Molecular Epidemiological Study On The Association Of Genetic Variations With Neuroblastoma Susceptibility And Prognosis

BackgroundNeuroblastoma(NB)is a malignant tumor originating from embryonic neuralgia and can occur in any part of the sympathetic nervous system.It is the most common malignancy in infants and young children.The 5-year survival rate is only 20-40%.To high-risk patients,despite the acceptance of a comprehensive treatment,the prognosis is still very poor.Chronic health problems greatly reduce the quality of patients' life.In summary,neuroblastoma has become a huge burden of public health and serious challenge of the society.The etiology and development process of neuroblastoma is extremely complex,the pathogenesis is not yet clear,and thus effective prediction,prevention and treatment are still lacking.In the past five GWAS performed among the European descent in the USA,nine NB susceptibility-related genes were found as:CASC15,BARD1,LMO1,HACE1,LIN28B,DUSP12,DDX4,IL31RA,HSD17B12.Their SNPs were considered as NB susceptibility-related and have been verified in African-Americans,Italians,but studies in Asia have not been reported.ObjectiveThis study aimed to analyze the differences of 23 SNP genotypes among NB patients and healthy people,to investigate the correlation between genetic variation and NB susceptibility and prognosis,and to provide a theoretical basis for the formation of new biological targeting therapy program for Chinese Han population.MethodsDNA samples were extracted from blood or paraffin pathology specimens of 256 patients with NB and blood of 531 healthy people.Epidemiological information was collected through questionnaires and medical records.Genetic variants were detected by qPCR(quantitative real-time PCR).Epidemiological characteristics and genotype distribution differences were examined by bilateral chi-square test and logistic regression adjusted by age and gender to investigate the association between SNPs and NB susceptibility.SNPs independently associated with overall survival(OS)was detected by Kaplan-Meier method,single factor and multivariate COX proportional hazards regression model adjusting for patients' demographic characteristics and clinical features.Stratified analysis was also performed according to epidemiological characteristics.Results1.SNP rs6939340?rs4712653?rs9295536 of CASC15,SNP rs7585356?rs6435862?rs3768716 of BARD1,rs11037575 of the HSD17B12,SNP rs221634?rs221634 of LIN28B,rs110419 of LMO1 were significantly associated with NB susceptibility in Chinese Han population.SNP rs2619046 of DDX4 was borderline significantly correlated with the risk of NB.The combined effects of multiple SNPs of the same gene were significantly or borderline significantly associated with the risk of NB.2.Older than 18 months,INSS clinical late stage(stage ?-?),tumors originated in the retroperitoneal region,adrenal region,other regions,low differentiation of tumors,metastasis and recurrence were risk factors of neuroblastoma prognosis.Among them,clinical stage,tumor differentiation,recurrence and age were statistically significant independent prognostic factors in multivariate analysis.SNP rs11037575CT/TT genotype of HSD17312 can significantly increase the risk of death in patients with neuroblastoma,when compared with the wild-type homozygous(single factor COX model);SNP rs204938 AG/GG genotype of LMO1 can significantly reduce the risk of death in patients with neuroblastoma,when compared with the wild-type homozygous(multi-factor COX model;forward likelihood analysis);SNP rs2619046 GA/A A genotype of DDX4 can significantly reduced the risk of death in patients with neuroblastoma,when compared with the wild-type homozygous(multivariate COX model).Conclusion1.Genetic variations and their combined effect are associated with NB susceptibility.2.Genetic variation and some demographics,clinical factors are associated with NB prognosis.3.This study validated the relationship between 23 GWAS-identified NB-related SNPs and susceptibility and prognosis of NB in Chinese Han population for the first time,which provided the theoretical basis for the further formation of new diagnosis and treatment based on genetic variation.Further invetigation by multi-center,large sample prospective studies is necessary.