Oka A, Hayashi H, Tomizawa M, Okamoto K, Suyun L, Hui J, Kulski J K, Beilby J, Tamiya G, Inoko H
Department of Genetic Information, Division of Molecular Life Science, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan.
Tissue Antigens. 2003 Mar;61(3):203-10. doi: 10.1034/j.1399-0039.2003.00007.x.
The major histocompatibility complex (MHC) is known to have a role in the development of non-melanoma skin cancer (NMSC), although the genes and mechanisms involved have yet to be determined. To identify the susceptibility locus for NMSC within the MHC, we used a collection of well-defined polymorphic microsatellite markers from the Human leucocyte antigen (HLA) region for an association analysis of 150 cases with NMSC and 200 healthy controls selected from the Busselton population in Western Australia. High-resolution mapping was undertaken using a total of 40 highly polymorphic markers located at regular intervals across the HLA region (3.6Mb). Polymerase chain reaction (PCR) analysis was initially performed on pooled DNA markers to detect those markers that showed different allele profiles. Statistically significant differences in allelic frequencies (differentiating alleles) were found between cases and controls at three polymorphic microsatellite loci within a 470-kb genomic susceptibility region ranging between 6 kb centromeric of the HLA-B gene and intron 5 of the DDR gene. Interestingly, this genome region corresponded completely with the psoriasis-susceptibility locus. The three differentiating alleles and another four markers outside the susceptibility region were then PCR tested by individual genotyping of cases and controls. The newly identified susceptibility locus for NMSC within the MHC was found to be significantly different between the cases and controls by comparisons of allele frequencies at the three differentiating loci estimated from DNA pools and then confirmed by individual genotyping. This is the first study using high density microsatellite markers to localize a NMSC susceptibility region within the human genome.
主要组织相容性复合体（MHC）在非黑色素瘤皮肤癌（NMSC）的发生发展中发挥作用，尽管其中涉及的基因和机制尚未确定。为了确定MHC内NMSC的易感基因座，我们使用了来自人类白细胞抗原（HLA）区域的一组定义明确的多态性微卫星标记，对150例NMSC患者和从西澳大利亚州巴瑟尔顿人群中选取的200名健康对照进行关联分析。使用总共40个高度多态性标记进行高分辨率定位，这些标记以规则间隔分布在HLA区域（3.6Mb）。最初对混合DNA标记进行聚合酶链反应（PCR）分析，以检测那些显示不同等位基因谱的标记。在一个470kb的基因组易感区域内，位于HLA - B基因着丝粒6kb处至DDR基因内含子5之间的三个多态性微卫星位点，病例组和对照组之间的等位基因频率（区分等位基因）存在统计学上的显著差异。有趣的是，这个基因组区域与银屑病易感基因座完全对应。然后通过对病例组和对照组进行个体基因分型，对这三个区分等位基因和易感区域外的另外四个标记进行PCR检测。通过比较从DNA池估计的三个区分位点的等位基因频率，发现MHC内新确定的NMSC易感基因座在病例组和对照组之间存在显著差异，随后通过个体基因分型得到证实。这是第一项使用高密度微卫星标记在人类基因组中定位NMSC易感区域的研究。
