scholarly journals Recent advances in prostate cancer research: large-scale genomic analyses reveal novel driver mutations and DNA repair defects

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1173 ◽  
Author(s):  
Sander Frank ◽  
Peter Nelson ◽  
Valeri Vasioukhin
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Immune Modulation ◽  
Large Scale ◽  
Genetic Alterations ◽  
Driver Mutations ◽  
Prostate Tumors ◽  
Structural Genomic ◽  
Primary Tumors ◽  
Recent Advances

Prostate cancer (PCa) is a disease of mutated and misregulated genes. However, primary prostate tumors have relatively few mutations, and only three genes (ERG, PTEN, and SPOP) are recurrently mutated in more than 10% of primary tumors. On the other hand, metastatic castration-resistant tumors have more mutations, but, with the exception of the androgen receptor gene (AR), no single gene is altered in more than half of tumors. Structural genomic rearrangements are common, including ERG fusions, copy gains involving the MYC locus, and copy losses containing PTEN. Overall, instead of being associated with a single dominant driver event, prostate tumors display various combinations of modifications in oncogenes and tumor suppressors. This review takes a broad look at the recent advances in PCa research, including understanding the genetic alterations that drive the disease and how specific mutations can sensitize tumors to potential therapies. We begin with an overview of the genomic landscape of primary and metastatic PCa, enabled by recent large-scale sequencing efforts. Advances in three-dimensional cell culture techniques and mouse models for PCa are also discussed, and particular emphasis is placed on the benefits of patient-derived xenograft models. We also review research into understanding how ETS fusions (in particular, TMPRSS2-ERG) and SPOP mutations contribute to tumor initiation. Next, we examine the recent findings on the prevalence of germline DNA repair mutations in about 12% of patients with metastatic disease and their potential benefit from the use of poly(ADP-ribose) polymerase (PARP) inhibitors and immune modulation. Lastly, we discuss the recent increased prevalence of AR-negative tumors (neuroendocrine and double-negative) and the current state of immunotherapy in PCa. AR remains the primary clinical target for PCa therapies; however, it does not act alone, and better understanding of supporting mutations may help guide the development of novel therapeutic strategies.

scholarly journals Prospective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors

2019 ◽  
pp. 1-23 ◽  
Author(s):  
Jon H. Chung ◽  
Ninad Dewal ◽  
Ethan Sokol ◽  
Paul Mathew ◽  
Robert Whitehead ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Homologous Recombination Repair ◽  
Genomic Profiling ◽  
Prostate Tumors ◽  
Primary Tumors ◽  
Metastatic Site ◽  
Recombination Repair ◽  
Comprehensive Genomic Profiling

PURPOSE Comprehensive genomic profiling (CGP) is increasingly used for routine clinical management of prostate cancer. To inform targeted treatment strategies, 3,476 clinically advanced prostate tumors were analyzed by CGP for genomic alterations (GAs) and signatures of genomic instability. METHODS Prostate cancer samples (1,660 primary site and 1,816 metastatic site tumors from unmatched patients) were prospectively analyzed by CGP (FoundationOne Assay; Foundation Medicine, Cambridge, MA) for GAs and genomic signatures (genome-wide loss of heterozygosity [gLOH], microsatellite instability [MSI] status, tumor mutational burden [TMB]). RESULTS Frequently altered genes were TP53 (44%), PTEN (32%), TMPRSS2-ERG (31%), and AR (23%). Potentially targetable GAs were frequently identified in DNA repair, phosphatidylinositol 3-kinase, and RAS/RAF/MEK pathways. DNA repair pathway GAs included homologous recombination repair (23%), Fanconi anemia (5%), CDK12 (6%), and mismatch repair (4%) GAs. BRCA1/2, ATR, and FANCA GAs were associated with high gLOH, whereas CDK12-altered tumors were infrequently gLOH high. Median TMB was low (2.6 mutations/Mb). A subset of cases (3%) had high TMB, of which 71% also had high MSI. Metastatic site tumors were enriched for the 11q13 amplicon ( CCND1/ FGF19/ FGF4/FGF3) and GAs in AR, LYN, MYC, NCOR1, PIK3CB, and RB1 compared with primary tumors. CONCLUSION Routine clinical CGP in the real-world setting identified GAs that are investigational biomarkers for targeted therapies in 57% of cases. gLOH and MSI/TMB signatures could further inform selection of poly (ADP-ribose) polymerase inhibitors and immunotherapies, respectively. Correlation of DNA repair GAs with gLOH identified genes associated with homologous recombination repair deficiency. GAs enriched in metastatic site tumors suggest therapeutic strategies for metastatic prostate cancer. Lack of clinical outcome correlation was a limitation of this study.

