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

Measuring DNA repair pathway choice determines the sensitivity of cancers to individual classes of treatment. Navigating Tumor Therapy with an RPS For cancer patients, DNA damage is a double-edged sword. Mutations can contribute to carcinogenesis, but the cancer cell can’t survive with too much DNA damage. Indeed, many cancer therapies aim at increasing DNA damage, but selecting the correct therapies for individual patients can be hit-or-miss. Pitroda et al. proposed that mechanisms of double-strand DNA break repair could correlate with cancer prognosis and could guide choices in cancer therapy. The authors devised a recombination proficiency score (RPS) based on the expression levels for four genes involved in DNA repair pathway preference. They then validated the RPS in patients with either breast or non–small cell lung cancer. Tumors with low RPS—suppressed homologous recombination (HR)—were associated with greater mutagenesis and decreased likelihood of patient survival. This prognosis could be counteracted with platinum-based adjuvant chemotherapy—patients with suppressed HR were more sensitive to this treatment. These data suggest that RPS can help determine treatment course for cancer patients. 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.

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