Dectection Of EML4-ALK And Gp130Mutation And Their Coincidence With EGFR And K-RAS Mutation In Lung Cancer

Lung cancer is the most frequent cause of cancer-related death worldwide, andits morbidity and mortality have been ranked first in a variety of malignant tumors,accounting for more than1million deaths per year. Despite therapeutic advances,lung cancer is often diagnosed at an advanced stage and has a poor prognosis.Palliative chemotherapy in advanced or metastatic lung cancer is associated with onlymodest survival prolongation and improved quality of life and the overall5-yearsurvival remains only15%.Beside smoking and environmental exposures, lung caner is also thought to berelated to genetic susceptibility, and is considered to be a multi-step process involvingoncogenes and tumor suppressor genes. In recent years, with a deep understanding ofthe molecular mechanism of tumorigenesis, the molecular targeting therapy, treatmentby blocking the function of specific target molecules involved in cancer, becomes themost promising tumor treatment because of its high specificity and less adversereaction. So far in the field of molecular targeted therapy of lung cancer, theepidermal growthfactor receptor (EGFR) and K-Ras are the main therapeutic targets.Lung cancer patients with activating EGFR mutations which are more common amongnever-smokers often respond well to EGFR tyrosine kinase inhibitor(TKI) and have asurvival advantage. But some of the patients would develop drug resistance finally.However, for patients who don’t harbor EGFR mutations or those who develop drugresistance to EGFR-TKI, finding other molecular targets would be an important focusin the rearch on molecular target therapy for lung cancer.of lung caner theraputicresearch.In2007, Soda et al identifed another potential driver mutation inNSCLC—fusion of the N-terminal portion of the protein encoded by the echinodermmicrotubule-associated protein-like4(EML4)gene with the intracellular signalingportion of the receptor tyrosine kinase encoded by the anaplastic lymphoma kinase(ALK) gene. At least thirteen different variants have been identifed and some of themyield gain of function in vitro. The frequency of EML4-ALK translocation ranges from3%to7%in unselected NSCLC. EML4-ALK translocations are lungcancer-specific, mutually exclusive with EGFR mutations and the effectiveness ofALK inhibitor treatment is closely related to the positivity of EML4-ALK fusion gene.Above all, the rapid accumulation of the clinical data of EML4-ALK in lung cancerbecomes the focus of current research.At present, a large number of clinical information about the EML4-ALK fusiongene comes from the foreign studies, such as Europe, America, Japan and SouthKorea; only a few studies have evaluated EML4-ALK fusion genes in Chinese lungcancer patients and the prevalence of different EML4-ALK fusion variants has notbeen particularly well studied. Considering the differences in genetic andenvironmental factors are related to lung cancer, it is possible that the profile ofEML4-ALK fusion variants in the context of Chinese lung cancer patients may differfrom those of other countries. Therefore, it’s very important to obtain clinical datasabout the occurrence of EML4-ALK transloction in Chinese lung cancer patients assoon as possible.Given this, we evaluated EML4-ALK fusion variants usingreverse-transcriptase-polymerase chain reaction (RT-PCR) in a cohort of75Chineselung caner patients. Within this cohort, the viriant1of EML4-ALK fusion gene wasidentified in a37-year-old female non-smoking adenocarcinomas patient. Furtheranalysis revealed that EML4-ALK was present at a frequency of1.7%(1/56) innon-small cell lung cancers (NSCLCs) and8.3%(1/12) in adenocarcinomas. Thepatient who is positive in EML4-ALK has no EGFR and KRas mutations. Our articleis the first report on the occurrence of EML4-ALK fusion gene and the clinicalcharacteristics of EML4-ALK positive patients of lung cancer in northern China.Although no statiscal difference has been caculated because of the limited number ofcases, our result about the frequency of EML4-ALK occurrence and its related clinicalfeature in lung cancer patients in north China is similar with those in Hong Kong andShanghai. So our research is a good supplement for the accumulation of clinical dataabout the EML4-ALK fusion gene, and provides a reference for further study on thefrequency and clinical features with EML4-ALK fusion gene in Northern Chinese lung cancer patients.Moreover, to identify new potential mocular targets for molecular target therapyof lung cancer, we pay our attention on Glycoprotein130（Gp130.Gp130isubiquitously expressed in tissues and mediates numerous homeostatic functions,including immune response, inflammation, bone metabolism, and hematopoiesis.Gain-of-function Gp130mutations is a novel class of mutations in a receptor that iscentral to the IL-6/Gp130/STAT3inflammation pathway and is important in thedevelopment of hepatocellular adenomas. Based on the close relationship betweenIL-6/Gp130/STAT3pathway and lung cancer, Gp130mutation maybe one of themechanisms responsible for activation of IL-6/Gp130/STAT3pathway in lung canerdevelopment. However, whether the Gp130mutation exists in lung cancer or not isstill unkown.To test the existence of Gp130mutation in lung cancer, we assessed gp130exon6mutations in a conhort of110Chinese lung cancer patients among which3cases ofadjacent normal lung tissues were included by using PCR coupled with sequencing.Within this cohort, a novel Gp130mutation, genomic599C G was identified inboth lung cancer and its adjcent normal lung tissues of only one patient who is femalenon-smoker with adenocarcinomas. This mutation leads to the200thamino acidchanged from Alanine to Glynine. Furthermore, gp130mutation-positive lung cancerwas proved to harbor no EGFR and K-Ras mutation.Therefore, further research isneeded to explore the functional significance of Gp130mutation in the developmentof lung caner.