Associations of DNA Repair Gene Polymorphisms in XRCC1 and ERCC2 with Clinical Outcome in ECOG Trial E9486.

Abstract Although multiple myeloma is clinically defined as the accumulation of clonal, malignant plasma cells in the bone marrow, the disease shows significant heterogeneity with regard to morphology, progression and therapeutic response. Our hypothesis is that this heterogeneity likely is due, in part, to germline genetic polymorphisms that contribute significantly to an individual’s disease course and response. In particular, individuals deficient in the repair of DNA damage are not only at high risk for developing cancer, but also could show DNA repair dependent responses associated with DNA damaging therapeutic agents. In this study we examined the association of functional genetic polymorphisms in the DNA repair genes, XRCC1 (SNP positions 280, 399) and ERCC2 (SNP positions 312, 751), with toxicities and clinical outcomes in the ECOG, 3 arm chemotherapeutic trial, E9486 [A-VBMCP, B-VBMCP+Cylophosphamide, C- VBMCP+interferon]. DNA from 359 patients was genotyped and examined for association with response, toxicities, blood counts, bone pathology, and survival parameters. Notably, in the interferon arm of the trial significant associations were observed in progression free survival and polymorphisms of XRCC399 (AA median survival 51 months versus AG/GG median survival of 33 months; p=,008), ERCC751 (AA/AC median survival 33 months versus CC median survival of 48 months; p=.05), and ERCC312 (AA median survival 49 months versus AG/GG median survival of 34 months; p=.02). Hazard ratios ranged form 1.7 to 2.05 for survival differences associated with DNA repair genes in this arm. Interestingly, T cell counts are known to be impacted by interferon; and DNA repair polymorphisms in this arm were also associated with CD8+ T cell counts. While this represents a single arm of one clinical trial, it is intriguing to consider the impact of genetic polymorphisms on DNA repair in light of chemotherapeutic agents that may affect cells of the immune system. Previous studies from the ECOG Myeloma Committee of the E9486 trial show highly significant associations of survival and immune status in myeloma patients. Our results suggest genetic polymorphisms in DNA repair genes may influence clinical outcome in certain therapeutic regimens. Genetic polymorphisms in these DNA repair genes are currently being completed in 800 patients of the SW9321 SWOG/ECOG intergroup trial and additional association studies will be included in the presentation.

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Patients with Systemic Sclerosis Present Increased DNA Damage Differentially Associated with DNA Repair Gene Polymorphisms

The Journal of Rheumatology ◽

10.3899/jrheum.130376 ◽

2014 ◽

Vol 41 (3) ◽

pp. 458-465 ◽

Cited By ~ 11

Author(s):

Gustavo Martelli Palomino ◽

Carmen L. Bassi ◽

Isabela J. Wastowski ◽

Danilo J. Xavier ◽

Yara M. Lucisano-Valim ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Systemic Sclerosis ◽

Blood Cells ◽

Gene Polymorphisms ◽

Peripheral Blood Cells ◽

Dna Repair Genes ◽

Repair Gene ◽

Dna Repair Gene ◽

Repair Genes

Objective.Patients with systemic sclerosis (SSc) exhibit increased toxicity when exposed to genotoxic agents. In our study, we evaluated DNA damage and polymorphic sites in 2 DNA repair genes (XRCC1Arg399Gln andXRCC4Ile401Thr) in patients with SSc.Methods.A total of 177 patients were studied for DNA repair gene polymorphisms. Fifty-six of them were also evaluated for DNA damage in peripheral blood cells using the comet assay.Results.Compared to controls, the patients as a whole or stratified into major clinical variants (limited or diffuse skin involvement), irrespective of the underlying treatment schedule, exhibited increased DNA damage.XRCC1(rs: 25487) andXRCC4(rs: 28360135) allele and genotype frequencies observed in patients with SSc were not significantly different from those observed in controls; however, theXRCC1Arg399Gln allele was associated with increased DNA damage only in healthy controls and theXRCC4Ile401Thr allele was associated with increased DNA damage in both patients and controls. Further, theXRCC1Arg399Gln allele was associated with the presence of antinuclear antibody and anticentromere antibody. No association was observed between these DNA repair gene polymorphic sites and clinical features of patients with SSc.Conclusion.These results corroborate the presence of genomic instability in SSc peripheral blood cells, as evaluated by increased DNA damage, and show that polymorphic sites of theXRCC1andXRCC4DNA repair genes may differentially influence DNA damage and the development of autoantibodies.

