Loss of tumour-specific ATM protein expression is an independent prognostic factor in early resected NSCLC
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Lars F. Petersen1, Alexander C. Klimowicz2,7, Shannon Otsuka1, Anifat A. Elegbede1, Stephanie K. Petrillo2, Tyler Williamson3, Chris T. Williamson4, Mie Konno2, Susan P. Lees-Miller5, Desiree Hao1, Don Morris1,2, Anthony M. Magliocco6, D. Gwyn Bebb1
1Department of Oncology, Tom Baker Cancer Centre and University of Calgary, Calgary, Alberta, T2N 4N2, Canada
2Functional Tissue Imaging Unit, Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, T2N 4N2, Canada
3Department of Community Health Sciences, TRW Building, University of Calgary, Calgary, Alberta, T2N 4Z6, Canada
4Gene Function Lab, The Institute for Cancer Research, London, SW3 6JB, UK
5Department of Biochemistry and Molecular Biology, HRIC Building, University of Calgary, Calgary, Alberta, T2N 4Z6, Canada
6Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, 33612, USA
7Present Address: Immunology and Inflammation Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, 06877, USA
D. Gwyn Bebb, email: [email protected]
Keywords: ATM, non-small cell lung cancer, outcome, early stage, digital pathology
Received: October 06, 2016 Accepted: February 21, 2017 Published: March 15, 2017
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.
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