| BackgroundNeuroblastoma is an embryonal cancer that arises from primordial sympathetic neural precursors,it is the most common solid extracranial malignancy of childhood.It can develop anywhere along the developing sympathetic nervous system.At least half of NB tumors originate in the adrenal medulla,and others commonly occur in paraspinal sympathetic ganglia of the neck,chest,abdomen,or pelvis.Around the world,it ranks as the third leading cause of cancer-related death in children.In China,neuroblastoma accounts for nearly 10% of childhood tumors,and its incidence is about 7.7 cases per million.Despite great achievements in multimodality treatment,the 5-year survival rate for neuroblastoma remains at less than 40% and prognosis is still very poor.Moreover,due to their chronic health conditions,it greatly reduces the quality of life of survivors.Thus,neuroblastoma remains a great burden for the affected children and for their families and society.The etiology and development process of neruoblastoma is very complex,thus the pathogenesis is still unknown.It is considered as the result of the combination of genetic and environmental factors.Neuroblastoma cases can be divided into two subgroups,namely,familial neruoblastoma(< 2% of all NBs)and sporadic neruoblastoma.The discovery ofgain-of-function mutations in the ALK receptor tyrosine kinase gene as the major cause of familial neuroblastoma led to the discovery of identical somatic mutations and rapid advancement of ALK as a tractable therapeutic target.Inactivating mutations in a master regulator of neural crest development,PHOX2 B,have also been identified in a subset of familial neuroblastomas.Other high penetrance susceptibility alleles likely exist,but together these heritable mutations account for less than 10% of neuroblastoma cases.The specific etiology of sporadic neuroblastoma is still not clear.A genome-wide association study of a large neuroblastoma cohort identified common and rare polymorphisms highly associated with the disease.It makes the genetic mechanisms of the neruoblastoma possible.Past genome-wide association study perfomed among the Caucasian and African ethnic groups showed that common single nucleotide polymorphisms in several genes are associated with the risk of developing neruoblastoma,these genes contain CASC15(6p22),LMO1(11p15),IL31RA(5q11.2),DUSP12(1q23.3),HSD17B12(11p11.2),BARD1(2q35),HACE1(6q16),LIN28B(6q16)and DDX4(5q11.2).Their 23 SNPs were considered as neruoblastoma-related,but studies in Chinese Han population is rare.Previous study reported that CASC15 and LMO1 gene polymorphisms were associated with neuroblastoma risk in Guangdong province.In this study,we evaluate the association between CASC15 and LMO1 gene polymorphisms and neuroblastoma risk in Henan province,and combine with cohorts of neuroblastoma patients from Guangdong province.ObjectiveBy analyzing three SNPs of CASC15 gene(rs6939340?rs4712653?rs9295536)and four SNPs of LMO1 gene(rs4758051?rs10840002?rs110419?rs204938)among118 neuroblastoma patients and 281 healthy controls in Chinese Han population of children in Henan province,and combined with previous Guangdong data,we assess the correlation between SNPs and neuroblastoma risk in two independent populations of China,and further explore the molecular mechanism of neuroblastoma pathogenesis,and hope to provide a theoretical basis for the future of early screening,prevention,risk classification and new targeted therapy.MethodsDNA samples were extracted from paraffin pathology specimens or blood samples from 118 neuroblastoma patients and 281 healthy controls,the demographic characteristics and clinic information were also collected.Genotyping these SNPs was performed using Taqman real-time quantitative PCR.The goodness-of-ft ?2 test was used to assess if the selected SNPs deviated from Hardy-Weinberg equilibrium among controls.The two-sided chi-squared test was used to compare demographic variables and genotype frequencies of the cases and controls.To evaluate the strength of the relationship between polymorphisms and neuroblastoma susceptibility,ORs and their corresponding 95% CIs were computed by unconditional logistic regression analyses with or without adjusting for age and gender.To determine whether the significant findings were noteworthy,the FPRP analysis was performed to evaluate the false positive rate.All reported P values were two sided and a P value < 0.05 was considered statistically signifcant.Results1.The study subjects from Henan province showed significant association with neuroblastoma risk only in the rs6939340 G>A variant(AA vs.GG: adjusted OR=0.47,95% CI=0.23-0.98,P=0.045),but not in the rs4712653 C>T and rs9295536A>C of CASC15 gene.On the other hand,all three CASC15 SNPs were associated with decreased neuroblastoma risk in the Guangdong population previously.Combining the two populations also resulted in similar results,it showed significant association with neuroblastoma risk in the rs6939340 G>A(AG/AA vs.GG: adjusted OR=0.56,95% CI=0.44-0.72,P<0.0001),rs4712653 C>T(CT/TT vs.CC: adjusted OR=0.65,95% CI=0.51-0.89,P=0.0009)and rs9295536 A>C(AC/CC vs.AA:adjusted OR=0.70,95% CI=0.54-0.90,P=0.0050).We also found that subjects with1-3 protective genotypes(rs6939340 A,rs4712653 T,rs9295536 C)showed decreased neuroblastoma risk.2.The study subjects from Henan province showed that carrying the rs4758051 A(AA vs.GG: adjusted OR = 0.28,95% CI =0.13–0.62,P = 0.002;AG/AA vs.GG: adjusted OR =0.62,95% CI = 0.40–0.97,P = 0.035;AA vs.GG/AG:adjusted OR = 0.33,95% CI = 0.15–0.69,P = 0.003)or rs10840002 G allele(AG vs.AA: adjusted OR = 0.67,95% CI= 0.51–0.88,P = 0.004;GG vs.AA: adjusted OR =0.58,95% CI = 0.40–0.84,P = 0.004;AG/GG vs.AA: adjusted OR = 0.65,95% CI =0.50–0.83,P=0.001)of LMO1 gene is associated with decreased risk of neuroblastoma,but not in rs110419 A > G and rs204938 A > G.Previous study of Guangdong population detected a significant protective association between only the rs110419 A > G polymorphism and neuroblastoma risk.We combined the results from our present study with those from Guangdong population.The combined analysis indicated that carrying the LMO1 rs4758051 A(AA vs.GG: adjusted OR =0.57,95% CI = 0.39–0.84,P = 0.005;AA vs.GG/AG: adjusted OR = 0.59,95% CI =0.41–0.84,P = 0.004),rs110419 G(AG vs.AA: adjusted OR = 0.67,95% CI=0.51–0.88,P = 0.004;GG vs.AA: adjusted OR = 0.58,95% CI = 0.40–0.84,P =0.004;AG/GG vs.AA: adjusted OR = 0.65,95% CI = 0.50–0.83,P = 0.001),or rs10840002 G allele(GG vs.AA: adjusted OR = 0.66,95% CI = 0.46–0.95,P = 0.026;GG vs.AG/AA: adjusted OR = 0.68,95% CI = 0.49–0.94,P = 0.020)was associated with a decreased risk for neuroblastoma,but not rs204938 G allele.Conclusion1.CASC15 gene rs6939340 G>A,rs4712653 C>T and rs9295536A>C variant genotypes may contribute to risk of neuroblastoma in Chinese Han population.2.LMO1 gene rs110419 A > G,rs4758051 G>A and rs10840002 A > G variant genotypes may contribute to risk of neuroblastoma in Chinese Han population.3.This study is the first to verify the genetic role of CASC15 and LMO1 gene polymorphisms in two independent populations in China,larger,multicenter-based,prospective case-control studies with different ethnic populations are warranted to validate our findings. |
PDF Full Text Request