Abstract
Ataxia-telangiectasia mutated (ATM) is critical in maintaining genomic integrity. In response to DNA double-strand breaks, ATM phosphorylates downstream proteins involved in cell-cycle checkpoint arrest, DNA repair, and apoptosis. Here we investigate the frequency, and influence of ATM deficiency on outcome, in early-resected non-small cell lung cancer (NSCLC). Tissue microarrays, containing 165 formalin-fixed, paraffin-embedded resected NSCLC tumours from patients diagnosed at the Tom Baker Cancer Centre, Calgary, Canada, between 2003 and 2006, were analyzed for ATM expression using quantitative fluorescence immunohistochemistry. Both malignant cell-specific ATM expression and the ratio of ATM expression within malignant tumour cells compared to that in the surrounding tumour stroma, defined as the ATM expression index (ATM-EI), were measured and correlated with clinical outcome. ATM loss was identified in 21.8% of patients, and was unaffected by clinical pathological variables. Patients with low ATM-EI tumours had worse survival outcomes compared to those with high ATM-EI (p < 0.01). This effect was pronounced in stage II/III patients, even after adjusting for other clinical co-variates (p < 0.001). Additionally, we provide evidence that ATM-deficient patients may derive greater benefit from guideline-recommended adjuvant chemotherapy following surgical resection. Taken together, these results indicate that ATM loss seems to be an early event in NSCLC carcinogenesis and is an independent prognostic factor associated with worse survival in stage II/III patients.
Highlights
Recent studies have suggested that non-small cell lung cancer (NSCLC) exhibits a greater degree of genetic instability than most other malignancies [1, 2]
We provide evidence that Ataxia-telangiectasia mutated (ATM)-deficient patients may derive greater benefit from guideline-recommended adjuvant chemotherapy following surgical resection. These results indicate that ATM loss seems to be an early event in nonsmall cell lung cancer (NSCLC) carcinogenesis and is an independent prognostic factor associated with worse survival in stage II/III patients
The key role held by ATM in maintaining genomic integrity as part of the DNA damage response (DDR) suggests that early loss of ATM function in the process of malignant transformation could herald the generation of a mutator phenotype, an “enabling feature” in the evolution of cancer [25]
Summary
Recent studies have suggested that non-small cell lung cancer (NSCLC) exhibits a greater degree of genetic instability than most other malignancies [1, 2]. The cause of such genomic instability in NSCLC is not well understood. Associated with extensive mutagen exposure through smoking in 80% of patients, this genetic instability is surprisingly matched and even exceeded in non-smoking related cases [3] Genetic heterogeneity, both between and within tumours, has been proposed as a barrier to successful treatment [4] of the advanced disease stage with which most NSCLC patients present, contributing to the disappointing 15% overall five-year survival [5]. This method is not quantitative, nor does it account for tissue heterogeneity within the sample
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