Human Colon Cancer

结直肠癌是美国发病率第三高的癌症，也是与癌症相关的死亡原因。MicroRNAs是一类小的非编码RNAs，与结直肠癌的发生和预后有关，但很少有研究探讨其种系突变与风险和预后的关系。因此，我们调查了位于10q24基因座的hsa-mir-608的SNP与结直肠癌之间的关系。对245名病例和446名对照的rs4919510进行了基因分型。非裔美国人的GC基因频率(15%)明显高于高加索人(3%)。Rs4919510与结直肠癌风险(非裔美国人：OR(GC与CC)0.89[95%CI，0.41-1.80])(高加索人：OR(GG与CC)1.76 CI，0.48-6.39]无显著相关性。然而，我们确实观察到了与生存的联系。在高加索人群中，GC基因型与死亡风险增加相关(HR(GG Vs CC)3.54[95%CI，1.38-9.12])，与非裔美国人死亡风险降低(HR(GG Vs CC)0.36([95%CI，0.12-1.07])相关。这些结果表明rs4910510可能以一种依赖于种族的方式与结直肠癌的生存相关。由于慢性肠炎是结直肠癌的危险因素，我们假设炎症介质的遗传变异，如甘露糖结合凝集素2(MBL2)，与结肠癌的易感性有关。在此，我们在一项病例对照研究中报告了24个MBL2单核苷酸多态(SNP)和相应的单倍型与结肠癌风险的关系。该基因3‘非翻译区的4个SNP(rs10082466、rs2120132、rs2099902和rs10450310)与非裔美国人患结肠癌的风险增加有关。纯合变异与野生型的OR值范围为3.17[95%可信区间(CI)1.57~6.40]至4.51(95%CI，1.94~10.50)，而由这四种变异组成的3‘-UTR区单倍型的OR值为2.10(95%CI，1.42~3.12)。Rs10082466的C等位基因表现出与miR-27A的亲和力，该等位基因与低MBL血浆水平和活性有关。我们发现，已知的与中低MBL血清水平相关的5‘分泌物单倍型与非裔美国人结肠癌风险的增加有关，特别是由两种单倍型LYPA和LYQC驱动，相对于参考的HYPA单倍型(LYPA：OR，2.60；95%CI，1.33-5.08和LYQC：OR，2.28；95%CI，1.20-4.30)。在高加索人中没有观察到类似的关联。总之，我们的结果支持这样的假设，即MBL2的基因变异增加了非裔美国人对结肠癌的易感性。MicroRNAs在包括癌症在内的各种生理和病理生物学过程中发挥着重要作用。对于直肠癌，只有有限的数据可以获得关于microRNA表达谱的数据，而潜在的基因组和转录异常已经牢固地建立起来。因此，在与Thomas Reid的合作中，我们的目标是全面绘制这种疾病的microRNA表达模式。实验设计：前瞻性收集57例局部进展期直肠癌患者的肿瘤活检组织和相应的配对粘膜样本。提取总RNA，随后建立所有患者的肿瘤和粘膜微RNA表达谱。用半定量实时定量聚合酶链式反应验证了所选的microRNAs的表达。49个microRNA在直肠癌和正常直肠黏膜中的表达差异有统计学意义(log2倍差大于0.50，p<0.001)。这些microRNAs的预测靶点丰富了以下KEGG信号通路：WNT、转化生长因子-β、mTOR、胰岛素、MAPK和ErbB信号。在这49个microRNAs中，有13个似乎是直肠癌特异的，以前没有报道过结肠癌：miR-492、miR-542-5p、miR-584、miR-483-5p、miR-144、miR-2110、miR-652*、miR-375、miR-147b、miR-148a、miR-190、miR-26a/b和miR-338-3p。在临床影响方面，在116名患者的独立多中心队列中，miR-135B的表达与无病生存率和癌症特异性生存率显著相关。这项对直肠癌microRNAome的综合分析发现了与直肠癌相关的新的microRNAs和通路。这些信息有助于对这种疾病的详细了解。此外，miR-135B的鉴定和验证可能有助于识别用于治疗开发的新的分子靶点和途径。

Colorectal cancer is the third most incident cancer and cause of cancer-related death in the United States. MicroRNAs, a class of small non-coding RNAs, have been implicated in the pathogenesis and prognosis of colorectal cancer, although few studies have examined the relationship between germline mutation in the microRNAs with risk and prognosis. We therefore investigated the association between a SNP in hsa-mir-608, which lies within the 10q24 locus, and colorectal cancer. A cohort consisting of 245 cases and 446 controls was genotyped for rs4919510. The frequency of the GC genotype was significantly higher in African Americans (15%) compared to Caucasians (3%) controls. There was no significant association between rs4919510 and colorectal risk (African American: OR (GC vs. CC) 0.89 [95% CI, 0.41-1.80]) (Caucasian: OR (GG vs. CC) 1.76 CI, 0.48-6.39]). However, we did observe an association with survival. The GC genotype was associated with an increased risk of death in Caucasians (HR (GG vs. CC) 3.54 ([95% CI, 1.38-9.12]) and with a reduced risk of death in African Americans (HR (GG vs. CC) 0.36 ([95% CI, 0.12-1.07]). These results suggest that rs4910510 may be associated with colorectal cancer survival in a manner dependent on race.Because chronic intestinal inflammation is a risk factor for colorectal cancer, we hypothesized that genetic variants of inflammatory mediators, such as mannose-binding lectin 2 (MBL2), are associated with