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Genetic polymorphisms in DNA repair genes and hepatocellular carcinoma risk

DNA Repair ◽

10.1016/j.dnarep.2021.103196 ◽

2021 ◽

pp. 103196

Author(s):

Hossein Ghaderi-Zefrehi ◽

Maryam Rezaei ◽

Farzin Sadeghi ◽

Mohammad Heiat

Keyword(s):

Hepatocellular Carcinoma ◽

Dna Repair ◽

Genetic Polymorphisms ◽

Dna Repair Genes ◽

Repair Genes ◽

Carcinoma Risk

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

10.20944/preprints201902.0042.v1 ◽

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.

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Occupational radiation exposure and genetic polymorphisms in DNA repair genes

Radioprotection ◽

10.1051/radiopro/2017025 ◽

2017 ◽

Vol 52 (4) ◽

pp. 241-249 ◽

Cited By ~ 4

Author(s):

F. Zakeri ◽

M.R. Farshidpour ◽

M.R. Rajabpour

Keyword(s):

Dna Repair ◽

Radiation Exposure ◽

Genetic Polymorphisms ◽

Dna Repair Genes ◽

Occupational Radiation Exposure ◽

Repair Genes ◽

Occupational Radiation

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Genetic polymorphisms in DNA repair genes (hOGG1 and APE1) and their association with oral cancer susceptibility in rural Indian population: a hospital based case-control study

International Journal of Medical Science and Public Health ◽

10.5455/ijmsph.2016.07062016541 ◽

2017 ◽

Vol 6 (1) ◽

pp. 23

Author(s):

Kailas Datkhile ◽

Madhavi Patil ◽

Tejasvi Khamkar ◽

Rohit Vhaval ◽

Pratik Durgawale ◽

...

Keyword(s):

Dna Repair ◽

Oral Cancer ◽

Genetic Polymorphisms ◽

Indian Population ◽

Case Control Study ◽

Cancer Susceptibility ◽

Case Control ◽

Dna Repair Genes ◽

Repair Genes ◽

Control Study

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Polymorphisms of DNA-repair genes associated with clinical outcome in metastatic breast cancer (MBC) patients treated with gemcitabine/cisplatin (GC) (California Cancer Consortium)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.675 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 675-675

Author(s):

M. A. Gordon ◽

W. Zhang ◽

D. Yang ◽

D. Spicer ◽

J. Doroshow ◽

...

Keyword(s):

