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

背景：结直肠癌（CRC）的发生被认为是由遗传和环境因素的相互作用决定的。影响结直肠癌发病率的具体相互作用因素尚未得到充分研究。患者和方法：采用多机构合作研究，1511名CRC患者和2098名对照受试者，比较11个已知单核苷酸多态性（snp）多态性发生的优势比，并进行GWAS研究。采用TaqMan PCR和问卷调查法评价环境暴露的影响。然后，我们对从110个原发肿瘤中提取的癌细胞进行了基因微阵列分析。结果：8q24上rs6983267的变异是CRC风险最显著的标志物（OR=1.16(1.06-1.27), p=0.0015）。非胰岛素依赖型糖尿病、20岁时较高的身体质量指数（BMI）和肉类消费是环境危险因素，而富含金枪鱼的饮食和维生素摄入是保护因素。8q24位点rs6983267 SNP主要(T)等位基因与糖尿病患者的风险比无糖尿病的主要等位基因患者高1.66倍。基因谱荟萃分析（Meta-analysis of gene profiles, MetaGP）为解释rs6983267主要等位基因与糖尿病患者发生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风险增加有关。在8q24 rs6983267 SNP上存在较小的g等位基因的风险，然而，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，特别是当糖尿病存在时。此外，位于19q13 （CRC致癌SNP）上的p53调节基因PICT1基因与CRC的进展有关，明确地决定了CRC病例的预后。

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.