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]

scholarly journals Tumor protein expression of the DNA repair gene BRCA1 and lethal prostate cancer

2020 ◽  
Vol 41 (7) ◽  
pp. 904-908
Author(s):  
Konrad H Stopsack ◽  
Travis Gerke ◽  
Piotr Zareba ◽  
Andreas Pettersson ◽  
Dipanjan Chowdhury ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Protein Expression ◽  
Metastatic Disease ◽  
Clinical Stage ◽  
Hazard Ratio ◽  
Repair Gene ◽  
Brca1 Protein ◽  
Dna Repair Gene

Abstract DNA repair genes are commonly altered in metastatic prostate cancer, but BRCA1 mutations are rare. Preliminary studies suggest that higher tumor expression of the BRCA1 protein may be associated with worse prognosis. We undertook a prospective study among men with prostate cancer in the Health Professionals Follow-up Study and evaluated BRCA1 via immunohistochemical staining on tissue microarrays. BRCA1 was expressed in 60 of 589 tumors. Prevalence of BRCA1 positivity was 43% in the 14 men with metastases at diagnosis compared with 9% in non-metastatic tumors [difference, 33 percentage points; 95% confidence interval (CI), 7–59]. BRCA1-positive tumors had 2.16-fold higher Ki-67 proliferative indices (95% CI, 1.18–3.95), higher tumor aneuploidy as predicted from whole-transcriptome profiling, and higher Gleason scores. Among the 575 patients with non-metastatic disease at diagnosis, we evaluated the association between BRCA1 expression and development of lethal disease (metastasis or cancer-specific death, 69 events) during long-term follow-up (median, 18.3 years). A potential weak association of BRCA1 positivity with lethal disease (hazard ratio, 1.61; 95% CI, 0.82–3.15) was attenuated when adjusting for age, Gleason score and clinical stage (hazard ratio, 1.11; 95% CI, 0.54–2.29). In summary, BRCA1 protein expression is a feature of more proliferative and more aneuploid prostate tumors and is more common in metastatic disease. While not well suited as a prognostic biomarker in primary prostate cancer, BRCA1 protein expression may be most relevant in advanced disease.

scholarly journals Asthma and risk of lethal prostate cancer in the Health Professionals Follow-Up Study

2015 ◽  
Vol 137 (4) ◽  
pp. 949-958 ◽  
Author(s):  
Elizabeth A. Platz ◽  
Charles G. Drake ◽  
Kathryn M. Wilson ◽  
Siobhan Sutcliffe ◽  
Stacey A. Kenfield ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Health Professionals ◽  
Follow Up Study ◽  
Lethal Prostate Cancer

scholarly journals C-MYC Protein Expression and High Ki-67 Proliferative Index are Predictives of Disease Relapse in Diffuse Large B Cell Lymphoma

2021 ◽  
Vol 6 (1) ◽  
pp. 15-20
Author(s):  
Mahmoud Tag El-Hussien ◽  
Nadia Mokhtar ◽  
Eman Naguib Khorshed
Keyword(s):  
Protein Expression ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Statistical Prediction ◽  
Proliferative Index ◽  
Ki 67 ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Objective: To evaluate the status of C-MYC protein expression and Ki-67 proliferative index and to clarify their role in predicting relapse of diffuse large B cell lymphoma (DLBL). Materials and Methods: A retrospective study conducted on 50 cases diagnosed as DLBL in a 3 years’ time period from January 2014 till December 2016, collected from the archive of Pathology Departments of the National Cancer Institute Cairo - Egypt, Misr University for Science and Technology and private labs of authors. The diagnosis of DLBL for all cases, both nodal and extranodal, was confirmed by histopathologic examination and immunophenotyping. Automated immunohistochemical staining using antibodies against C-MYC protein and MIB-1 was used to evaluate the C-MYC expression in tumor cells and to assess their proliferative ability by calculating Ki-67 labelling index. The relation between the percentage of C-MYC protein expression, Ki-67 proliferative index, clinical data and the relapse status during the follow up period were analyzed. Results: A total of 50 cases of DLBL in both nodal and extra-nodal sites were included. Twenty-three cases (46%) were expressing the C-MYC protein, and 29 cases (58%) showed high Ki-67 proliferative index. Twenty-two cases (44%) relapsed during the follow-up period. Positive C-MYC protein expression was significantly associated with high Ki-67 proliferative index. C-MYC protein expression and high Ki-67 proliferative index were independently associated with disease relapses in 81.8% and 86.4% of cases respectively. Cases with combined C-MYC protein expression and high Ki-67 proliferative index showed statistical prediction of relapse in 81.8% of cases. Conclusion: C-MYC protein expression and high Ki-67 proliferative index were independently associated with relapse of diffuse large B cell lymphoma. Furthermore, the combined positive C-MYC protein expression and high Ki-67 proliferative index is better than a single positive test in predicting relapses among DLBL patients.

