| Background and Objective:Small cell lung cancer(SCLC)is an invasive neuroendocrine tumor and is defined as a highly differentiated epithelial malignancy which composed of small cells.The treatment of SCLC is progressing slowly,and chemotherapy is currently an important part of various treatments.However,according to clinical results,small cell lung cancer is highly susceptible to drug resistance,ie,chemotherapy resistance,and studies have shown that individual genetic variation may affect drug response and patient prognosis.A number of studies have shown that miRNAs and their target genes play important roles in the development of tumors.In addition,it has recently been discovered that key molecules in the process of cross-injury synthesis play an important role in maintaining genomic stability and preventing carcinogenesis of DNA-damaging cells.In this study,candidate gene strategy was used to investigate the associations between genetic variations in miRNA seed regions and cross-injury synthesis pathway genes and response or survival in small cell lung cancer patients receiving platinum-based chemotherapy,and to find molecular markers related to chemotherapy response and prognosis.Methods:This study enrolled patients of SCLC who were treated with the first-pass platinum-based chemotherapy in Cancer Hospital of Chinese Academy of Medical Sciences from March 2001 to June 2017.The patients were mainly from Beijing and surrounding areas.The Sequenom MassARRAY platform was used to detect genotypes of 14 SNPs in miRNA seed regions and 24 tagSNPs in TLS pathway genes in DNA from peripheral blood of patients.Chemotherapy response of correlation analysis and survival analysis were performed using statistical methods such as Logistic and Cox proportional hazards multivariate regression models.Results:Among 1030 cases,558(54.2%)cases received cis-platinum and etoposide treatment while others treated with carboplatin and etoposide.Seven hundred and eighty eight patients were chemotherapy responders in the study with a response rate of 76.5%.Patients were followed up to get their survival information.The median survival time(MST)of these patients was 22.5 months.Six hundred and seventy three patients(65.3%)had died by the last date of follow-up to get their survival information(Dec 21,2017).Cox proportional hazards regression model analysis showed that the genetic variation of rs266435 G>C in the seed region of miRNA-4804-5p was associated with overall survival in patients with small cell lung cancer(additve modle:HR=0.87,95%CI=0.78-0.97,P=0.012).The target gene of miRNA-4804-5p was verified to be NUS1 by software prediction and experiments.Genetic variations of TLS pathway rs73120833 T>C variation in the intron region of POLK and rsl0584411 CGA deletion variation in the 5' near-gene region of POLI were associated with overall survival in SCLC patients(additve modle:HR=0.87,95%CI=0.77-0.97,P=0.021;HR=1.14,95%CI=1.01-1.29,P=0.037,respectively).These SNPs were not associated with the chemotherapy response of SCLC patients who received platinum-based chemotherapy(all P>0.05).Correlation analysis showed that patients with KPS>80 and those with limited-stage had a better chemotherapy response than those with KPS<80 and with extensive-stage(all P<0.05).Age?56,KPS>80,limited-stage,chemotherapy response and radiation therapy can remarkably prolong OS(all P<0.05).Conclusions:This study found that rs266435 in the seed region of miRNA-4804-5p,rs73120833 of POLK gene and rs10584411 of POLI gene were all associated with the survival of small cell lung cancer,and NUS1 was found to be the target gene of miRNA-4804-5p.This study is helpful to provide a comprehensive understanding of the relationship between genetic variation and the prognosis of patients with small cell lung cancer.These SNPs may be potential genetic biomarker for SCLC personalized treatment. |
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