Linkage Mapping Hepatocellular-Carcinoma Susceptibility Loci on Chromosome 1p

背景：肝細胞癌為複雜性疾病，肝炎病毒感染和其他外生性或內生性因子間的交互作用為導致肝細胞癌的主要原因。肝細胞癌腫瘤組織染色體基因缺失的研究結果，已暗示在1號染色體短臂可能具有肝細胞癌的易感受性基因。材料與方法：我們在1號染色體短臂的區域選定37個微衛星標記，共涵蓋147.0 cM，以71家肝細胞癌多發病例家族為研究樣本，進行連鎖分析。藉由conditional logistic regression模式，分析可能導致基因座異質性的的變項對連鎖關係的影響。結果：當分別將發病年齡、性別、飲酒習慣，以及B型肝炎病毒的病毒量與基因型，做為變項放入模式中後，在1p染色體的三個區域發現有連鎖的情形：1p35.3 (位置59.0 cM，LOD score = 4.14，P<0.0001)，1p32.2-34.2 (位置79.8 cM，LOD score = 2.32，P = 0.0029)以及1p32.1 (位置92.5 cM，LOD score = 1.33，P = 0.0301)。當未放入變項時，則沒有與疾病連鎖的證據。分層分析顯示在1p32.2-34.2可能有肝細胞癌易感受性基因，尤其在有女性病例且沒有酗酒病例的22個家族(最大母數連鎖分析LOD值 = 3.26；最大無母數連鎖分析Z值 = 2.14，region-wide empirical P value = 0.0081)，和在病例病毒量較低的26個家族(最大母數連鎖分析LOD值 = 2.00；最大無母數連鎖分析Z值 = 2.34，region-wide empirical P value = 0.0108)。結論：未來應針對1p32.2-36.1的區域，進一步細部定位，以鑑定肝細胞癌易感受性基因。

Background: Hepatocellular carcinoma (HCC) is a complex disease with etiological heterogeneity, largely attributed to the interactions between hepatitis virus infection and many exogenous and/or endogenous factors. Chromosome 1p has been identified as a strong candidate region to contain HCC-susceptibility gene(s) on the basis of frequent allelic loss in sporadic HCCs. Materials and Methods: Linkage analysis was performed with a total of 37 microsatellite markers spanning 147.0 cM on chromosome 1p among 71 HCC multiplex families. We modeled locus heterogeneity among affected relative pairs with HCC by including covariates in the conditional logistic regression analysis. Results: By including age at onset, sex, lifetime habit of alcohol consumption, and/or hepatitis B viral load or genotype as covariates, we identified linkage signals in three chromosomal regions: 1p35.3 (LOD score= 4.14 at 59.0 cM, P<0.0001), 1p32.2-34.2 (LOD score=2.32 at 79.8 cM, P = 0.0029), and 1p32.1 (LOD score=1.33 at 92.5 cM, P = 0.0301). Without covariates, no evidence for disease linkage was found. Stratified analyses revealed that the 1p32.3-34.2 markers are likely to cosegregate with an HCC-susceptibility locus among families with female patients that had no alcoholic patients (maximum parametric LOD score = 3.26; nonparametric linkage Z score = 2.14, region-wide empirical P value = 0.0081) and among families with low HBV viral load (maximum parametric LOD score = 2.00; nonparametric linkage Z score = 2.34, region-wide empirical P value = 0.0108). Conclusion: Fine mapping studies to facilitate identification of HCC-susceptibility genes in the 1p32.2-36.1 regions are warranted.