Analysis Of Genomic Alterations And Its Prognosis Relevance In Esophageal Squamous Cell Carcinoma

Esophageal cancer is the fourth most common malignancy in China, and squamous cell carcinoma (ESCC) is the most prevalent type. Multiple changes have been found in ESCC, but little is known about major oncogenes and tumor suppressor genes involved in this disease. In the present study, we investigated the genomic alterations and prognosis relevance in esophageal squamous cell carcinoma.We analyzed the whole-genome copy number changes of 5 moderate dysplasias. 11 severe dysplasias and 79 ESCCs using oligo array comparative genomic hybridization (array CGH), and found that gains of 3q,8q, llq13.3 and losses of 3p, 9p,9q were common events in all the three types of samples. High-level amplifications of 7pl1.2 (SEC61G, EGFR, LANCL2), llq13.3 (CCND1,0RA0V1, FGF19, FGF4, FGF3, AN01, FADD, PPFIA1, CTTN, SHANK2) and homozygous deletion of 9p21.3 (CDKN2A, CDKN2B) existed in both ESCC and dysplasia.Gains of llq13.2 and losses of 7q34 and 18q21.1-q23 were associated with poor prognosis of ESCC. We selected the CPT1A and AN01 on Hql3 for further validation. In two independent sets of samples, copy number increase of CPT1A on Ilql3.2 was correlated with short overall survival (P-.015, n= 151 and P=.044, n = 84). Multivariate analysis confirmed that CPT1A gain provided prognostic information in ESCC (HR,1.643; 95% CI,1.076 to 2.509; P=.022; HR,2.488; 95% CI,1.235 to 5.013; P=.011). Immunohistochemistry assay showed significant correlation between strong expression of CPTl A protein and poor outcome of ESCC patients (P=.018, n= 73). Amplification of ANO1 located on Ilql3.3 was also associated with unfavorable outcome of ESCC (n= 35, P=.024). From the normal esophageal epithelium, mild dysplasia, moderate dysplasia to invisive squamous cell carcinoma, ANOl mRNA expression was gradually increased. IHC showed that ANOl was overexpressed in 25% of ESCCs compared to adjacent normal tissues. Down-regulation of ANOl can promote the apoptosis of KYSE30.Our results suggested that amplifiactions of 7p11,2, llq13.3 and homozygous deletion of 9p21.3 were the early events in the development of ESCC. Copy number increase of CPTIA and ANOl were correlated with short overall survival respectively, and CPTIA alteration was an independent poor prognosticator for the disease.