Loss of tumour-specific ATM protein expression is an independent prognostic factor in early resected NSCLC

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.

Targeted next generation sequencing identified a high frequency genetic mutated profile in wood smoke exposure-related lung adenocarcinoma patients

“…Our findings also report frequent frameshift mutations in the ATM tumor suppressor gene leading to protein truncation in patients with lung adenocarcinoma. This is consistent with the fact that ATM mutations represent an early event in NSCLC pathogenesis and over 40% of lung adenocarcinomas are negative for ATM protein expression [ 22 ]. This gene has been found to be deficient serving as an independent prognostic factor associated with worse survival in stages II/III and chemotherapy resistance [ 22 ].…”

“…This is consistent with the fact that ATM mutations represent an early event in NSCLC pathogenesis and over 40% of lung adenocarcinomas are negative for ATM protein expression [ 22 ]. This gene has been found to be deficient serving as an independent prognostic factor associated with worse survival in stages II/III and chemotherapy resistance [ 22 ]. Moreover, several ATM polymorphisms are risk factors for developing lung cancer in never smokers with low levels of carcinogen exposure [ 23 ].…”

“…Moreover, several ATM polymorphisms are risk factors for developing lung cancer in never smokers with low levels of carcinogen exposure [ 23 ]. Upon loss of ATM function, patients experience genomic instability that can be targeted through inhibition of alternative DNA repair mechanisms in combination with TKIs, which result in better response and overall survival [ 22 , 23 ].…”

Combined poly-ADP ribose polymerase and ataxia-telangiectasia mutated/Rad3-related inhibition targets ataxia-telangiectasia mutated-deficient lung cancer cells

“…22,24,25 We also demonstrated that relative loss of ATM has clinical implications, conferring worse outcome and associated with improved benefit from cisplatin therapy. 26 Another potential target for PARP inhibitor therapy is lung cancer. Lung cancer is the leading cause of cancer death worldwide.…”

Cell Fate Regulation upon DNA Damage: p53 Serine 46 Kinases Pave the Cell Death Road

“…AMPK shows an overall mutation rate of 2.1–3% (for the two isoforms of the catalytic subunit, respectively), ATM of 6%, DYRK2 of 2.7%, HIPK2 of 2.9%, p38α of 1.4%, and PKCδ of 1.7% (assessed via http://cbioportal.org). Reduced expression of the p53 Ser46 kinases in human tumors has been reported for four of the kinases: ATM in hormone‐negative breast cancer and non‐ small cell lung cancer; DYRK2 in colorectal cancer, hepatocellular carcinoma, and breast cancer; HIPK2 in oesophageal squamous cell carcinoma; and PKCδ in colon cancer . However, since the function of kinases depends on their specific activity and a number of Ser46 kinases, including DYRK2, HIPK2, PKCδ, and p38α, are regulated by their subcellular localization, it will be a complex task to determine their potential deregulation in cancer.…”