Angel Joe M, Abel Erika L, Riggs Penny K, McClellan S Alex, DiGiovanni John
Division of Pharmacology & Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712
Department of Biology, Baylor University, Waco, Texas 76798.
G3 (Bethesda). 2014 Apr 3;4(6):1071-9. doi: 10.1534/g3.113.009688.
Although it is well known that the majority of human cancers occur as the result of exposure to environmental carcinogens, it is clear that not all individuals exposed to a specific environmental carcinogen have the same risk of developing cancer. Considerable evidence indicates that common allelic variants of low-penetrance, tumor susceptibility genes are responsible for this interindividual variation in risk. We previously reported a skin tumor promotion susceptibility locus, Psl1, which maps to the distal portion of chromosome 9, that modified skin tumor promotion susceptibility in the mouse. Furthermore, Psl1 was shown to consist of at least two subloci (i.e., Psl1.1 and Psl1.2) and that glutathione S-transferase alpha 4 (Gsta4), which maps to Psl1.2, is a skin tumor promotion susceptibility gene. Finally, variants of human GSTA4 were found to be associated with risk of nonmelanoma skin cancer. In the current study, a combination of nested and contiguous C57BL/6 congenic mouse strains, each inheriting a different portion of the Psl1 locus from DBA/2, were tested for susceptibility to skin tumor promotion with 12-O-tetradecanoylphorbol-13-acetate. These analyses indicate that Psl1 is a compound locus with at least six genes, including Gsta4, that modify skin tumor promotion susceptibility. More than 550 protein-coding genes map within the Psl1 locus. Fine mapping of the Psl1 locus, along with two-strain haplotype analysis, gene expression analysis, and the identification of genes with amino acid variants, has produced a list of fewer than 25 candidate skin tumor promotion susceptibility genes.
虽然众所周知，大多数人类癌症是由于接触环境致癌物所致，但显然并非所有接触特定环境致癌物的个体患癌风险都相同。大量证据表明，低 penetrance 的常见等位基因变异、肿瘤易感性基因是个体间这种风险差异的原因。我们之前报道了一个皮肤肿瘤促进易感性位点 Psl1，它定位于 9 号染色体的远端，可改变小鼠的皮肤肿瘤促进易感性。此外，Psl1 被证明至少由两个亚位点（即 Psl1.1 和 Psl1.2）组成，且定位于 Psl1.2 的谷胱甘肽 S - 转移酶α4（Gsta4）是一个皮肤肿瘤促进易感性基因。最后，发现人类 GSTA4 的变异与非黑色素瘤皮肤癌的风险相关。在当前研究中，对一系列嵌套和连续的 C57BL/6 同源近交系小鼠进行了测试，每个品系从 DBA/2 继承了 Psl1 位点的不同部分，以检测它们对 12 - O - 十四酰佛波醇 - 13 - 乙酸酯诱导的皮肤肿瘤促进的易感性。这些分析表明，Psl1 是一个复合位点，至少有六个基因，包括 Gsta4，可改变皮肤肿瘤促进易感性。超过 550 个蛋白质编码基因定位于 Psl1 位点内。对 Psl1 位点的精细定位，以及两品系单倍型分析、基因表达分析和氨基酸变异基因的鉴定，产生了一份少于 25 个候选皮肤肿瘤促进易感性基因的清单。