scholarly journals N-cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer

2010 ◽  
Vol 17 (2) ◽  
pp. 469-479 ◽  
Author(s):  
Karin Jennbacken ◽  
Tajana Tešan ◽  
Wanzhong Wang ◽  
Heléne Gustavsson ◽  
Jan-Erik Damber ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Neuroendocrine Differentiation ◽  
Hormonal Treatment ◽  
Androgen Deprivation ◽  
Prostate Tumors ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Molecular Alterations

Androgen-deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer. One factor that has been implicated in the metastatic process is the cell adhesion molecule N-cadherin. In this study, we investigated if the expression of N-cadherin was influenced by androgen deprivation and was associated with metastasis in prostate cancer. The effect of androgen deprivation on N-cadherin expression was initially studied in androgen-dependent (AD) LNCaP and androgen-independent (AI) LNCaP-19 and PC-3 prostate cancer cell lines. Expression of N-cadherin increased in the absence of androgens in AI LNCaP-19 primary tumors and metastases and also in vitro, but not in AI PC-3 tumors, indicating a possible involvement of the androgen receptor in the regulation of N-cadherin. N-cadherin was absent in AD LNCaP tumors. No clear associations between N-cadherin and factors related with epithelial–mesenchymal transition or neuroendocrine differentiation could be established. In addition, N-cadherin was evaluated by immunohistochemistry in human prostate tumors. Expression of N-cadherin was more frequently found in tumors from patients treated with ADT than in tumors from patients with no prior hormonal treatment. N-cadherin expression was also associated with metastasis and Gleason score. Furthermore, increased N-cadherin was detected in prostate cancer biopsies already 3 months after initiation of ADT when tumors were in a regressed state. In summary the results indicate that androgen deprivation induces N-cadherin in prostate tumors. Moreover, N-cadherin was increased in castration-resistant tumors in patients with established metastases. This might indicate that castration induces molecular alterations in the tumor cells, resulting in a more invasive and metastatic phenotype.

Copy number variations in AR-associated and DNA repair genes from plasma cell-free DNA of metastatic CRPC patients.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 281-281 ◽  
Author(s):  
Ratish Gambhira ◽  
Elisa M. Ledet ◽  
Aryeneesh Dotiwala ◽  
Diptasri Mandal ◽  
A. Oliver Sartor
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Cancer Progression ◽  
Copy Number ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Dna Repair Genes ◽  
Prostate Cancer Progression ◽  
Free Dna ◽  
Repair Genes

