Recent studies underscore the general cytoprotective role of PARP1 and PAR in response to multiple extrinsic and intrinsic stress signals. Moreover, elevated levels of PARP have been correlated with increased tumor aggressiveness in breast cancer. Based on these premises, we decided to test whether PARP/PAR levels would be associated with prognosis in a cohort of localised NSCLC patients. Our cohort of patients underwent surgery from 1994 to 2002 and did not receive any chemotherapy. In these tumors, expression of PARP enzyme and the presence of its product, PAR, exhibited a significant, though not absolute, correlation, as determined by immunohistochemistry. The staining of PAR and PARP was almost exclusively nuclear, though highly variable in its intensity. Ninety-two NSCLC specimens were scored on a continuous scale of 0-300 and patients were stratified (separated by the median) into PAR low, PAR high, PARP low and PARP high groups. Tumor-infiltrating lymphocytes (which manifest high PARP and PAR levels) were used as an internal positive control of the staining procedure. Of note, among PARP low tumors, 32.5% were PAR high, indicating that low PARP protein levels do not preclude a high enzymatic activity. While high PAR levels had a significant negative impact on both disease-free (DFS) and overall survival (OS) (p=0.02 and 0.01, in univariate and 0.07 and 0.04 in multivariate analysis respectively), PARP expression did not correlate with either of these outcomes. We could validate PAR as a negative prognostic biomarker in a second cohort of 136 patients operated from 2002 to 2006. Altogether, these results identify high PAR levels as a biomarker of dismal prognosis in NSCLC.
Citation Format: Judith Michels, Aïcha Goubar, Julien Adam, Lorenzo Galluzzi, Ken André Olaussen, Angélique Robin, Philippe Girard, Isabelle Kremer, Maria Castedo, Jean-Charles Soria, Guido Kroemer. Overactivation of poly (ADP-ribose) polymerase (PARP) in localised non-small cell lung cancer (NSCLC) predicts dismal prognosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4691. doi:10.1158/1538-7445.AM2014-4691
