Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

Abstract

BACKGROUND.The double‐strand break (DSB) repair capacity has been implicated in the survival of patients in several cancer types. However, little is known about the prognostic importance of the key DSB repair genes—ataxia‐telangiectasia mutated (ATM), DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs), and the Ku heterodimeric regulatory complex 86‐kD subunit (Ku80)—in nonsmall cell lung cancer (NSCLC). To address this issue, the authors determined the messenger RNA (mRNA) expression of these genes in patients NSCLC and assessed their prognostic relevance.METHODS.mRNA expression levels of ATM, DNA‐PKcs, and Ku80 were measured in tumor and adjacent normal tissues from 140 patients with NSCLC by using quantitative real‐time polymerase chain reaction analysis. Then, a Cox proportional hazards regression model and Kaplan‐Meier plots were used to evaluate the association between the tumor:normal (T/N) expression ratios of the 3 genes and the overall survival rate and duration in patients with NSCLC.RESULTS.mRNA expression of ATM and DNA‐PKcs, but not of Ku80, was significantly higher in tumor tissues than in adjacent normal tissues (P = .003 and P < .001, respectively). The high T/N expression ratios of ATM and DNA‐PKcs were associated significantly with a 1.82‐fold increased risk of death (95% confidence interval, 1.05–2.70) and a 2.13‐fold increased risk of death (95% confidence interval, 1.21–3.76), respectively. However, no significant association with risk was observed for Ku80. Kaplan‐Meier analyses revealed that patients with high T/N expression ratios of ATM or DNA‐PKcs had notably shorter median survival than patients with low ratios.CONCLUSIONS.The current findings suggested that the T/N expression ratios of ATM and DNA‐PKcs may be useful for identifying NSCLC patients with a poor prognosis who may benefit from more aggressive therapy. Cancer 2008. ©2008 American Cancer Society.

Influence of XRCC4 expression in esophageal cancer cells on the response to radiotherapy

“…XRCC4 expression could also relate with treatment effects of platinum-based chemotherapy, contributing to its significant relationship with results of our study. There are several reports demonstrating that decreased expression of proteins involved with NHEJ, such as Ku70, Ku86, DNA-PKcs, and XRCC4 in cancer tissues [17][18][19][20][21]. The regulatory mechanisms of expression of NHEJ proteins have not been elucidated.…”

Ku80 Is Differentially Expressed in Human Lung Carcinomas and Upregulated in Response to Irradiation in Mice

“…L ung cancer, which has the highest mortality among all malignancies worldwide, has a current 5-year survival rate of < 15% and constitutes a major threat to human health (Greenlee et al, 2000;Xing et al, 2008). Radiotherapy with gamma irradiation is one important strategys used in the treatment of lung cancers and has been shown to cause DNA damage, cell cycle arrest, and apoptosis.…”

“…DNA double-strand breaks (DSBs) resulting from ionizing radiation are among the most severe types of DNA damage (Xing et al, 2008), with unrepaired DSBs leading to oncogenic transformation and genetic instability. The two major pathways for DSB repair are homologous recombination and nonhomologous end joining (NHEJ) (Kotnis et al, 2009).…”

Inflammatory response to isocyanates and onset of genomic instability in cultured human lung fibroblasts

“…Incidentally, ATM gene mutations are implicated in many human cancers including lung cancer (Xing et al, 2008). Moreover, p53 tumor suppressor is considered to be a mutational target of many environmental carcinogens (Xiao and Singh, 2007), and previous studies have reported that p53 mutations are common in lung cancer and range from 40 to 70% (Zhang et al, 2006;Bumroongkit et al, 2008).…”