Genetic analysis of cancer stems cells in the carcinogenesis and the intractability of treatment of cancer.

背景：结直肠癌(CRC)的致癌作用被认为是由遗传因素和环境因素相互作用决定的。影响结直肠癌发病率的具体相互作用因素尚未得到充分调查。患者和方法：对1511名结直肠癌患者和2098名对照受试者进行多机构合作研究，比较11个已知的单核苷酸多态(SNPs)发生多态的优势比，并进行GWAS研究。使用TaqMan聚合酶链式反应和问卷调查来评估环境暴露的影响。然后，我们对110个原发肿瘤的激光显微切割提取的癌细胞的基因进行了微阵列分析。结果：rs6983267基因8q24上的变异是结直肠癌最显著的危险标记(OR=1.16(1.06~1.27)，p=0.0015)。非胰岛素依赖型糖尿病、20岁时较高的体重指数(BMI)和肉类消费是环境风险因素，而富含金枪鱼的饮食和维生素摄入是保护因素。位于8q24的rs6983267单核苷酸多态(T)等位基因与糖尿病患者的风险比是非糖尿病患者的1.66倍。MetaGP基因图谱分析为解释rs6983267等位基因与糖尿病合并结直肠癌的风险提供了线索。结论：我们证实遗传背景和环境因素之间的相互作用与结直肠癌的风险增加有关。位于8q24 rs6983267 SNP的G等位基因具有较强的危险性，但当存在糖尿病时，一个主要的T等位基因SNP可以更清楚地揭示与结直肠癌的相关性。此外，PICT1基因定位于19q13(CRC致癌基因SNP)，是一种P53调控基因，与结直肠癌的进展和预后密切相关。

Background : Colorectal cancer (CRC) oncogenesis is considered to be determined by interactions between genetic and environmental factors. Specific interacting factors that influence CRC morbidity have yet to be fully investigated. Patients and Methods : A multi-institutional collaborative study with 1511 CRC patients and 2098 control subjects was used to compare the odds ratios for the occurrence of polymorphisms at eleven known single nucleotide polymorphisms (SNPs) and performed GWAS study. TaqMan PCR and questionnaires were used to evaluate the effects of environmental exposures. Then, we performed microarray analysis of genes from cancer cells extracted from 110 primary tumors by laser microdissection. Results : Variants of rs6983267 on 8q24 were the most significant markers of risk for CRC (OR=1.16(1.06-1.27), p=0.0015). Non-insulin-dependent diabetes mellitus, a higher body mass index (BMI) at age 20 and meat consumption were environmental risk factors, whereas a tuna-rich diet and vitamin intake were protective factors. The cohort of rs6983267 SNP major (T) allele at 8q24 and diabetes had a 1.66 fold higher risk ratio than the cohort of major allele patients without diabetes. Meta-analysis of gene profiles (MetaGP) provide a clew to explain the risk for CRC in major allele at rs6983267 with diabetes mellitus. Conclusion : We confirmed that interactions between the genetic background and environmental factors are associated with increased risk for CRC. There is a robust risk of the minor G-allele at the 8q24 rs6983267 SNP, however, a major T-allele SNP could more clearly reveal a correlation with CRC specifically when diabetes mellitus is present. In addition, PICT1 gene, located on 19q13 (CRC oncogenic SNP), a p53 regulating gene, is associated with the progression of CRC and determined prognosis of CRC cases definitely.