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

背景：大肠癌（CRC）的肿瘤发生被认为是由遗传和环境因素之间的相互作用决定的。影响CRC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：一项多机构合作研究包括1511例CRC患者和2098例对照受试者，用于比较11个已知单核苷酸多态性（SNP）的多态性发生的比值比，并进行GWAS研究。TaqMan PCR和问卷调查被用来评估环境暴露的影响。然后，我们用激光显微切割技术对110例原发性肿瘤的癌细胞基因进行了微阵列分析。结果：8 q24上rs6983267的变异是大肠癌最显著的危险标志物（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。8 q24上rs6983267 SNP主要（T）等位基因与糖尿病的队列比无糖尿病的主要等位基因患者队列的风险比高1.66倍。基因图谱的Meta分析（MetaGP）为解释糖尿病患者rs6983267主效等位基因与结直肠癌的关系提供了线索。结论：我们证实了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。8 q24 rs6983267 SNP处的次要G等位基因存在很大的风险，然而，主要T等位基因SNP可以更清楚地揭示与CRC的相关性，特别是在存在糖尿病时。此外，位于19 q13的p53调控基因PICT 1基因（CRC致癌SNP）与结直肠癌的进展有关，并明确决定结直肠癌患者的预后。

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.