Allelic Imbalance at an 8q24 Oncogenic SNP is Involved in Activating MYC in Human Colorectal Cancer
Allelic Imbalance at an 8q24 Oncogenic SNP is Involved in Activating MYC in Human Colorectal Cancer
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DOI：
10.1245/s10434-013-3468-6
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发表时间：
2014-12-01
影响因子：
3.7
通讯作者：
Mimori, Koshi
中科院分区：
文献类型：
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作者：
Sugimachi, Keishi;Niida, Atsushi;Mimori, Koshi
背景位于8q24.21的rs6983267已被确定为与癌症相关的显著单核苷酸多态性（SNP）。该危险等位基因与激活MYC转录的转录因子TCF 4/LEF 1的结合位点相似。然而，关于该SNP在增加结直肠癌（CRC）中MYC活性中的作用知之甚少。检测107例CRC外周血和原发癌中rs6983267基因型、MYC活性和拷贝数（CN）改变。接下来，我们在桑格研究所数据库的746个癌细胞系中绘制了表现出特定G/T基因型的癌细胞系的数量。并对68例CRC中8 q24 SNP位点的杂合性缺失（洛）与临床病理参数的关系进行了验证。MYC模块活性通过风险等位基因（G）中的转录或通过非风险等位基因（T）中的扩增来激活。然后，我们证实CN扩增主要发生在非危险等位基因，而CN中性洛，这表明单亲二体性（UPD）更频繁地观察到的危险等位基因。最后，我们证实了，无论是通过扩增还是通过UPD，危险等位基因显性病例都表明比非危险等位基因显性病例更恶性的临床表型。CRC的发展需要通过保留风险等位基因或在原发性肿瘤部位的致癌SNP处扩增非风险等位基因来激活MYC。
Background. The rs6983267 at 8q24.21 has been established as a significant cancer-related single nucleotide polymorphism (SNP). The risk allele showed similarity to the binding site of transcription factor TCF4/LEF1 that activates transcription of MYC. However, little is known about the role of this SNP in increasing MYC activity in colorectal cancers (CRCs).Methods. The genotypes of rs6983267 in peripheral blood and primary cancers, MYC activity and copy number (CN) alteration were examined in 107 CRCs. Next, we plotted the number of cancers cell lines exhibiting specific G/T genotypes in 746 cancer cell lines of the Sanger Institute database. Then we validated the relationship between the 8q24 SNP status and clinicopathologic parameters in 68 CRCs with loss of heterozygosity (LOH).Results. The MYC module activity was activated by either transcription in the risk allele (G) or by amplification in the non-risk allele (T). Then, we confirmed that the CN amplification dominantly occurred in the non-risk allele, whereas CN neutral LOH, which indicated uniparental disomy(UPD) was more frequently observed for the risk allele. Finally, we confirmed that risk allele dominant cases, either by amplification or by UPD, indicated a more malignant clinical phenotype than non-risk allele dominant cases.Conclusions. The development of CRC requires MYC activation through retention of the risk allele, or amplification of the non-risk allele at the oncogenic SNP in the site of primary tumor.