Abstract
Lung cancer is the leading cause of cancer deaths worldwide. Clinical staging classification is generally insufficient to providea reliable prognosis, particularly for early stages. In addition, prognostic factors are therefore needed to better forecast lifeexpectancy and optimize adjuvant therapeutic strategy. Recent evidence indicates that alterations of the DNA replication programcontribute to neoplasia from its early stages and that cancer cells are frequently exposed to endogenous replication stress.We therefore hypothesized that genes involved in the replication stress response may represent an under-explored source ofbiomarkers. Expressions of 77 DNA replication-associated genes implicated in different aspects of chromosomal DNA replication,including licensing, firing of origins, elongation, replication fork maintenance and recovery, lesion bypass and post-replicative repairwere determined in primary tumors and adjacent normal tissues from 93 patients suffering from early- or mid-stage non-small celllung cancer (NSCLC). We then investigated a statistically significant interaction between gene expressions and survival of early-stage NSCLC patients.The expression of five genes, that is,POLQ, PLK1, RAD51, CLASPINandCDC6was associated with overall,disease-free and relapse-free survival. The expression levels are independent of treatment and stage classification. ExceptRAD51,their prognostic role on survival persists after adjustment on age, sex, treatment, stage classification and conventional proliferationmarkers, with a hazard ratio of 36.3 forPOLQ(95%CI 2.6–517.4,P¼0.008), 23.5 forPLK1(95%CI 1.9–288.4,P¼0.01), 20.7 forCLASPIN(95%CI 1.5–275.9,P¼0.02) and 18.5 forCDC6(95%CI 1.3–267.4,P¼0.03). We also show that a five-gene signature includingPOLQ,PLK1, RAD51, CLASPINandCDC6separates patients into low- and high-risk groups, with a hazard ratio of 14.3 (95% CI 5.1–40.3,Po0.001). This ‘replication stress’ metamarker may be a reliable predictor of survival for NSCLC, and may also help understand themolecular mechanisms underlying tumor progression.