Prognostic impact of DNA repair germline variants in hormone sensitive prostate cancer stage.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 262-262
Author(s):  
Manish Kohli ◽  
Steven Hart ◽  
Jenna Lilyquist ◽  
Chunling Hu ◽  
David W. Hillman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Median Time ◽  
P Value ◽  
Prognostic Impact ◽  
Time To Progression ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Group A ◽  
Group B

262 Background: Inherited and somatic aberrations in DNA repair genes in castrate resistant prostate cancer (CRPC) are associated with poor prognosis, but respond well to poly ADP ribose polymerase (PARP) inhibitors. We evaluated the prevalence and prognostic impact of harboring germline DNA repair variants in hormone sensitive prostate cancer (HSPC). Methods: Germline DNA from buffy coat was sequenced on HiSeq4000 with a median coverage of 200X for DNA repair variants in 20 genes in HSPC and CRPC patients (pts) enrolled in a hospital registry. Pts were divided into two groups; Group A: pts enrolled at the time of CRPC stage; Group B: treatment naïve HSPC stage pts. The primary endpoints were to determine any impact of harboring DNA repair variants on time to progression from HSPC to CRPC and, from CRPC to death. Group A pts were retrospectively analyzed for time to progression from HSPC to CRPC while Group B patients were followed prospectively for outcomes. Statistical analysis included Cox proportional hazard models and Wilcoxon Rank sum test with significance at p≤0.05. Results: In Group A, 51/562 CRPC pts (9.07%) had variants in the 20 genes (most frequently in BRCA2; n = 15). 44/51 pts with variants and 399/511 without variants had died. Median time of progression from HSPC to CRPC with/without variants was 22.1 vs. 25.1 months (mths); p-value = 0.679. Median time from CRPC to death with/without variants was 32.2 Vs. 27.7 mths (p = 0.6). In HSPC Group B, 14/100 pts were identified with germline variants in ATM (n = 5), CHEK2 (n = 3), BRCA1 (n = 2), BRCA2 (n = 2), RAD50 (n = 1), and MSH2 (n = 1). 31/100 have died and median time to progression from HSPC to CRPC with/without variants was 15.6 vs.11.8 mths, p-value = 0.76. Conclusions: Pts with germline DNA repair variants detected in HSPC stage were not associated with poor prognosis. Presence of additional somatic DNA repair gene aberrations in cell-free DNA, not investigated in this cohort may add to the prevalence of DNA repair gene variations in HSPC and together impact prognosis adversely so as to provide a rationale for PARP inhibitor therapy in select HSPC stage pts.

Concordance of DNA Repair Gene Mutations in Paired Primary Prostate Cancer Samples and Metastatic Tissue or Cell-Free DNA

JAMA Oncology ◽  
2021 ◽  
Author(s):  
Michael T. Schweizer ◽  
Smruthy Sivakumar ◽  
Hanna Tukachinsky ◽  
Ilsa Coleman ◽  
Navonil De Sarkar ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Gene Mutations ◽  
Repair Gene ◽  
Cell Free Dna ◽  
Metastatic Tissue ◽  
Free Dna ◽  
Primary Prostate Cancer ◽  
Dna Repair Gene

scholarly journals DNA Repair Gene Expression Adjusted by the PCNA Metagene Predicts Survival in Multiple Cancers

2019 ◽  
Author(s):  
Leif Peterson ◽  
Tatiana Kovyrshina
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Gene Selection ◽  
P Value ◽  
Survival Prediction ◽  
Dna Repair Genes ◽  
Repair Gene ◽  
A Genome ◽  
Dna Repair Gene ◽  
Repair Genes

Removal of the proliferation component of gene expression by PCNA adjustment has been addressed in numerous survival prediction studies for breast cancer and all cancers in the TCGA. These studies indicate that widespread co-regulation of proliferation upwardly biases survival prediction when gene selection is performed on a genome-wide basis. In addition, removal of the correlative effects of proliferation does not reduce the random bias associated with survival prediction using random gene selection. Since most cancers become addicted to DNA repair as a result of forced cellular replication, increased oxidation, and repair deficiencies from oncogenic loss or genetic polymorphisms, we pursued an investigation to remove the proliferation component of expression in DNA repair genes to determine survival prediction. This translational hypothesis-driven focus on DNA repair genes is directly amenable to finding new sets of DNA repair genes that could potentially be studied for inhibition therapy. Overall survival (OS) prediction was evaluated in 18 cancers by using normalized RNA-Seq data for 126 DNA repair genes with expression available in TCGA. Transformations for normality and adjustments for age at diagnosis, stage, and PCNA metagene expression were performed for all DNA repair genes. We also analyzed genomic event rates (GER) for somatic mutations, deletions, and amplification in driver genes and DNA repair genes. After performing empirical p-value testing with use of randomly selected gene sets, it was observed that OS could be predicted significantly by sets of DNA repair genes for 61% (11/18) of the cancers. Interestingly, PARP1 was not a significant predictor of survival for any of the 11 cancers. Results from cluster analysis of GERs indicates that the most opportunistic cancers for inhibition therapy may be AML, colorectal, and renal papillary, because of potentially less confounding due to lower GERs for mutations, deletions, and amplifications in DNA repair genes. However, the most opportunistic cancer for inhibition therapy is likely to be AML, since it showed the lowest GERs for mutations, deletions, and amplifications in DNA repair genes. In conclusion, our hypothesis-driven focus to target DNA repair gene expression adjusted for the PCNA metagene as a means of predicting OS in various cancers resulted in statistically significant sets of genes.

