染色體5q22-34區域之肝細胞癌易感受基因定位:連鎖和家族為基礎的相關性分析

Genetic Mapping of Hepatocelular Carcinoma Susceptibility Locus in the Chromosome 5q22-34 Candidate Region: Linkage Analysis and Family-based Association Study

陳嘉珮(Chia-Pei Chen)

指導教授 ： 于明暉

國立臺灣大學/公共衛生學院/流行病學研究所/碩士(2004年)

https://doi.org/10.6342/NTU.2004.01978

摘要

背景：以往對肝癌組織的研究發現5q染色體常有LOH現象。慢性hepatic necroinflammatory disease是導致肝細胞癌（hepatocellular carcinoma；HCC）的重要致病機轉，目前已知5q22-34區域群聚許多細胞激素基因，可能在產生發炎和免疫調控上扮演重要角色。本研究同時進行連鎖分析和傳遞不平衡檢定（transmission/disequilibrium test；TDT），探尋是否在染色體5q22-34區域可能存在HCC易感受基因。
方法：共有71個多發病例家族和253個病例－雙親三元體。於染色體5q22-34間，選取11個microsatellite標記，標記間距為0.19-8.43 cM。我們對多發病例家族進行多點LOD score及無母數連鎖（nonparametric linkage；NPL）Z score分析，以single allele及multiallelic test進行TDT分析。利用permutation test進行100,000次模擬試驗計算empirical P值，並以Bonferroni’s程序進行多重比較校正。
結果：對全部家族，或以指標病例是否具酗酒習慣、HBV基因型進行分層分析，均未發現任何值得注意的連鎖或連鎖不平衡訊息。但依指標病例之HBV DNA濃度為106 copies/mL作切點分層，發現5q31.1區域的D5S2117在HBV DNA濃度≧106 copies/mL的家族，multiallele 檢定P值為0.00155，且220鹼基數之allele的empirical P=0.082。對於12個男性指標病例、無酗酒習慣且HBV DNA濃度≧106 copies/mL之多發病例家族的連鎖分析，發現最高LOD score=1.56064、NPL Z sore=1.45467（P value=0.059582），落在5q23.2區域的標記D5S471位置。
結論：5q23.2-31.1染色體區段綿亙7.96 cM可能含有HCC易感受基因，一旦被證實，此基因可能和高病毒複製活性所引起的HCC有關。未來需於此段染色體區域進行精密定位分析。

關鍵字

肝細胞癌 ； 連鎖不平衡 ； 細胞激素 ； B型肝炎 ； 連鎖分析

並列摘要

Background: Frequent loss-of-heterozygosity on chromosome 5q has been reported in hepatocellular carcinoma (HCC). Chronic phasic necroinflammation is an important mechanism responsible for hepatocarcinogenesis, and chromosomal region 5q22-34 contains cluster of cytokine genes that may mediate inflammation response. The aim of this study was to perform both linkage analysis and transmission/disequilibrium test (TDT) to explore whether there exist a HCC susceptibility gene on 5q22-34. We also assessed the possible HBV-gene interaction by using analyses stratified according to HBV genotype and DNA levels.
Method: There were 71 HCC multiplex families and 253 case-parent triads. We genotyped a total of 11 microsatellite markers with intermarker distance 0.19~8.43 cM. Multipoint LOD score and multipoint nonparametric linkage (NPL) Z score were calculated for linkage analysis. TDT was performed with the use of single allelic and multiallelic tests. Empirical P values were calculated using the permutation test with 100,000 simulations. Bonferroni’s correction procedure was used to adjust for multiple testing.
Results: We did not detect any notable linkage or linkage disequilibrium (LD) signal overall or in any subgroup analysis stratified by HBV genotype. In families each with a patient having HBV DNA levels of 106 copies/mL or greater (75 families); however, we detected a significant LD signal at marker D5S2117 within 5q31.1 (multiallelic test P=0.00155); the empirical P for the 220 base-pair allele was 0.082. Linkage analysis in 12 families with high viral replication activity(≧106 copies/mL) and no female or alcoholic patients also revealed a suggestive linkage signal at marker D5S471 within 5q23.2, giving the maximum multipoint LOD score and multipoint NPL Z score of 1.56064 and 1.45467 (P value=0.059582), respectively.
Conclusion: 5q23.2-31.1 chromosomal region across 7.96 cM may contains a HCC-susceptibility locus. If confirmed, this locus may be specially associated with high HBV replication activity-related HCC. Further fine mapping studies with a larger number of families in this chromosomal region is needed.

並列關鍵字

linkage analysis ； hepatocellular carcinoma ； hepatitis B virus ； linkage disequilibrium ； cytokine

參考文獻

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