Studies On Chromosome Aberrations And Amplified Oncogene Candidates 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 genetic changes have been found in ESCC,but little is known about major oncogenes and tumor suppressor genes involved in this disease.To surveying chromosome imbalances in this disease,we analyzed statistically high-frequency chromosomal changes of ESCC from the previous studies by multicolour fluorescence in situ hybridization(M-FISH) and comparative genomic hybridization(CGH).Chromosome 3,5,8,and centromeric rearrangements,were the most common structural aberrations.The gains of 3q and 8q were the recurrent numerical abnormalities.We focused on the genes within 75Mb of 3q24-q29 with frequent aberrations, especially 3q26.2,3q26.31,and 3q26.33 with highest copy numbers in tumors.Four cancer-related genes(MDS1,PRKCI,ECT2,and PIK3CA) on chromosome 3q26 were further investigated.To assess the prevalence of copy number gains of putative genes,fluorescence in situ hybridization(FISH) was applied on 108 ESCCs and 9 ESCC cell lines.Our data showed that MDS1 and PRKCI were more frequently gained.Positive correlation was found only for PRKCI between amplification and pT(P=0.043),lymph node metastasis(P=0.015),and clinical stage(P=0.002).PRKCI gene(also as PKCι) located at 3q26.2,is one mumber of the protein kinase C(PKC) family of serine/threonine kinases,plays a pivotal role in transformed growth,invasion and survival.In the present study,PRKCI gene amplification was highly correlated with protein overexpression(P=0.009),suggesting that gene amplification is one important mechanism involved in PRKCI overexpression.A tissue microarray containing samples from 180 ESCCs was used for irnmunohistochemistry.Statistical analysis revealed that PRKCI overexpression was correlated with lymph node metastasis(P=0.002) and higher stage(P=0.004). Multivariate logistic regression analysis showed a significant positive correlation between PRKCI overexpression and presence of lymph node metastasis(P=0.004).Our results indicate that PRKCI is an attractive target in the 3q26 amplicon and may serve as a candidate molecular marker for metastasis and advanced tumor stages in ESCC.