281 Background: Cell-free DNA (cfDNA) present in the plasma of advanced cancer patients can reflect tumor related genetic alterations. Recent data suggests copy number variations (CNVs) in AR-associated and DNA repair pathway genes play a potential role in prostate cancer progression. Here, we performed sequencing of cfDNA from 13 mCRPC patients to evaluate its potential in elucidating tumor related genetic variations. The long-term goal of our project is to correlate cfDNA derived genetic alterations with prostate cancer progression and/or therapeutic resistance/responses. Methods: cfDNA was isolated from 13 advanced mCRPC patient plasma samples using the Qiagen circulating nucleic acid kit. 100ng of cfDNA was utilized for library construction; and the libraries were paired-end sequenced on the Illumina HiSeq 2000. The resulting data was analyzed using the GATK best practices bioinformatics pipeline and the visualized using the SNP & Variation Suite v8.x. Results: The bioanalyzer profiles of cfDNA derived from mCRPC patients is highly fragmented with an average fragment size of 306-605bp. Although, several CNVs were found across the genome, we focused analysis on CNVs related to AR associated and DNA repair genes. Our preliminary analysis of cfDNA, despite low sequencing depth, shows full or partial amplifications in AR (13/13), and other genes including FOXA1, NCOR1, NCOR2 and/or PIK3CA (7/13) and NCOR2 (10/13). For DNA repair genes partial/full amplifications were present in BRAC1, BRAC2, ATM, CDK12, MLH1 and/or MSH2 (7/13). Deletions are less reliably detected in the highly fragmented cfDNA. The majority of these CNVs have been reported in the WGS studies from metastatic CRPC tissue derived genomic DNA (cBioPortal). We are currently validating cfDNA genomic alterations by comparing it to germ line DNA derived via qPCR. Conclusions: Our preliminary study indicates that AR and DNA repair related genetic alterations could be found in the cfDNA derived from metastatic CRPC patients. This warrants more detailed examination of these cfDNA genetic alterations for identifying clinically relevant issues in mCRPC patients.

CDK12 upregulation and adverse correlation with tumor-associated immune cell infiltrates in prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 181-181
Author(s):  
Marie C. Hupe ◽  
Anne Offermann ◽  
Cleopatra Schreiber ◽  
Axel Stuart Merseburger ◽  
Sven Perner
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Immune Cell ◽  
Locally Advanced ◽  
Survival Rates ◽  
Distant Metastases ◽  
Genetic Alterations ◽  
Primary Tumors ◽  
Locally Advanced Tumors ◽  
Advanced Tumors

181 Background: Biallelic loss of CDK12 has recently been identified as a novel subtype of prostate cancer (PCa). CDK12 altered PCa associates with elevated neoantigen burden and thus may be suitable for checkpoint inhibition. Up to now, data about CDK12 refer to its genetic alterations in PCa while its characterization on protein level and its association with tumor infiltrating T-cells are lacking. Methods: Immunohistochemistry (IHC) for CDK12 was performed on a PCa cohort including 74 benigns, 391 primary tumors from 222 patients, 63 locally advanced tumors, 92 lymph node (LN) metastases, and 56 distant metastases. CDK12 was categorized into negative, weak, moderate and high expression. Density of tumor associated T-cells per tumor area was assessed by IHC for CD3 and graduated into negative (<1%), slight (1-5%), weak (5-10%), moderate (10-50%) and high (>50%). Results: CDK12 significantly increases during PCa progression showing highest levels in LN and distant metastases while benign samples harbor no or weak CDK12 expression (ANOVA p<0.001). Kaplan-Meier curve reveals 5-year-biochemical recurrence free survival rates of 89.5%, 69.1%, 59.1% and 20.0% for primary tumors expressing no, weak, moderate and high CDK12 (log-rank p=0.05). High CDK12 expression significantly associates with attenuated tumor associated T-cells (p=0.009) revealing CD3 negativity in 64.7% of CDK12 high expressing tumors. Intratumoral CDK12 and density of CD3 positive T-cells correlates adversely in particular in locally advanced tumors (p=0.007). Overall, tumor associated T-cells are significantly reduced in distant metastases compared to local PCa (p<0.001). Conclusions: Our study highlights the prognostic potential of CDK12 for PCa and its overexpression in advanced tumors. Of note, CDK12 overexpressing tumors can be designated as immunologic “cold” tumors which is in line with their more aggressive phenotype. Concordantly, distant metastases show attenuated tumor associated T-cells supporting the poor response to immunotherapy.

