Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
Department of Bioinformatics, Semmelweis University, Budapest, Hungary.
Clin Transl Gastroenterol. 2023 Feb 1;14(2):e00517. doi: 10.14309/ctg.0000000000000517.
By linking cellular content and molecular subtypes of colorectal cancer (CRC), we aim to uncover novel features useful for targeted therapy. Our first goal was to evaluate gene expression alterations linked to CRC pathogenesis, and then, we aimed to evaluate the cellular composition differences between normal colon mucosa and tumor and between different colon cancer molecular subtypes.
We collected microarray and RNA sequencing data of patients with CRC from the Genome Expression Omnibus and The Cancer Genome Atlas. We combined all cases and performed quantile normalization. Genes with a fold change of >2 were further investigated. We used xCell for cellular decomposition and CMScaller for molecular subtyping. For statistical analyses, the Kruskal-Wallis H test and Mann-Whitney U tests were performed with Bonferroni correction.
We established an integrated database of normal colon and CRC using transcriptomic data of 1,082 samples. By using this data set, we identified genes showing the highest differential expression in colon tumors. The top genes were linked to calcium signaling, matrix metalloproteinases, and transcription factors. When compared with normal samples, CD4+ memory T cells, CD8+ naive T cells, CD8+ T cells, Th1 cells, Th2 cells, and regulatory T cells were enriched in tumor tissues. The ImmuneScore was decreased in tumor samples compared with normal samples. The CMS1 and CMS4 molecular subtypes were the most immunogenic, with the highest ImmuneScore but also high infiltration by CD8+ T cells, Th1 cells, and Th2 cells in CMS1 and B-cell subtypes and CD8+ T cells in CMS4.
Our analysis uncovers features enabling advanced treatment selection and the development of novel therapies in CRC.
通过将结直肠癌（CRC）的细胞内容物和分子亚型联系起来，我们旨在发现对靶向治疗有用的新特征。我们的首要目标是评估与 CRC 发病机制相关的基因表达改变，然后评估正常结肠黏膜与肿瘤之间以及不同结直肠癌分子亚型之间的细胞组成差异。
我们从基因组表达综合数据库和癌症基因组图谱中收集了结直肠癌患者的微阵列和 RNA 测序数据。我们合并了所有病例并进行了分位数归一化。进一步研究了 fold change > 2 的基因。我们使用 xCell 进行细胞分解，使用 CMScaller 进行分子分型。对于统计分析，使用 Kruskal-Wallis H 检验和 Mann-Whitney U 检验，并进行了 Bonferroni 校正。
我们使用 1082 个样本的转录组数据建立了一个正常结肠和 CRC 的综合数据库。使用这个数据集，我们确定了在结肠肿瘤中表现出最高差异表达的基因。排名靠前的基因与钙信号、基质金属蛋白酶和转录因子有关。与正常样本相比，肿瘤组织中富集了 CD4+记忆 T 细胞、CD8+幼稚 T 细胞、CD8+T 细胞、Th1 细胞、Th2 细胞和调节性 T 细胞。与正常样本相比，肿瘤样本中的 ImmuneScore 降低。CMS1 和 CMS4 分子亚型最具免疫原性，具有最高的 ImmuneScore，但也有高浸润的 CD8+T 细胞、Th1 细胞和 Th2 细胞在 CMS1 和 B 细胞亚型和 CD8+T 细胞在 CMS4。
我们的分析揭示了在 CRC 中实现先进治疗选择和开发新疗法的特征。
