (2.3%; 95% confidence interval 0.8%-5.0%), and all of the ...[more]
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Project description:BACKGROUND:African Americans have both a higher incidence of prostate cancer and greater disease-specific mortality compared with non-Hispanic whites. Historically, the investigation of the contribution of rare genetic variants to prostate cancer in African American men has been hampered by low participation in large genetic studies, particularly those focused on early-onset and familial disease. METHODS:We sequenced 160 genes purported to be involved in carcinogenic pathways in germline DNA samples collected from 96 African American men diagnosed with early-onset prostate cancer (?55 years at diagnosis). REVEL software was used to determine the pathogenic potential of observed missense variants. RESULTS:We observed three protein-truncating mutations, one in BRCA2 and two in BRIP1 in three African American men diagnosed with early-onset prostate cancer. Furthermore, we observed five rare, mostly private, missense variants among four genes (BRCA1, BRCA2, PMS2, and ATM) that were predicted to be deleterious and hence likely pathogenic in our patient sample. CONCLUSIONS:Protein-truncating mutations in BRCA2 and BRIP1 were discovered in African American men diagnosed with early-onset prostate cancer. Further study is necessary to determine the role of rare, missense variants to prostate cancer incidence, and progression in this group of high-risk men.
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Project description:Objective To investigate the inherited mutations and their association with clinical features and treatment response in young-onset prostate cancer patients. Method Targeted gene sequencing on 139 tumor susceptibility genes was conducted with a total of 24 patients diagnosed with PCa under the age of 63 years old. Meanwhile, the related clinical information of those patients is collected and analyzed. Results Sixty-two germline mutations in 45 genes were verified in 22 patients. BRCA2 (20.8%) and GJB2 (20.8%) were found to be the most frequently mutated, followed by CHEK2, BRCA1, PALB2, CDKN2A, HOXB13, PPM1D, and RECQL (8.3% of each, 2/24). Of note, 58.3% (14/24) patients carry germline mutations in DNA repair genes (DRGs). Four families with HRR (homologous recombination repair)-related gene mutations were described and analyzed in detail. Two patients with BRCA2 mutation responded well to the combined treatment of androgen deprivation therapy (ADT) and radiotherapy/chemotherapy. Conclusion Mutations in DRGs are more prevalent in early-onset PCa with advanced clinical stages, and these patients had shorter progression-free survival. ADT Combined with either radiotherapy or chemotherapy may be effective in treating PCa caused by HRR-related gene mutations.
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Project description:Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.
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Project description:BackgroundAmong men with metastatic prostate cancer, about 10% have germline alterations in DNA damage response genes. Most studies have examined BRCA2 alone or an aggregate of BRCA1/2 and ATM. Emerging data suggest that ATM mutations may have distinct biology and warrant individual evaluation. The objective of this study is to determine whether response to prostate cancer systemic therapies differs between men with germline mutations in ATM (gATM) and BRCA2 (gBRCA2).MethodsThis is an international multicenter retrospective matched cohort study of men with prostate cancer harboring gATM or gBRCA2. PSA50 response (≥50% decline in prostate-specific antigen) was compared using Fisher's exact test.Results and limitationsThe study included 45 gATM and 45 gBRCA2 patients, matched on stage and year of germline testing. Patients with gATM and gBRCA2 had similar age, Gleason grade, and PSA at diagnosis. We did not observe differences in PSA50 responses to abiraterone, enzalutamide, or docetaxel in metastatic castration resistant prostate cancer between the two groups; however, 0/7 with gATM and 12/14 with gBRCA2 achieved PSA50 response to PARPi (p < .001). Median (95% confidence interval) overall survival from diagnosis to death was 10.9 years (9.5-not reached) versus 9.9 years (7.1-not reached, p = .07) for the gATM and gBRCA2 cohorts, respectively. Limitations include the retrospective design and lack of mutation zygosity data.ConclusionsConventional therapies can be effective in gATM carriers and should be considered before PARPi, which shows limited efficacy in this group. Men with gATM mutations warrant prioritization for novel treatment strategies.
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Project description:BACKGROUND:Families with a high incidence of hereditary breast cancer, and subsequently shown to have terminating mutations in BRCA1 or BRCA2, appear to have a higher incidence of prostate cancer among male relatives. We aimed to determine whether the common germline mutations of BRCA1 or BRCA2 in Ashkenazi Jewish men predisposed them to prostate cancer. METHODS:We examined genomic DNA from 83 (for BRCA1 185delAG) or 82 (for BRCA2 6174delT) Ashkenazi Jewish prostate cancer patients, most of whom were treated at a relatively young age, for the most common germline mutation in each gene seen in the Ashkenazi population. RESULTS:Our study should have been able to detect a 4-5-fold increase in the risk of prostate cancer due to mutation of BRCA1 or BRCA2. However, only one (1.15%; 95% confidence interval, 0-3.6%) of the patients was heterozygous for the BRCA1 mutant allele, and only two were heterozygous for the BRCA2 mutation (2.4%; 95% confidence interval, 0-6.2%). CONCLUSIONS:The incidence of each of the germline mutations in these prostate cancer patients closely matched their incidence (about 1%) in the general Ashkenazi Jewish population. This suggests that unlike cases of breast and ovarian cancers, mutations in BRCA1 or BRCA2 do not significantly predispose men to prostate cancer.
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Project description:Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.
2017-01-10 | GSE80685 | GEO
Project description:BackgroundPathogenic germline mutations in the BRCA1 and BRCA2 (BRCA1/2) genes contribute to hereditary breast/ovarian cancer (OC) in White/mestizo Colombian women. As there is virtually no genetic data on breast cancer (BC) in Colombians of African descent, we conducted a comprehensive BRCA1/2 mutational analysis of 60 Afro-Colombian families affected by breast/OC.Materials and methodsMutation screening of the complete BRCA1/2 genes for small-scale mutations and large genomic alterations was performed in these families using next-generation sequencing and multiplex ligation-dependent probe amplification analysis.ResultsFour pathogenic germline mutations, including one novel mutation, were identified, comprising 3 in BRCA1 and one in BRCA2. The prevalence of BRCA1/2 mutations, including one BRCA1 founder mutation (c.5123C>A) previously identified in this sample set, was 3.9% (2/51) in female BC-affected families and 33.3% (3/9) in those affected by both breast and OC. Haplotype analysis of 2 BRCA2_c.2701delC carriers (one Afro-Colombian and one previously identified White/mestizo Colombian patient with BC) suggested that the mutation arose in a common ancestor.ConclusionOur data showed that 2/5 (40%) mutations (including the one previously identified in this sample set) are shared by White/mestizo Colombian and Afro-Colombian populations. This suggests that these 2 populations are closely related. Nevertheless, variations in the BRCA1/2 mutational spectrum among Afro-Colombian subgroups from different regions of the country were observed, suggesting that specific genetic risk assessment strategies need to be developed.
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