Development of prognostic biomarker in pathologic stage I NSCLC patients: Protein expressions involving in DNA damage response

초록

Background: Although mechanism of proteins involving DNA damage-response (DDR) pathway remains to be further elucidated, these proteins have role of suppressing tumor development or progression. Current guidelines has argued that postoperative treatment is not beneficial for patients with stage I non-small cell lung cancer (NSCLC). Therefore, development of prognostic biomarker is very important clinical issue in stage I NSCLC. Methods: We constructed tissue microarrays with paraffin-embedded primary lung cancer tissue from 889 pathologic stage I NSCLC patients (401 squamous cell carcinoma, SQC 488 adenocarcinoma, ADC) who received completely surgical resection. Expression levels of 12 proteins (ATM, ATMpS1981, H2AX, MCPH1/BRIT1, 53BP1, 53BP1pS25, Chk2, Chk2pT68, MDC1, MDC1pS964, BRCA1pS1423, ERCC1), clinicopathologic variables and overall survival were investigated. Results: Overall survival of a total of 889 patients was 128 months (MST: 123.8 months in SQC vs NR in ADC, log-rank P .1337). Higher level of expressions in H2AX, BRCA1pS1423 or ERCC1 were significantly associated with better survival in the patients after adjustment for significant clinicopathologic variables [aHR (95%CI), Cox P: 1.271 (1.005 to 1.680), 0.045 for H2AX, 1.348 (1.067 to 1.704) for BRCA1pS1423, 0.012 and 1.326 (1.042 to 1.689), 0.022 for ERCC1]. When analyzed by cell types, higher level of expressions in H2AX, Chk2pT68 or ERCC1 were shown to be good prognostic factors even after adjustment for significant clinicopathologic variables in SQC patients [aHR (95%CI), Cox P: 1.537 (1.096 to 2.157), 0.013 for H2AX, 1.618 (1.120 to 2.336), 0.010 for Chk2pT68 and 1.689 (1.197 to 2.383), 0.003 for ERCC1]. However these effects (on survival) were not shown to be in ADC patients. Conclusions: The proteins’ expressions involving DDR pathway as well as ERCC1 are determinant of survival in stage I SQC patients that could be helpful in classifying the patients into groups of high or low risk for