scholarly journals The Genomic Landscape of Prostate Cancer Brain Metastases

2020 ◽  
Author(s):  
Antonio Rodriguez ◽  
John Gallon ◽  
Dilara Akhoundova ◽  
Sina Maletti ◽  
Alison Ferguson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Brain Metastases ◽  
Large Scale ◽  
Parp Inhibition ◽  
State Transitions ◽  
Primary Tumors ◽  
Available N ◽  
Cancer Metastases ◽  
Whole Exome ◽  
Significant Enrichment

AbstractLethal prostate cancer commonly metastasizes to bone, lymph nodes, and visceral organs but with more effective therapies, there is an increased frequency of metastases to the brain. Little is known about the genomic drivers of prostate cancer brain metastases (PCBM). To address this, we conducted a comprehensive multi-regional, genomic, and targeted transcriptomic analysis of PCBM from 28 patients. We compared whole-exome and targeted RNA sequencing with matched primary tumors when available (n = 10) and with publicly available genomic data from non-brain prostate cancer metastases (n = 416). In addition to common alterations in TP53, AR, RB1, and PTEN, we identified highly significant enrichment of mutations in NF1 (25% cases (6/28), q = 0.049, 95% CI = 2.38 – 26.52, OR = 8.37) and RICTOR (17.9% cases (5/28), q = 0.01, 95% CI = 6.74 – 480.15, OR = 43.7) in PCBM compared to non-brain prostate cancer metastases, suggesting possible activation of the druggable pathways RAS/RAF/MEK/ERK and PI3K/AKT/mTOR, respectively. Compared to non-brain prostate cancer metastases, PCBM were almost three times as likely to harbor DNA homologous repair (HR) alterations (42.9% cases (12/28), p =0.016, 95% CI = 1.17 – 6.64, OR = 2.8). When considering the combination of somatic mutations, copy number alteration, and Large-scale State Transitions, 64.3% of patients (18/28) were affected. HR alterations may be critical drivers of brain metastasis that potentially provide cancer cells a survival advantage during re-establishment in a special microenvironment. We demonstrate that PCBM have genomic dependencies that may be exploitable through clinical interventions including PARP inhibition.

scholarly journals Comprehensive characterization of distinct genetic alterations in metastatic breast cancer across various metastatic sites

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Soojin Cha ◽  
Esak Lee ◽  
Hong-Hee Won
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Large Scale ◽  
Metastatic Breast ◽  
Genetic Alterations ◽  
Driver Mutations ◽  
Site Specific ◽  
Metastatic Site ◽  
Treatment Naïve ◽  
Metastatic Sites

AbstractMetastasis is the major cause of death in breast cancer patients. Although previous large-scale analyses have identified frequently altered genes specific to metastatic breast cancer (MBC) compared with those in primary breast cancer (PBC), metastatic site-specific altered genes in MBC remain largely uncharacterized. Moreover, large-scale analyses are required owing to the low expected frequency of such alterations, likely caused by tumor heterogeneity and late dissemination of breast cancer. To clarify MBC-specific genetic alterations, we integrated publicly available clinical and mutation data of 261 genes, including MBC drivers, from 4268 MBC and 5217 PBC patients from eight different cohorts. We performed meta-analyses and logistic regression analyses to identify MBC-enriched genetic alterations relative to those in PBC across 15 different metastatic site sets. We identified 11 genes that were more frequently altered in MBC samples from pan-metastatic sites, including four genes (SMARCA4, TSC2, ATRX, and AURKA) which were not identified previously. ARID2 mutations were enriched in treatment-naïve de novo and post-treatment MBC samples, compared with that in treatment-naïve PBC samples. In metastatic site-specific analyses, associations of ESR1 with liver metastasis and RICTOR with bone metastasis were significant, regardless of intrinsic subtypes. Among the 15 metastatic site sets, ESR1 mutations were enriched in the liver and depleted in the lymph nodes, whereas TP53 mutations showed an opposite trend. Seven potential MBC driver mutations showed similar preferential enrichment in specific metastatic sites. This large-scale study identified new MBC genetic alterations according to various metastatic sites and highlights their potential role in breast cancer organotropism.

