【摘要】 鼻咽癌(NPC)是一种多因素复杂疾病。其发病过程涉及EB病毒慢性感染、环境致癌因素及宿主基因之间的相互作用。在这一过程中,那些宿主基因在EB病毒感染及鼻咽癌的发生发展中起了关键作用仍不清楚。本研究的目的是发现与鼻咽癌发生发展中两个关键步骤相关的遗传变异,即EB病毒持续性感染鼻咽部上皮细胞和鼻咽癌的形成。我们在广西梧州市及苍梧县鼻咽癌高发区收集汉族鼻咽癌患者350例、EB病毒壳抗原IgA抗体阳性者(IgA/VCA+)288例和EB病毒壳抗原IgA抗体阴性者(IgA/VCA-)346例。对先前鼻咽癌家系研究显示的鼻咽癌易感区4号染色体短臂(4p15.1~q12)进行了微卫星精细扫描,在18 Mb的范围内选择34个微卫星标记,包括319个等位基因,对其进行基因分型。比较分析NPC组和IgA/VCA+组等位基因频率结果显示,9个等位基因与鼻咽癌呈相关,其中5个为易感等位基因(OR=1.51~5.36,P=0.01~0.03),4个为限制性等位基因(OR值为0.3~0.71,P值为0.02~0.045)。比较分析IgA/VCA+组和IgA/VCA-组及比较所有IgA/VCA+者(包括NPC患者)和IgA/VCA-者等位基因频率的结果显示,12个等位基因与EB病毒壳抗原IgA抗体持续存在相关,其中3个在两组比较中均呈显著相关。等位基因D4S3241~136(P=0.004,OR=1.9,95%CI=1.2~3.0)和D4S3347-213(P=0.001,OR=1.6,95%CI=1.2~2.1)可增加EB病毒IgA/VCA抗体形成的危险,为易感基因;而等位基因D4S174-202(P=0.001,OR=0.5,95%CI=0.3~0.7)可限制IgA/VCA抗体的形成。但上述结果经多因素比较校正后,均失去相关性。结果不能确定该区域与非家族性鼻咽癌的形成相关,但本研究却提供了进一步发现鼻咽癌相关基因的研究模式。有关4号染色体短臂与EB病毒慢性持续感染及鼻咽癌的形成仍值得进一步深入研究。更多还原

【Abstract】 Nasopharyngeal carcinoma(NPC) is a complex disease caused by an interaction of EBV chronic infection,environment and host genes,in a multi-step process of carcinogenesis.However,which genetic factors play an important role in the development of chronic EBV infection and NPC remain elusive.The objective of this study is to identify genetic variations associated with two key clinical stages of NPC development: persistent Epstein-Barr virus(EBV) infection of nasopharyngeal epithelia and progression to NPC.We inspected a NPC-associated region on the short arm of chromosome 4 previously implicated by a genome-wide linkage analysis of familial NPC.We determined genotypes for 319 alleles in 34 microsatellite markers spanning an 18 Mb region in 350 NPC cases,288 individuals with IgA antibodies to EBV capsid antigen(IgA/VCA+) and 346 controls seronegative for IgA antibodies to EBV capsid antigen(IgA/VCA-).The cases and controls were Han Chinese from Wuzhou city and Cangwu county,Guangxi province where the incidence of NPC is as high as 25-50 per 100 000 individuals.Comparing NPC cases to IgA/VCA+ subjects,we found 9 alleles marginally associated with developing NPC from IgA+ status,5 for risk(OR=1.51-5.36,P=0.01-0.03) and 4 for restrictive(OR=0.3-0.71,P=0.02-0.045).Comparing IgA/VCA+ subjects and IgA/VCA-controls,and comparing all IgA seropositives with and without NPC to IgA seronegatives revealed 12 significant and 3 highly significant(P<0.01) alleles associated with IgA+ serostatus in the two comparing groups.Alleles D4S3241-136(P=0.004,OR=1.91,95% CI=1.2-3.0) and D4S3347-213(P=0.001,OR=1.6,95% CI=1.2-2.1) were for risk.Allele D4S174-202(P=0.001,OR=0.5,95% CI=0.3-0.7) was restrictive.However,statistical significance was lost for all when corrected for multiple comparisons test.Our study could not affirm the genetic association within this region with NPC as did another pedigree study,but provide an opportunity for further gene discovery in this highly endemic NPC population and suggest that this region warrants further study.更多还原