Dataset Information

Prostate Cancer Risk by BRCA2 Genomic Regions.

ABSTRACT: A BRCA2 prostate cancer cluster region (PCCR) was recently proposed (c.7914 to 3') wherein pathogenic variants (PVs) are associated with higher prostate cancer (PCa) risk than PVs elsewhere in the BRCA2 gene. Using a prospective cohort study of 447 male BRCA2 PV carriers recruited in the UK and Ireland from 1998 to 2016, we estimated standardised incidence ratios (SIRs) compared with population incidences and assessed variation in risk by PV location. Carriers of PVs in the PCCR had a PCa SIR of 8.33 (95% confidence interval [CI] 4.46-15.6) and were at a higher risk of PCa than carriers of other BRCA2 PVs (SIR?=?3.31, 95% CI 1.97-5.57; hazard ratio?=?2.34, 95% CI 1.09-5.03). PCCR PV carriers had an estimated cumulative PCa risk of 44% (95% CI 23-72%) by the age of 75?yr and 78% (95% CI 54-94%) by the age of 85?yr. Our results corroborate the existence of a PCCR in BRCA2 in a prospective cohort. PATIENT SUMMARY: In this report, we investigated whether the risk of prostate cancer for men with a harmful mutation in the BRCA2 gene differs based on where in the gene the mutation is located. We found that men with mutations in one region of BRCA2 had a higher risk of prostate cancer than men with mutations elsewhere in the gene.

SUBMITTER: Nyberg T

PROVIDER: S-EPMC7532700 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Prostate Cancer Risk by BRCA2 Genomic Regions.

Nyberg Tommy T Frost Debra D Barrowdale Daniel D Evans D Gareth DG Bancroft Elizabeth E Adlard Julian J Ahmed Munaza M Barwell Julian J Brady Angela F AF Brewer Carole C Cook Jackie J Davidson Rosemarie R Donaldson Alan A Eason Jacqueline J Gregory Helen H Henderson Alex A Izatt Louise L Kennedy M John MJ Miller Claire C Morrison Patrick J PJ Murray Alex A Ong Kai-Ren KR Porteous Mary M Pottinger Caroline C Rogers Mark T MT Side Lucy L Snape Katie K Tripathi Vishakha V Walker Lisa L Tischkowitz Marc M Eeles Rosalind R Easton Douglas F DF Antoniou Antonis C AC

European urology 20200610 4

A BRCA2 prostate cancer cluster region (PCCR) was recently proposed (c.7914 to 3') wherein pathogenic variants (PVs) are associated with higher prostate cancer (PCa) risk than PVs elsewhere in the BRCA2 gene. Using a prospective cohort study of 447 male BRCA2 PV carriers recruited in the UK and Ireland from 1998 to 2016, we estimated standardised incidence ratios (SIRs) compared with population incidences and assessed variation in risk by PV location. Carriers of PVs in the PCCR had a PCa SIR of ...[more]

PMID: 32532514

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Project description:BackgroundUltraconserved regions (UCR) are genomic segments of more than 200 base pairs that are evolutionarily conserved among mammalian species. They are thought to have functions as transcriptional enhancers and regulators of alternative splicing. Recently, it was shown that numerous RNAs are transcribed from these regions. These UCR-encoded transcripts (ucRNAs) were found to be expressed in a tissue- and disease-specific manner and may interfere with the function of other RNAs through RNA: RNA interactions. We hypothesized that ucRNAs have unidentified roles in the pathogenesis of human prostate cancer. In a pilot study, we examined ucRNA expression profiles in human prostate tumors.MethodsUsing a custom microarray with 962 probesets representing sense and antisense sequences for the 481 human UCRs, we examined ucRNA expression in resected, fresh-frozen human prostate tissues (57 tumors, 7 non-cancerous prostate tissues) and in cultured prostate cancer cells treated with either epigenetic drugs (the hypomethylating agent, 5-Aza 2'deoxycytidine, and the histone deacetylase inhibitor, trichostatin A) or a synthetic androgen, R1881. Expression of selected ucRNAs was also assessed by qRT-PCR and NanoString®-based assays. Because ucRNAs may function as RNAs that target protein-coding genes through direct and inhibitory RNA: RNA interactions, computational analyses were applied to identify candidate ucRNA:mRNA binding pairs.ResultsWe observed altered ucRNA expression in prostate cancer (e.g., uc.106+, uc.477+, uc.363 + A, uc.454 + A) and found that these ucRNAs were associated with cancer development, Gleason score, and extraprostatic extension after controlling for false discovery (false discovery rate < 5% for many of the transcripts). We also identified several ucRNAs that were responsive to treatment with either epigenetic drugs or androgen (R1881). For example, experiments with LNCaP human prostate cancer cells showed that uc.287+ is induced by R1881 (P < 0.05) whereas uc.283 + A was up-regulated following treatment with combined 5-Aza 2'deoxycytidine and trichostatin A (P < 0.05). Additional computational analyses predicted RNA loop-loop interactions of 302 different sense and antisense ucRNAs with 1058 different mRNAs, inferring possible functions of ucRNAs via direct interactions with mRNAs.ConclusionsThis first study of ucRNA expression in human prostate cancer indicates an altered transcript expression in the disease.

Project description:BackgroundDespite the historic association of higher prostate cancer volume with worse oncologic outcomes, little is known about the impact of tumor volume on cancer biology.ObjectiveTo characterize the relationship between tumor volume (measured by percent positive cores [PPC]) and cancer biology (measured by Decipher genomic risk classifier [GC]) in men who underwent prostate biopsy.Design setting and participantsProstate biopsies from 52 272 men profiled with Decipher captured in a population-based prospective tumor registry were collected from 2016 to 2021.Outcome measurements and statistical analysisThe degree of distribution and correlation of PPC with a GC score across grade group (GG) strata were examined using the Mann-Whitney U test, Pearson correlation coefficient, and multivariable linear regression controlled for clinicopathologic characteristics.Results and limitationsA total of 38 921 (74%) biopsies passed quality control (14 331 GG1, 16 159 GG2, 5661 GG3, 1775 GG4, and 995 GG5). Median PPC and GC increased with sequentially higher GG. There was an increasingly positive correlation (r) between PPC and GC in GG2-5 prostate cancer (r [95% confidence interval {CI}]: 0.07 [0.5, 0.8] in GG2, 0.15 [0.12, 0.17] in GG3, 0.20 [0.15, 0.24] in GG4, and 0.25 [0.19, 0.31] in GG5), with no correlation in GG1 disease (r = 0.01, 95% CI [-0.001, 0.03]). In multivariable linear regression, GC was significantly associated with higher PPC for GG2-5 (all p < 0.05) but was not significantly associated with PPC for GG1. Limitations include retrospective design and a lack of final pathology from radical prostatectomy specimens.ConclusionsHigher tumor volume was associated with worse GC for GG2-5 prostate cancer, whereas tumor volume was not associated with worse GC for GG1 disease. The finding that tumor volume is not associated with worse cancer biology in GG1 disease encourages active surveillance for most patients irrespective of tumor volume.Patient summaryWe studied the relationship between prostate cancer tumor volume and cancer biology, as measured by the Decipher genomic risk score, in men who underwent prostate biopsy. We found that tumor volume was not associated with worse cancer biology for low-grade prostate cancer. Our findings reassuringly support recent guidelines to recommend active surveillance for grade group 1 prostate cancer in most patients, irrespective of tumor volume.

Dataset Information

Prostate Cancer Risk by BRCA2 Genomic Regions.

Publications

Prostate Cancer Risk by BRCA2 Genomic Regions.

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