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DNA repair pathway gene expression score correlates with repair proficiency and tumor sensitivity to chemotherapy.

ABSTRACT: Mutagenesis is a hallmark of malignancy, and many oncologic treatments function by generating additional DNA damage. Therefore, DNA damage repair is centrally important in both carcinogenesis and cancer treatment. Homologous recombination (HR) and nonhomologous end joining are alternative pathways of double-strand DNA break repair. We developed a method to quantify the efficiency of DNA repair pathways in the context of cancer therapy. The recombination proficiency score (RPS) is based on the expression levels for four genes involved in DNA repair pathway preference (Rif1, PARI, RAD51, and Ku80), such that high expression of these genes yields a low RPS. Carcinoma cells with low RPS exhibit HR suppression and frequent DNA copy number alterations, which are characteristic of error-prone repair processes that arise in HR-deficient backgrounds. The RPS system was clinically validated in patients with breast or non-small cell lung carcinomas (NSCLCs). Tumors with low RPS were associated with greater mutagenesis, adverse clinical features, and inferior patient survival rates, suggesting that HR suppression contributes to the genomic instability that fuels malignant progression. This adverse prognosis associated with low RPS was diminished if NSCLC patients received adjuvant chemotherapy, suggesting that HR suppression and associated sensitivity to platinum-based drugs counteract the adverse prognosis associated with low RPS. Therefore, RPS may help oncologists select which therapies will be effective for individual patients, thereby enabling more personalized care.

SUBMITTER: Pitroda SP

PROVIDER: S-EPMC4889008 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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DNA repair pathway gene expression score correlates with repair proficiency and tumor sensitivity to chemotherapy.

Pitroda Sean P SP Pashtan Itai M IM Logan Hillary L HL Budke Brian B Darga Thomas E TE Weichselbaum Ralph R RR Connell Philip P PP

Science translational medicine 20140301 229

Mutagenesis is a hallmark of malignancy, and many oncologic treatments function by generating additional DNA damage. Therefore, DNA damage repair is centrally important in both carcinogenesis and cancer treatment. Homologous recombination (HR) and nonhomologous end joining are alternative pathways of double-strand DNA break repair. We developed a method to quantify the efficiency of DNA repair pathways in the context of cancer therapy. The recombination proficiency score (RPS) is based on the ex ...[more]

PMID: 24670686

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Project description:BackgroundNew tools are needed to predict outcomes of ovarian cancer patients treated with platinum-based chemotherapy. We hypothesized that a molecular score based on expression of genes that are involved in platinum-induced DNA damage repair could provide such prognostic information.MethodsGene expression data was extracted from The Cancer Genome Atlas (TCGA) database for 151 DNA repair genes from tumors of serous ovarian cystadenocarcinoma patients (n = 511). A molecular score was generated based on the expression of 23 genes involved in platinum-induced DNA damage repair pathways. Patients were divided into low (scores 0-10) and high (scores 11-20) score groups, and overall survival (OS) was analyzed by Kaplan-Meier method. Results were validated in two gene expression microarray datasets. Association of the score with OS was compared with known clinical factors (age, stage, grade, and extent of surgical debulking) using univariate and multivariable Cox proportional hazards models. Score performance was evaluated by receiver operating characteristic (ROC) curve analysis. Correlations between the score and likelihood of complete response, recurrence-free survival, and progression-free survival were assessed. Statistical tests were two-sided.ResultsImproved survival was associated with being in the high-scoring group (high vs low scores: 5-year OS, 40% vs 17%, P < .001), and results were reproduced in the validation datasets (P < .05). The score was the only pretreatment factor that showed a statistically significant association with OS (high vs low scores, hazard ratio of death = 0.40, 95% confidence interval = 0.32 to 0.66, P < .001). ROC curves indicated that the score outperformed the known clinical factors (score in a validation dataset vs clinical factors, area under the curve = 0.65 vs 0.52). The score positively correlated with complete response rate, recurrence-free survival, and progression-free survival (Pearson correlation coefficient [r(2)] = 0.60, 0.84, and 0.80, respectively; P < .001 for all).ConclusionThe DNA repair pathway-focused score can be used to predict outcomes and response to platinum therapy in ovarian cancer patients.

Project description:Objective:Multiple factors are involved in oxaliplatin-resistant process in colorectal cancer (CRC) patients including decreased drug accumulation and enhanced capacity to repair and tolerate DNA damage. In the present study, we aimed to assess the impact of six single-nucleotide polymorphisms (SNPs) in DNA repair genes and ABCG2 gene on prognosis in advanced CRC patients treated with oxaliplatin-based chemotherapy. Methods:In this study, 580 advanced CRC patients were recruited. Six SNPs of DNA repair genes (XPA rs10817938, XPA rs2808668, XPC rs2607775, and WRN rs1346044) and ABCG2 gene (rs2231142 and rs2622621) were genotyped by using the TaqMan assay. Results:Regarding interaction with environmental factors, ABCG2 rs2231142 and the first-degree family history of cancer and XPC rs2607775 or ABCG2 rs2622621 and lymph node metastases status demonstrated significant interactions. Of these six SNPs, XPA rs10817938 CT/ TT genotypes retained its significant association with longer overall survival (OS) (P=0.008) in CRC patients receiving oxaliplatin-based chemotherapy (n=580). Furthermore, a significantly better impact on the disease-free survival (DFS) (P=0.001) and OS (P<0.0001) was found in ABCG2 rs2231142CA/AA carriers. Furthermore, ABCG2 rs2622621 CG/GG genotype was verified to be an independent poor prognostic factor in DFS (P=0.010) and OS (P=0.030). In the stratification analysis, XPA rs10817938 CT/CC, rs2231142 CA/AA, and rs2622621 CC genotypes of ABCG2 were predictive of significantly better prognosis in the patients with tumor differentiation grade 3 (n=523), clinical stage IV (n=73), or lymph node-positive status (n=557). Additionally, multivariate logistic regression and multiple dimension reduction analysis consistently revealed that the combination of selected SNPs and five known risk factors showed a better prediction prognosis and represented the best model to predict CRC prognosis. Conclusion:The current data indicated that the XPA gene and ABCG2 gene had significant interaction with environmental factors and prognosis, which could provide a comprehensive understanding of the implications of those SNPs in the prediction of prognosis in advanced CRC patients receiving oxaliplatin-based chemotherapy.

Dataset Information

DNA repair pathway gene expression score correlates with repair proficiency and tumor sensitivity to chemotherapy.

Publications

DNA repair pathway gene expression score correlates with repair proficiency and tumor sensitivity to chemotherapy.

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