scholarly journals Genetic Aberrations of DNA Repair Pathways in Prostate Cancer: Translation to the Clinic

2021 ◽  
Vol 22 (18) ◽  
pp. 9783
Author(s):  
Aruni Ghose ◽  
Michele Moschetta ◽  
George Pappas-Gogos ◽  
Matin Sheriff ◽  
Stergios Boussios
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Large Scale ◽  
Expression Patterns ◽  
Specific Antigen ◽  
Distant Metastases ◽  
Parp Inhibitors ◽  
High Recurrence Rate ◽  
Clinical Implications ◽  
Genomic Landscape

Prostate cancer (PC) is the second most common cancer in men worldwide. Due to the large-scale sequencing efforts, there is currently a better understanding of the genomic landscape of PC. The identification of defects in DNA repair genes has led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients. The identification of molecularly defined subgroups of patients has also other clinical implications; for example, we now know that carriers of breast cancer 2 (BRCA2) pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rate; BRCA2 PSVs confer lower overall survival (OS). Distinct tumor PSV, methylation, and expression patterns have been identified in BRCA2 compared with non-BRCA2 mutant prostate tumors. Several DNA damage response and repair (DDR)-targeting agents are currently being evaluated either as single agents or in combination in patients with PC. In this review article, we highlight the biology and clinical implications of deleterious inherited or acquired DNA repair pathway aberrations in PC and offer an overview of new agents being developed for the treatment of PC.

scholarly journals Genetic alterations in the 3q26.31-32 locus confer an aggressive prostate cancer phenotype

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Benjamin S. Simpson ◽  
Niedzica Camacho ◽  
Hayley J. Luxton ◽  
Hayley Pye ◽  
Ron Finn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Copy Number ◽  
Large Scale ◽  
Genetic Alterations ◽  
Gleason Grade ◽  
Copy Number Alterations ◽  
Aggressive Prostate Cancer ◽  
Prostate Cancer Development ◽  
Transcriptional Changes ◽  
Cancer Phenotype

AbstractLarge-scale genetic aberrations that underpin prostate cancer development and progression, such as copy-number alterations (CNAs), have been described but the consequences of specific changes in many identified loci is limited. Germline SNPs in the 3q26.31 locus are associated with aggressive prostate cancer, and is the location of NAALADL2, a gene overexpressed in aggressive disease. The closest gene to NAALADL2 is TBL1XR1, which is implicated in tumour development and progression. Using publicly-available cancer genomic data we report that NAALADL2 and TBL1XR1 gains/amplifications are more prevalent in aggressive sub-types of prostate cancer when compared to primary cohorts. In primary disease, gains/amplifications occurred in 15.99% (95% CI: 13.02–18.95) and 14.96% (95% CI: 12.08–17.84%) for NAALADL2 and TBL1XR1 respectively, increasing in frequency in higher Gleason grade and stage tumours. Gains/amplifications result in transcriptional changes and the development of a pro-proliferative and aggressive phenotype. These results support a pivotal role for copy-number gains in this genetic region.

Frequency of DNA repair gene mutations in localized and metastatic prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 10-10 ◽  
Author(s):  
Marc Dall'Era ◽  
Allison Glass ◽  
Primo Lara ◽  
Ryan Hartmaier ◽  
Ralph deVere White ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Mutations ◽  
Prostate Tumors ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Platinum Based Chemotherapy ◽  
Visceral Metastases ◽  
Prostate Cancers ◽  
Repair Genes

