Frequent Loss of CACNA1C Is Associated With Poor Prognosis in Non‐Small Cell Lung Cancer

Lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are common histologic subtypes of non-small cell lung cancer (NSCLC), usually diagnosed at advanced stages with a dismal survival rate. A high-resolution SNP array (Affymetrix 250 NspI) analysis of five primary NSCLC tumors and their follow-up mucosal biopsies (n = 25) identified frequent copy neutral loss of heterozygosity (LOH, loss of 59 SNPs) of CACNA1C, a calcium voltage-gated channel subunit. Transcriptomic profiling utilizing The Cancer Genome Atlas (TCGA) revealed frequent loss of mRNA expression of CACNA1C in LUAD and LUSC tumors compared to the normal counterparts. Loss of CACNA1C mRNA expression was significantly associated with stage, grade, lymph node metastasis, P53 gene mutation, and the worst survival of these patients. We also recorded significantly higher promoter methylation of CACNA1C in the tumors compared to the normal counterparts. Increased level of promoter hypermethylation of CACNA1C was significantly associated with stage, grade, lymph node metastasis, P53 gene mutation, and poor survival of the patients. We also identified frequent mutations in CACNA1C among the NSCLC patients, which were associated with immune function modulation. Analysis of an independent cohort of NSCLC subjects revealed significant loss of CACNA1C protein expression in primary tumors (n = 31) and lymph node metastases (n = 10) compared to normal tissues. Loss of CACNA1C protein expression appeared to be an early event in LUAD patients. Further validation of CACNA1C expression in larger cohorts and functional characterization would be beneficial for potential biomarkers and therapeutic development.