Roles Of Genetic Polymorphism And Mutation In Esophageal Squamous Cell Carcinoma (ESCC) And Non-small Cell Lung Cancer (NSCLC)

Part Ⅰ Genetic variants in PLCE1and risk of esophageal squamous cell carcinomaEsophageal squamous cell carcinoma (ESCC) is one of the malignant tumors driven by genetic abbreviations and several environmental factors including dietary content and dietary habit. Until recently, no driver mutations has ever been identified to contribute to the carcinogenesis of ESCC exclusively. However, a novel single nucleotide polymorphisms (SNP, rs2274223) located in the phospholipase C epsilon1(PLCE1) gene was found to be associated with risk of esophageal squamous cell carcinoma (ESCC) by two large-scale genome-wide association studies (GWASs), indicating its genetic and epidemiologic value in Chinese populations with high ESCC incidences (northern and western Chinese populations). As there are yet no studies focus on the PLCE1variants in the populations with low ESCC incidences (e.g. eastern Chinese populations) as well as its biological function, we aimed to assess such an association in an eastern Chinese population and to address its possibly functional role in the etiology of ESCC in this study.As a hospital-based case-control study, a total of1061ESCC cases and1211controls were recruited and successfully genotyped for two single nucleotide polymorphisms (rs2274223and rs11187870) of the PLCE1gene by the TaqMan assay. According to the result of genotyping, quantitative real-time PCR and immunohistochemical (IHC) analysis were applied to assess mRNA and protein expression levels in matched tu-mor/normal tissues with diverse genotypes respectively.In this eastern Chinese population, SNP rs2274223was independently associated with risk of ESCC (adjusted OR,1.49;95%CI,1.03-2.17for GG vs. AA). The Grs2274223Crs11187870haplotype increased the risk for ESCC by1.22-fold (95%CI,1.04-1.42). Further experiments showed that overall PLCE1mRNA expression level in tumor was lower than that in paired normal tissues (0.067±0.016vs.0.264±0.067, P<0.05), and the IHC analysis showed the normal tissues of rs2274223GG genotype had a lower PLCE1staining score than that of the AG genotype (0.40±0.22vs.1.33±0.32,P<0.05).PLCE1SNP rs2274223A>G change might reduce gene expression and contribute to risk of ESCC. Part II Identification of RET fusion gene in non-small cell lung can-cer with analysis of clinicopathological characteristicsThe carcinogenesis of lung cancer is considered as a cumulative process with multiple genetic abbreviations, and can be deifned by several exclusive driver mutations into corresponding molecular subtypes for further targeted therapy application and inves-tigation. For non-small cell lung cancer (NSCLC), especially for lung adenocarcino-mas, major known driver mutations including abbreviations in EGFR, KRAS, HER2, BRAF and ALK genes in forms of point mutations, insertions, deletions or fusions. Most recently, the RET fusion gene has been described in a subset of non-small-cell lung cancers (NSCLCs). As we still have limited knowledge about these tumors, this study was aimed at determining the RET fusion gene in Chinese NSCLC samples as well as the clinicopathologic characteristics of patients harboring the RET fusion gene.We examined the RET fusion gene in936patients with surgical resected NSCLCs us-ing a reserve transcript polymerase chain reaction (RT-PCR) plus quantitative re-al-time PCR strategy, and validated them using fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) assays. The subset of633patients with lung ade-nocarcinomas were also detected for EGFR, KRAS, HER2, BRAF mutations as well as ALK rearrangements. Patient characteristics including age, sex, smoking history, stage, grade, IASLC/ATS/ERS classification of subtypes of lung adenocarcinoma, and re-lapse-free survival were collected.From936patients with NSCLCs, the RET fusion gene was exclusively detected in13patients (11out of633patients with adenocarcinomas, and2out of24patients with adenosquamous cell carcinomas), including9with KIF5B-RET,3with CCDC6-RET, and1with a novel NCOA4-RET fusions. Patients with lung adenocarcinomas with RET fusion gene had more poorly differentiated tumors (63.6%,P=0.029for RET vs. ALK, P=0.007for RET vs. EGFR),with a tendency to younger patients (<60,72.7%), never smokers (81.8%), solid subtype (63.6%), and early N2disease(54.4%). The median relapse-free survival of the patients with RET fusion-positive NSCLCs was20.6months.RET fusion defines an exclusive subtype of NSCLCs with identifiable clinicopatho-logical characteristics. This novel driver mutation as well as a NCOA4-RET fusion form first detected in NSCLC warrant further clinical consideration and targeted therapy investigations.