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Loss of tumour-specific ATM protein expression is an independent prognostic factor in early resected NSCLC
Lars F Petersen1, Alexander C Klimowicz2,3, Shannon Otsuka1
1Department of Oncology, Tom Baker Cancer Centre and University of Calgary, Calgary, Alberta, Canada, T2N 4N2.
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.
Insights
Ataxia-telangiectasia mutated (ATM) deficiency occurs in nearly a quarter of early non-small cell lung cancer (NSCLC) patients. ATM loss is linked to poorer survival, particularly in stage II/III NSCLC, and may predict chemotherapy benefit.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Ataxia-telangiectasia mutated (ATM) is crucial for maintaining genomic integrity, responding to DNA double-strand breaks.
- ATM signaling pathways regulate cell-cycle arrest, DNA repair, and apoptosis.
- ATM deficiency's role in early non-small cell lung cancer (NSCLC) progression and patient outcomes requires further investigation.
Purpose of the Study:
- To determine the frequency of ATM deficiency in early-resected NSCLC.
- To evaluate the influence of ATM expression levels on clinical outcomes in NSCLC patients.
- To assess the potential of ATM deficiency as a prognostic biomarker and predictor of chemotherapy response.
Main Methods:
- Quantitative fluorescence immunohistochemistry was used to analyze ATM expression in 165 NSCLC tumor tissue microarrays.
- ATM expression in malignant cells and the ATM expression index (ATM-EI) were measured.
- Correlation analysis was performed between ATM expression, ATM-EI, and clinical outcomes, including survival and response to adjuvant chemotherapy.
Main Results:
- ATM loss was identified in 21.8% of early-resected NSCLC patients, independent of clinical pathological variables.
- Patients with low ATM-EI tumors exhibited significantly worse survival outcomes compared to those with high ATM-EI (p < 0.01).
- The negative prognostic impact of low ATM-EI was particularly pronounced in stage II/III NSCLC patients (p < 0.001) and suggested potential benefit from adjuvant chemotherapy.
Conclusions:
- ATM loss is an early event in NSCLC carcinogenesis.
- ATM deficiency, indicated by low ATM-EI, is an independent prognostic factor associated with worse survival in stage II/III NSCLC.
- ATM status may inform treatment decisions, particularly regarding adjuvant chemotherapy efficacy in NSCLC.