10 Background: DNA repair gene mutations are important molecular alterations in prostate cancer pathogenesis. Germline mutations in DNA repair genes, particularly BRCA2, were recently recognized as associated with metastatic prostate cancer and may also be particularly sensitive to platinum based chemotherapy and PARP inhibitor therapy. We sought to characterize alterations in DNA repair pathway genes in both primary and metastatic prostate tumors. Methods: We studied the distribution of DNA repair gene mutations in 936 prostate cancers harvested from localized and metastatic tumors. Tumor DNA underwent hybrid capture for all coding exons of 395 cancer-related genes plus select introns from 19 or 31 genes frequently rearranged in cancer and sequenced to a median exon coverage depth of >500x using Illumina sequencing and were analyzed for base substitutions/insertions, copy number alterations and rearrangements. We utilized two described lists of genes involved in DNA repair : our own in-house list of 74 (UCD) and a list of 20 DNA repair genes associated with cancer predisposition syndromes utilized in a recent publication by Pritchard et al. We further stratified the frequency of mutations by tissue site (prostate versus metastases). Results: We identified 228/936 unique samples with at least one likely functional mutation in a DNA repair gene (24.4%). Mutations were identified in 20.1% of prostate tumors (13% UCD, 18.4% Pritchard et al.) and in 18.8% of bone metastases. The highest rates of DNA repair mutations were found in visceral metastases including brain, pelvis and liver, higher than either prostate tissue or bone sites (p=<0.01). The most commonly (≥1% of samples) mutated genes in the DNA repair pathways are: BRCA2 (11.43%), ATM (5.77%), MSH6 (2.46%), MSH2 (2.14%), ATR (1.60%), MLH1 (1.28%), and BRCA1(1.18%). Conclusions: DNA repair gene mutations are more common in metastatic than localized prostate tumors. Visceral metastases appear enriched for these mutations compared with localized tumors or bone metastases. Genomic profiling may identify prostate cancers potentially sensitive to platinum-based chemotherapy or PARP inhibition.

Tumor protein expression of BRCA1 and development of lethal prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 65-65
Author(s):  
Carl Ceraolo ◽  
Travis A. Gerke ◽  
Piotr Zareba ◽  
Andreas Pettersson ◽  
Konrad H. Stopsack ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Protein Expression ◽  
Positive Association ◽  
Proliferation Index ◽  
Proliferative Index ◽  
Prostate Tumors ◽  
Brca1 Protein ◽  
Lethal Prostate Cancer

65 Background: DNA repair genes including BRCA1 are commonly altered in metastatic prostate tumors. However, mutations and copy number aberrations in these genes are rare in primary tumors. Instead, preliminary studies suggest that higher tumor expression of the BRCA1 protein may be associated with worse prognosis. Methods: We undertook a prospective study of tumor BRCA1 protein expression and lethal prostate cancer among men with clinically localized prostate cancer in the Health Professionals Follow-up Study. We performed immunohistochemical staining for BRCA1 on tumor tissue microarrays using a validated antibody and scored expression as positive or negative. We also assessed tumor proliferation by immunostaining for Ki67, angiogenesis by immunostaining for CD34, and apoptosis using a TUNEL assay. Proportional hazards regression was used to evaluate the association between BRCA1 protein expression and development of lethal prostate cancer (metastasis or cancer-specific death). Results: Ten percent of tumors (60 of 589) stained positive for the BRCA1 protein. BRCA1-positive tumors were characterized by higher Gleason scores, a higher proliferative index, and a higher apoptotic index. During a median follow-up of 14.3 years, 18 men (34%) in the BRCA1-positive group and 74 men (14%) in the BRCA1-negative group developed lethal prostate cancer. There was a strong positive association between BRCA1 protein expression and lethal prostate cancer in both unadjusted analyses (HR 2.71, 95% CI 1.73–4.26) and after adjusting for clinical factors (HR 2.00, 95% CI 1.26–3.18). The positive association with BRCA1 protein expression was also independent of proliferation index. Conclusions: Primary prostate tumors expressing the BRCA1 protein have a highly proliferative phenotype and are more likely to progress to lethal disease, independent of its higher proliferative index. Assessing tumor protein expression of BRCA1 may help elucidate the Janus-faced role of DNA repair pathways in prostate cancer progression.[Table: see text]

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