Aspirin Use and Lethal Prostate Cancer in the Health Professionals Follow-up Study

2019 ◽  
Vol 2 (2) ◽  
pp. 126-134 ◽  
Author(s):  
Mary K. Downer ◽  
Christopher B. Allard ◽  
Mark A. Preston ◽  
Kathryn M. Wilson ◽  
Stacey A. Kenfield ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Health Professionals ◽  
Follow Up Study ◽  
Lethal Prostate Cancer

Rare DNA repair gene mutations predispose to young onset and lethal prostate cancer in the UK

2018 ◽  
Vol 44 ◽  
pp. S23
Author(s):  
Rosalind Eeles ◽  
Daniel Leongamornlert ◽  
Edward Saunders ◽  
Sarah Wakerell ◽  
Ian Whitmore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Mutations ◽  
Repair Gene ◽  
Young Onset ◽  
Dna Repair Gene ◽  
The Uk ◽  
Lethal Prostate Cancer

scholarly journals Alcohol Intake and Risk of Lethal Prostate Cancer in the Health Professionals Follow-Up Study

2019 ◽  
Vol 37 (17) ◽  
pp. 1499-1511 ◽  
Author(s):  
Mary K. Downer ◽  
Stacey A. Kenfield ◽  
Meir J. Stampfer ◽  
Kathryn M. Wilson ◽  
Barbra A. Dickerman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
At Risk ◽  
Health Professionals ◽  
Lower Risk ◽  
Alcohol Intake ◽  
Red Wine ◽  
Follow Up Study ◽  
Total Alcohol ◽  
Lethal Prostate Cancer

PURPOSE It is unknown whether alcohol intake is associated with the risk of lethal (metastatic or fatal) prostate cancer. We examine (1) whether alcohol intake among men at risk of prostate cancer is associated with diagnosis of lethal prostate cancer and (2) whether intake among men with nonmetastatic prostate cancer is associated with metastasis or death. METHODS This prospective cohort study uses the Health Professionals Follow-Up Study (1986 to 2012). Our analysis of alcohol intake among men at risk of prostate cancer included 47,568 cancer-free men. Our analysis of alcohol intake among men with prostate cancer was restricted to 5,182 men diagnosed with nonmetastatic prostate cancer during follow-up. We examine the association of total alcohol, red and white wine, beer, and liquor with lethal prostate cancer and death. Multivariate Cox proportional hazards regression estimated hazard ratios (HRs) and 95% CIs. RESULTS Alcohol drinkers had a lower risk of lethal prostate cancer (any v none: HR, 0.84 [95% CI, 0.71 to 0.99]) without a dose-response relationship. Total alcohol intake among patients with prostate cancer was not associated with progression to lethal prostate cancer (any v none: HR, 0.99 [95% CI, 0.57 to 1.72]), whereas moderate red wine intake was associated with a lower risk (any v none: HR, 0.50 [95% CI, 0.29 to 0.86]; P trend = .05). Compared with none, 15 to 30 g/d of total alcohol after prostate cancer diagnosis was associated with a lower risk of death (HR, 0.71 [95% CI, 0.50 to 1.00]), as was red wine (any v none: HR, 0.74 [95% CI, 0.57 to 0.97]; P trend = .007). CONCLUSION Cancer-free men who consumed alcohol had a slightly lower risk of lethal prostate cancer compared with abstainers. Among men with prostate cancer, red wine was associated with a lower risk of progression to lethal disease. These observed associations merit additional study but provide assurance that moderate alcohol consumption is safe for patients with prostate cancer.

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.

scholarly journals Prostate-Specific Membrane Antigen Protein Expression in Tumor Tissue and Risk of Lethal Prostate Cancer

2013 ◽  
Vol 22 (12) ◽  
pp. 2354-2363 ◽  
Author(s):  
Julie L. Kasperzyk ◽  
Stephen P. Finn ◽  
Richard Flavin ◽  
Michelangelo Fiorentino ◽  
Rosina Lis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Protein Expression ◽  
Tumor Tissue ◽  
Prostate Specific Membrane Antigen ◽  
Antigen Protein ◽  
Specific Membrane ◽  
Lethal Prostate Cancer

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.

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