Abstract 3868: Clinical significance of MRE11A/ATM/CHEK1 DNA damage response genes in oral cavity squamous cell carcinomas

Abstract

Abstract Oral cavity squamous cell carcinoma (OSCC) is one of the most common cancers in Taiwan and worldwide. Except cigarette smoking and alcohol drinking, areca quid (AQ) chewing is also the major risk factor of OSCC in Southeast Asia including Taiwan. Despite better methods of diagnosis and new treatment procedures, there has not been a significant improvement in the five year survival rate for OSCC in the past 30 years. To explore some clues for clinical management of OSCC, we carried out whole genome loss of heterozygosity (LOH) and copy number alterations (CNAs) analysis and found high frequency of minimal deleted region (MDR) in11q13.4-q25 and significant CNA region in 11q22.3-q24.3. In this region, several DNA damage response (DDR) genes are located including MRE11A, ATM, H2AFX and CHEK1. The DDR pathway represents a complex network of multiple signaling pathways involving cell cycle checkpoints, DNA repairs, transcriptional programs, and apoptosis, through which cells maintain genomic integrity following various endogenous or environmental stress. To investigate the clinical significance of DDR pathway in OSCC, CNAs and LOH of ATM, MRE11A, and CHEK1 gene were analyzed in the present study. A total number of 324 OSCCs were first examined for CNAs using TaqMan CNV analysis and the copy number neutral cases were then examined for LOH using TaqMan SNP analysis and denaturing high performance liquid chromatography (DHPLC). Preliminary results indicated that only 8% (26/324) of OSCCs did not have any alterations in these 3 genes. The frequency of loss of MRE11A, ATM and CHEK1 gene was 7.10% (23/324), 15.74% (51/324) and 13.89% (45/324), respectively. Loss of MRE11A, ATM, and CHEK1 was associated with tumor differentiation and lymph node metastasis. The frequency of LOH in MRE11A, ATM, and CHEK1 gene was 37.84% (42/111), 50% (61/122) and 58.28% (95/163), respectively and LOH of MRE11A was associated with tumor differentiation. Combined the loss and LOH as the alteration event, we found that alterations of MRE11A, ATM, and CHEK1 gene were associated with tumor differentiation. Alterations of MRE11A and ATM were associated with early lymph node metastasis, while alterations of CHEK1 were associated with late lymph node metastasis. Alterations of MRE11A, ATM, and CHEK1 gene were associated with poor disease-free survival (DFS) and overall survival (OS) and gene loss had a stronger effect than LOH. Furthermore, alterations of MRE11A/ATM/CHEK1 as a whole were strongly associated with poor DFS and OS. These results confirmed our previous MDR findings and indicated that MRE11A/ATM/CHEK1 pathway might play a crucial role in the development and progression of OSCCs. Citation Format: Huei-Tzu Chien, Shiang-Fu Huang, I-How Chen, Chun-Ta Liao, Hung-Ming Wang, Ling-Ling Hsieh. Clinical significance of MRE11A/ATM/CHEK1 DNA damage response genes in oral cavity squamous cell carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3868. doi:10.1158/1538-7445.AM2015-3868