Mice Lacking a Myc Enhancer Element that Includes Human SNP rs6983267 Are Resistant to Intestinal Tumors

Multiple cancer-associated single nucleotide polymorphisms (SNPs) have been mapped to conserved sequences within a 500 kilobase region upstream of the MYC oncogene on human chromosome 8q24. These SNPs may affect cancer development through altered regulation of MYC expression, but this hypothesis has been difficult to confirm. We generated mice deficient in Myc-335, a putative MYC regulatory element that contains rs6983267, a SNP accounting for more human cancer- related morbidity than any other genetic variant or mutation. In Myc-335 null mice, Myc transcripts were expressed in the intestinal crypts in a pattern similar to that in wild-type mice but at modestly reduced levels. The mutant mice displayed no overt phenotype but were markedly resistant to intestinal tumorigenesis induced by the APCmin mutation. These results establish that a cancer-associated SNP identified in human genome-wide association studies has a functional effect in vivo. Exon-array analysis of mouse colon tissues from Myc-335 null and wild-type mouse (both mice are male and from the same litter). Related ChIP-seq data available in Short Read Archive, Accession ERP001919多个癌症相关单核苷酸多态性（single nucleotide polymorphisms, SNPs）已被定位至人类8号染色体8q24区域内MYC癌基因上游500千碱基对的保守序列中。此类单核苷酸多态性或可通过改变MYC基因的表达调控影响癌症发生，但该假说始终难以得到验证。我们构建了缺失Myc-335的小鼠模型：Myc-335是一种推定的MYC调控元件，其包含rs6983267位点的单核苷酸多态性，该位点相关的人类癌症相关发病率高于其他任何遗传变异或突变。在Myc-335基因敲除小鼠中，Myc转录本在肠隐窝中的表达模式与野生型小鼠相似，但表达水平略有下调。该突变小鼠未表现出明显的表型，但对APCmin突变诱导的肠道肿瘤发生具有显著的抵抗能力。本研究结果证实，通过人类全基因组关联研究鉴定出的癌症相关单核苷酸多态性在体内具有功能性作用。本研究对来自同窝雄性Myc-335基因敲除小鼠与野生型小鼠的结肠组织开展了外显子芯片分析。相关染色质免疫共沉淀测序（Chromatin Immunoprecipitation sequencing, ChIP-seq）数据可在短读长档案库（Short Read Archive）中获取，登录号为ERP001919。