title: 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.
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60647, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Pitroda
authors.forename: Itai M
authors.initials: IM
authors.lastname: Pashtan
authors.forename: Hillary L
authors.initials: HL
authors.lastname: Logan
authors.forename: Brian
authors.initials: B
authors.lastname: Budke
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Darga
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: Philip P
authors.initials: PP
authors.lastname: Connell
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D004358:Drug Therapy; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D042822:Genomic Instability / Q000187:drug effects; D059765:Homologous Recombination / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D011379:Prognosis; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents