尋找4q染色體肝細胞癌易感受基因：以家族為基礎之相關性研究—初步結果

Abstract

摘要 背景 在肝腫瘤組織的研究中已經常發現4q染色體有高頻率染色體缺損現象。在先前的連鎖分析裡，利用微衛星標記在4q染色體偵測到連鎖訊息。本研究將針對上述染色體4q25連鎖區域，進行以家族為基礎之相關性分析，以進一步縮小可能存在肝細胞癌易感受基因之區域。 方法 總計163個來自北台灣之單發家庭與35個多發家庭納入研究。共有25個單一核苷酸多形性標記(single nucleotide polymorphisms, SNPs)，標記間平均間距約250 kb，進行基因型檢測。我們採用the pedigree disequilibrium test (PDT)和 transmission disequilibrium test (TDT)兩種方法進行分析。同時利用quantitative PDT將肝細胞癌發病年齡視為連續性狀來探討肝細胞癌與各SNP標記之相關。 結果 透過PDT方法，我們在標記rs1514728偵測到顯著之訊號(P=0.0038)。半型分析結果顯示rs1514728與rs2271590中T-T半型與肝細胞癌呈現顯著相關(empirical P =0.015)。在分層分析中，我們發現rs1514728與早發家庭(罹病年齡<43歲)呈現顯著相關(P =0.024)；而rs2704108則與晚發家庭有顯著相關(P =0.037)。TDT分析結果和PDT分析結果類似。連續性狀分析發現rs2704108與肝細胞癌的發病年齡呈現顯著相關(P =0.032)。 討論 本研究結果指出染色體4q25之連鎖區域或許存在一個或多個肝細胞癌易感受基因，並與先前研究呈現一致性。這些易感受基因可能與肝細胞癌罹病危險性或罹病年齡有關。

Abstract Background High fre uencies of allelic loss in hepatocellular carcinomas (HCCs) were usually observed on chromosome 4q. Previous linkage analysis had found a linkage signal on chromosome 4q25. The aim of this study was to perform a family-based association study on chromosome 4q25 for further narrowing down the region that may contain HCC-susceptibility locus. Method The sample consisted of 163 singleton families and 35 multiplex families from northern Taiwan. A total of 25 single nucleotide polymorphism (SNP) markers with average intermarker distance of ~250 kb were genotyped. Both pedigree disequilibrium test (PDT) and transmission disequilibrium test (TDT) were applied. We also investigated the association between SNPs and age at onset of HCC through Quantitative PDT. Results The most significant signal was detected at SNP rs1514728 by the PDT (P=0.0038). Haplotype analyses revealed a haplotype T-T at SNPs rs1514728 and rs2271590 that was associated with HCC (empirical P =0.015). In stratified analysis, rs1514728 showed a significant association with early-onset HCC defined as diagnosis of HCC at younger than 43 years of age (P =0.024), while rs2704108 was associated with late-onset HCC (P =0.037). Results from TDT were generally compatible with the results from PDT. Quantitative PDT analysis also revealed a significant association between rs2704108 and age at onset of HCC (P =0.032). Conclusion Consistent with previous linkage and association study, our findings suggested that the linkage region at chromosome 4q25 might contain one or more susceptible loci of HCC.