Gallic acid provokes DNA damage and suppresses DNA repair gene expression in human prostate cancer PC-3 cells

2011 ◽  
Vol 28 (10) ◽  
pp. 579-587 ◽  
Author(s):  
Kuo-Ching Liu ◽  
Heng-Chien Ho ◽  
An-Cheng Huang ◽  
Bin-Chuan Ji ◽  
Hui-Yi Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Gallic Acid ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Repair Gene ◽  
Dna Repair Gene

scholarly journals RAD25 (SSL2), the yeast homolog of the human xeroderma pigmentosum group B DNA repair gene, is essential for viability.

1992 ◽  
Vol 89 (23) ◽  
pp. 11416-11420 ◽  
Author(s):  
E. Park ◽  
S. N. Guzder ◽  
M. H. Koken ◽  
I. Jaspers-Dekker ◽  
G. Weeda ◽  
...  
Keyword(s):  
Dna Repair ◽  
Xeroderma Pigmentosum ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Group B ◽  
Yeast Homolog

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

Phase 2 biomarker-driven study of ipilimumab plus nivolumab (Ipi/Nivo) for ARV7-positive metastatic castrate-resistant prostate cancer (mCRPC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5035-5035 ◽  
Author(s):  
Karim Boudadi ◽  
Daniel L. Suzman ◽  
Brandon Luber ◽  
Hao Wang ◽  
John Silberstein ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Response Rate ◽  
Objective Response ◽  
Gene Mutations ◽  
Immune Checkpoint Blockade ◽  
Phase 2 ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Castrate Resistant

5035 Background: ARV7+ mCRPC is an aggressive phenotype with a median PFS of 3-4 mo and OS of 7-9 mo. We hypothesized that ARV7+ tumors would be enriched for DNA repair mutations, rendering them more responsive to combined immune checkpoint blockade. Methods: We enrolled 15 mCRPC pts with ARV7+ CTCs (using a CLIA-certified assay) into a single arm phase 2 study. Pts received Nivo 3 mg/kg plus Ipi 1 mg/kg every 3 wk x 4 doses, then maintenance Nivo 3 mg/kg every 2 wk. Targeted sequencing for DNA repair defects was performed on pretreatment tumor biopsies (n=11) or cell-free DNA (n=4). Primary endpoint: PSA50response rate. Secondary endpoints: objective response rate (ORR) in pts with measurable disease, durable PFS (lack of progression ≥24 wk), PSA‐PFS, radiographic (r)PFS, overall survival (OS), and frequency/intensity of AEs. Results: 15 ARV7+ men were enrolled, with median f/u 8.4 (range 1.9–10.5) mo. Median age was 65, 47% had ECOG ≥1, median PSA was 115 ng/mL, 67% had visceral/nodal mets, all had bone mets, and 60% had ≥4 prior regimens for mCRPC. Mean ARV7/AR ratio was 23% (range 3–75%). 6/15 men (40%) had pathogenic DNA repair gene mutations ( BRCA2, ATM, MSH6, FANCM, FANCA, POLH). Overall, the PSA50rate was 1/15 (7%), ORR was 2/8 (25%), durable PFS rate was 3/15 (20%), PSA-PFS was 3.0 (95%CI 2.1–4.9) mo, rPFS was 3.9 (95%CI 2.8–5.5) mo, and OS was 9.5 (95%CI 7.2–NA) mo. Outcomes appeared better in DNA repair deficient (DRD+) tumors vs. DNA repair proficient (DRD–) tumors (TABLE). 15 grade 3-4 treatment-related AEs occurred in 7/15 (46%) men (including 2 hepatitis, 2 colitis, 1 pneumonitis); there were no treatment-related deaths. Conclusions: In this first study targeting ARV7+ mCRPC, treatment with Ipi/Nivo had acceptable safety and encouraging efficacy, particularly in men with DRD+ tumors. DNA repair mutations may be enriched in ARV7+ prostate cancer. Clinical trial information: NCT02601014. [Table: see text]

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