Overall Survival ◽

Dna Repair ◽

Clinical Outcome ◽

Tumor Progression ◽

Tumor Response ◽

Dna Repair Genes ◽

Repair Capacity ◽

Repair Enzymes ◽

Repair Genes ◽

Time To Tumor Progression

675 Background: DNA repair enzymes may play an important role in determining efficacy of chemotherapy in MBC. In particular, GC combination therapy may be dependent on activity of DNA repair enzymes in host cells, since cisplatin acts by inducing DNA damage. Cancer cells with increased DNA repair capacity may be resistant to GC, and specific genes may be responsible for this increased repair capacity. We examined whether polymorphisms in genes related to DNA repair were associated with clinical outcome in MBC patients treated with GC, enrolled in a parent phase II clinical trial (Ph II-14 A & B). Methods: Fifty-five patients with MBC were evaluated. Patients received the following regimen: 25 mg/m2 cisplatin on days 1–4; 1000 mg/m2 gemcitabine on days 2 and 8 of 21-day cycle. Thirteen polymorphisms in 10 cancer-related genes were tested for association with overall survival, time to tumor progression, and tumor response using a PCR RFLP based assay. Results: Of 55 patients evaluated, there were 17 responders (31%) and 33 non-responders (60%). Five patients (9%) inevaluable for response. Of 33 non-responders, 15 had stable disease, 18 had progressive disease. Median survival: 11.7 months with median follow-up 32.4 months for 4 patients alive at time of analysis. Median progression-free survival: 4.2 months. XPD Lys751Gln polymorphism was associated with overall survival and time to tumor progression (p=0.0003, p=0.006, respectively, log-rank test). Thirty-five patients carried Lys/Lys genotype, of which 29% resopnded. Fourteen patients carried Lys/Gln genotype, of which 54% resopnded. Five patients carried Gln/Gln genotype, with no responders. XRCC3 Thr241Met polymorphism was associated with time to tumor progression and tumor response (p=0.03, p=0.002, respectively). Eighteen patients had Met/Met genotype, of which 47% responded. Twenty-six patients had heterozygous genotype, of which 17% responded. Five patients had homozygous Thr/Thr, of which 100% responded. Conclusions: Our results suggest that polymorphisms in DNA repair genes XPD and XRCC3 may be important markers in predicting clinical outcome in MBC patients treated with GC. Supported by the following NCI grant: N01 CM1701. [Table: see text]

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Correlation of primary biopsy mutational landscape to pre-docetaxel LDH for prediction of docetaxel therapeutic response.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.220 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 220-220

Author(s):

Kenneth Hiew ◽

Claire Alexandre Hart ◽

Adnan Ali ◽

Maurice Lau ◽

Vijay A.C. Ramani ◽

...

Keyword(s):

Dna Repair ◽

Meta Analysis ◽

Linear Regression Analysis ◽

Wilcoxon Test ◽

Next Generation Sequencing Data ◽

Dna Repair Genes ◽

Dna Repair Gene ◽

Pre Treatment ◽

Castrate Resistant ◽

Repair Genes

220 Background: There is a lack of biomarkers to predict docetaxel response. Here we assess the potential of pre-treatment LDH, associated to the mutational background of the primary biopsy taken prior to 1st line therapy with ADT, to predict docetaxel response in the castrate resistant setting. Methods: Clinical and associated primary biopsy targeted next-generation sequencing data from matched training (n = 150) and test (n = 120) sets of retrospective progressive mCRPC patients (diagnosed 1996-2006) treated with docetaxel therapy were analyzed. LDH thresholds were determined and validated on the training and test sets respectively. Clinico-pathological associations with LDH were assessed using student t-test, Wilcoxon test and Chi-square test and predictive value of LDH determined by linear regression analysis for PSA and radiologic response. Time to event outcomes (PFS & OS) was evaluated by Kaplan-Meier. Meta-analysis of LDH association with DNA repair genes in the MSKCC and SU2C/PCF was conducted using cBioPortal Results: Using pre-docetaxel serum LDH of ≥450U/L as a prognostic threshold (AUC:0.75 (SD 0.054, 95% CI, 0.650–0.864, P < 0.001)) patients with LDH ≥450U/L were poorer PSA responders, with shorter PFS (213 vs 372 days, HR 1.876 (95% CI, 1.289-2.730)) and OS (362 vs 563 days, HR 1.630 (95% CI, 1.127-2.357)). LDH was also an independent surrogate marker for prediction of poor radiologic response and survival following docetaxel chemotherapy (P = 0.043). Genomic analysis showed that patients with LDH ≥450U/L (9/14 (64.3%)) have a higher tumour mutational burden (TMB) at the point of primary pre-ADT biopsy (mean, 46.2 vs 6.2 mutations/MB; p = 0.129) and that they were more likely to have DNA repair gene mutation(s) (BRCA1/2, ATM, CHEK2 and Fanconi’s anemia gene). Meta-analysis of the large MSKCC and the SU2C-PCF patient genomic databases confirmed the positive correlation between the LDH gene LDHA and PARP1 gene (r = 0.667, p < 0.01) expression and expression of other DNA repair genes. Conclusions: High pre-treatment serum LDH coupled with mutations in the DNA repair pathway in primary pre-ADT biopsy correlates with poor docetaxel response and overall survival in the castrate resistant state.

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