Abstract 3318: Frequent loss of CACNA1C, a calcium voltage-gated channel subunit is associated with lung adenocarcinoma progression and poor prognosis

Abstract

Abstract Lung adenocarcinoma (LUAD) is a common non-small cell lung cancer disease most commonly found among non-smokers. This cancer is usually diagnosed at an advanced stage and can recur frequently and quickly with low chances of survival. Moreover, LUAD patients live with the fear of developing second primary tumors in their lifetime. A high-resolution SNP array (Affymetrix 250 NspI) analysis of primary LUAD tumors and their follow-up mucosal biopsies identified frequent copy neutral loss of heterozygosity (LOH, loss of 59 SNPs) of CACNA1C, a calcium voltage-gated channel subunit, located to human chromosome 12p13.33. Transcriptomic profiling utilizing The Cancer Genome Atlas (TCGA) revealed frequent loss of mRNA expression of CACNA1C in LUAD tumors (n=515) compared to the normal counterparts (n=59). Loss of CACNA1C mRNA expression was significantly associated with stage, grade, lymph node metastasis, P53 gene mutation, and worst survival of the LUAD patients. Epigenetic alteration such as DNA methylation could be a potential mechanism of the inactivation of a tumor suppressor gene (TSG) other than LOH, frequently observed in human cancers. We also recorded significantly higher promoter methylation of CACNA1C in the above LUAD tumors compared to the normal counterparts. Higher promoter methylation of CACNA1C was significantly associated with stage, grade, lymph node metastasis, P53 gene mutation, and poor survival of the LUAD patients. Thus, both allelic loss and methylation appear to be potential mechanisms behind the loss of function of CACNA1C in LUAD patients. Further validation of CACNA1C expression at the protein level confirmed its high membranous expression in normal lung tissues. Analysis of an independent cohort of LUAD subjects revealed significant loss of CACNA1C in primary tumors (n=30) and lymph node metastases (n=10) of LUAD patients compared to their normal counterparts. Loss of CACNA1C protein expression was associated with lymph node metastasis and stage-wise progression of the LUAD patients. Further validation of CACNA1C expression in larger cohorts and functional characterization would be beneficial for potential biomarkers and therapeutic development in the longer run. On the other hand, epigenetically silenced TSGs can be reactivated by CRISPR-CAS9-based technology or demethylating agents, implicating the therapeutic promise of targeting TSGs. Citation Format: Saanvi Dasgupta, Srijan Acharya, Mohammad A. Khan, Paramahansa Pramanik, Stephen M. Marbut, Furhan Yunus, Jose N. Galeas, Seema Singh, Ajay P. Singh, Santanu Dasgupta. Frequent loss of CACNA1C, a calcium voltage-gated channel subunit is associated with lung adenocarcinoma progression and poor prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3318.