肝細胞癌家族17號染色體短臂遺傳標記之連鎖及相關分析

Abstract

Background: Familial aggregation and segregation analyses of hepatocellular carcinoma (HCC) have revealed that genetic factors may be involved in familial clustering of HCC. Studies of loss-of-heterozygosity in HCCs have reported frequent allelic loss on chromosome 17p. Materials and Methods: A hierarchical strategy has been performed for mapping HCC-susceptibility loci on 17p. Firstly, linkage analysis was conducted with 9 equally-spaced microsatellite markers spanning chromosome 17p among 72 multiplex families. After finding linkage signal, additional 10 markers were genotyped to further refine the linked region. Next, we performed recombinant mapping and family-based association analysis in the linked region. To examine further the roles of new loci, we performed a replication study for markers around candidate genes in the linked region using an independent case-control sample of 832 cases with HCC and 684 controls. Results: There are suggestive evidence for linkage of HCC to chromosome 17 p12 (maximum NPL=2.46 and maximum MOD=3.00) in 34 informative multiplex families. Using recombinant mapping, we identified an 870-kb minimum consensus haplotype-sharing region at 17p12. Family-based association analysis mapped the HCC-susceptibility locus in a 970-kb interval overlapping large parts of the 870-kb region defined by recombinant mapping. However, we failed to detect any association with HCC for markers on 17p12 in the case-control study overall or in subgroup analysis. Conclusion: A 1.19 Mb interval at chromosome 17p12, which is about 5.5 Mb apart from the p53 gene, may contain HCC-susceptibility loci. Future studies focusing on characterization of such loci in the linked region are warranted.