DNA Repair Pathway Gene Expression Score Correlates with Repair Proficiency and Tumor Sensitivity to Chemotherapy

Abstract

Homologous recombination (HR) and non-homologous end joining (NHEJ) 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) utilizes 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 (NSCLC). Tumors with low RPS were associated with greater mutagenesis, adverse clinical features, and inferior patient survival rates, suggesting that HR suppression plays a central role in promoting 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 counteracts the adverse prognosis associated with low RPS. Therefore, RPS may predict which therapies will be effective for individual patients, thereby enabling more personalized oncology care.

Patient-Level DNA Damage and Repair Pathway Profiles and Prognosis After Prostatectomy for High-Risk Prostate Cancer

“…There have been several attempts at hybrid approaches to develop biomarkers using large-scale gene expression data with guidance from pathway knowledge in lung and ovarian cancer. 11,12 This approach has not been pursued in prostate cancer, in which long disease outcome intervals dictate that few data sets with the most meaningful outcomes—metastatic progression and overall survival—are available.…”

“…These DNA repair pathway scores have prognostic and/or predictive power in lung and ovarian cancer. 11,12 In prostate cancer, no such analyses have been performed, and a lack of gene expression data with long-term follow-up hampers biomarker studies in general.…”

Methylation of RASSF1A and CDH13 Genes in Individualized Chemotherapy for Patients with Non-small Cell Lung Cancer

“…Chemotherapy is still the important method for the treatment of advanced non small cell lung cancer patients.However, due to individual differences in sensitivity to chemotherapy drugs, the effect of chemotherapy is not ideal, even lead to the progression of disease (Linda et al, 2009). Therefore, in order to prolong the survival of patients with NSCLC, to improve the quality of life of these patients, the application of individualized chemotherapy is particularly important (Pitroda et al, 2014). The methylation of RASSF1A and CDH13 genes occur frequently in NSCLC.…”

Forging Ahead through Darkness: PCNA, Still the Principal Conductor at the Replication Fork

“…High PARI expression in tumors is associated with increased sensitivity to genotoxic cancer therapy, presumably through its HR-inhibiting activity (Pitroda et al, 2014). Mice expressing the K164R mutant as the only source of PCNA show altered somatic hypermutation at the IgG loci (Roa et al, 2008), suggesting that human B-cell deficiency syndromes may also be caused by defective PCNA ubiquitination.…”