colon cancer susceptibility. Here, we report the association of 24 MBL2 single-nucleotide polymorphisms (SNP) and corresponding haplotypes with colon cancer risk in a case-control study. Four SNPs in the 3'-untranslated region (UTR) of the gene (rs10082466, rs2120132, rs2099902, and rs10450310) were associated with an increased risk of colon cancer in African Americans. ORs for homozygous variants versus wild-type ranged from 3.17 [95% confidence interval (CI), 1.57-6.40] to 4.51 (95% CI, 1.94-10.50), whereas the 3'-UTR region haplotype consisting of these four variants had an OR of 2.10 (95% CI, 1.42-3.12). The C allele of rs10082466 exhibited a binding affinity of miR-27a and this allele was associated with both lower MBL plasma levels and activity. We found that 5' secretor haplotypes known to correlate with moderate and low MBL serum levels exhibited associations with increased risk of colon cancer in African Americans, specifically as driven by two haplotypes, LYPA and LYQC, relative to the referent HYPA haplotype (LYPA: OR, 2.60; 95% CI, 1.33-5.08 and LYQC: OR, 2.28; 95% CI, 1.20-4.30). Similar associations were not observed in Caucasians. Together, our results support the hypothesis that genetic variations in MBL2 increase colon cancer susceptibility in African Americans.MicroRNAs play a prominent role in a variety of physiological and pathological biological processes, including cancer. For rectal cancers, only limited data are available on microRNA expression profiles, while the underlying genomic and transcriptomic aberrations have been firmly established. In collaboration with Thomas Reid, we therefore aimed to comprehensively map the microRNA expression patterns of this disease. Experimental design: Tumor biopsies and corresponding matched mucosa samples were prospectively collected from 57 patients with locally advanced rectal cancers. Total RNA was extracted, and tumor and mucosa microRNA expression profiles were subsequently established for all patients. The expression of selected microRNAs was validated using semi-quantitative real-time PCR. Forty-nine microRNAs were significantly differentially expressed (log2-fold difference greater than 0.5 and p less than 0.001) between rectal cancer and normal rectal mucosa. The predicted targets for these microRNAs were enriched for the following KEGG pathways: Wnt, TGF-beta, mTOR, insulin, MAPK, and ErbB signaling. Thirteen of these 49 microRNAs seem to be rectal cancer-specific, and have not been previously reported for colon cancers: miR-492, miR-542-5p, miR-584, miR-483-5p, miR-144, miR-2110, miR-652*, miR-375, miR-147b, miR-148a, miR-190, miR-26a/b, and miR-338-3p. Of clinical impact, miR-135b expression correlated significantly with disease-free and cancer-specific survival in an independent multicenter cohort of 116 patients. This comprehensive analysis of the rectal cancer microRNAome uncovered novel microRNAs and pathways associated with rectal cancer. This information contributes to a detailed view of this disease. Moreover, the identification and validation of miR-135b may help to identify novel molecular targets and pathways for therapeutic exploitation.