Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN.
Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN.
Clin Colorectal Cancer. 2019 Jun;18(2):149-158. doi: 10.1016/j.clcc.2019.02.002. Epub 2019 Feb 14.
Cancers of the right colon have been shown to differ from left-side colon cancers in prognosis, response to epithelial growth factor receptor inhibitors, microsatellite instability and BRAF mutation status, and other molecular characteristics. Clinical application of these differences will benefit from a deeper understanding of how tumor location defines and is defined by gene expression.
This study was carried out using Affymetrix microarray datasets (Cohort A: training set, n = 352; validation set, n = 519) and samples from The Cancer Genome Atlas Colon Adenocarcinoma database (Cohort B: n = 408), in which tumor location was reported. Gene expression patterns characteristic of tumor side were identified in a manner unbiased by statistical classification method.
In the Cohort A validation set, the anatomic locations of 75% of tumors agree with the locations predicted by gene expression (so-called genomic location), whereas 8% of tumors had genomic locations discordant with their anatomic locations, and 17% of tumors had ambiguous genomic locations. Genomic location was a better predictor of microsatellite instability, CpG island methylator phenotype status, and BRAF mutation status than anatomic location. Tumors with ambiguous genomic location were significantly (P = 1.3 × 10) more likely to have the mesenchymal consensus molecular subtype (40%) than those with a specific genomic location (18%). A genomic signature to predict genomic location was defined.
Tumor location is increasingly considered in deciding treatment of a colon tumor. We showed that genomic location was superior to anatomic location as a predictor of molecular characteristics, suggesting that it may be a more accurate predictor of response.
右半结肠癌的预后、对表皮生长因子受体抑制剂的反应、微卫星不稳定性和 BRAF 突变状态以及其他分子特征与左半结肠癌不同。对这些差异的临床应用将受益于对肿瘤位置如何定义和由基因表达定义的更深入理解。
本研究使用 Affymetrix 微阵列数据集（队列 A：训练集，n=352；验证集，n=519）和来自癌症基因组图谱结肠腺癌数据库的样本（队列 B：n=408），其中报告了肿瘤位置。通过不受统计分类方法影响的方式识别出肿瘤侧特有的基因表达模式。
在队列 A 的验证集中，75%的肿瘤的解剖位置与基因表达预测的位置（所谓的基因组位置）一致，而 8%的肿瘤的基因组位置与解剖位置不一致，17%的肿瘤的基因组位置不确定。基因组位置是微卫星不稳定性、CpG 岛甲基化表型状态和 BRAF 突变状态的更好预测指标，而不是解剖位置。基因组位置不确定的肿瘤比具有特定基因组位置的肿瘤更有可能具有间充质共识分子亚型（40%）（P=1.3×10）。定义了一个预测基因组位置的基因组特征。
肿瘤位置在决定结肠癌的治疗方案时越来越被考虑。我们表明，基因组位置作为分子特征的预测指标优于解剖位置，这表明它可能是更准确的反应预测指标。
