Genomic characterization of liver metastases from colorectal cancer patients [PrimeView]

Metastatic dissemination is the most frequent cause of death sporadic colorectal cancer (sCRC) patients. The genomic abnormalities which are potentially characteristic of such advanced stages of the disease are complex and so far, they have been poorly described and only partially understood. We evaluate the molecular heterogeneity of sCRC tumors based on simultaneous assessment of the overall GEP of both coding mRNA and non-coding RNA genes in primary sCRC tumor samples from 23 consecutive patients and their paired liver metastases. Liver metastases from the sCRC patients analyzed, systematically showed deregulated transcripts of those genes identified as also deregulated in their paired primary colorectal carcinomas. However, some transcripts were found to be specifically deregulated in liver metastases while expressed at normal levels in their primary tumors, suggesting an increased genomic instability of neoplastic cells from metastatic versus primary tumor samples. Of note, once tumoral samples were normalized vs. non-tumoral colorectal tissue, only three mRNAS (i.e.: DEFB1, COL12A and PTGER3) and one miRNA (i.e.: miR-572) emerged as significantly deregulated in the liver metastases vs. the primary tumor. Canonical pathways found to be specifically deregulated in liver metastatic samples included multiple genes related with intercellular adhesion and the metastatic processes (e.g., IGF1R, PIK3CA, PTEN and EGFR), endocytosis (e.g., the PDGFRA, SMAD2, ERBB3, PML and FGFR2), and cell cycle (e.g., SMAD2, CCND2, E2F5 and MYC). Our results also highlight the activation of genes associated with the TGFβ signaling pathway, which thereby emerge as candidate genes to play an important role in CRC tumor metastasis. Tissue specimens from 23 sporadic colorectal adenocarcinomas and 19 liver metastases (n=42 samples) were obtained from 23 patients with metastatic lesions susceptible of being resected (16 males and 7 females; median age of 66 years, ranging from 48 to 80 years) after informed consent had been given by each subject. The studied cases corresponded to 23 consecutive metastatic colorectal cancer patients.

肿瘤转移播散是散发性结直肠癌（sporadic colorectal cancer, sCRC）患者最常见的死亡原因。该疾病晚期阶段的潜在特征性基因组异常极为复杂，迄今为止相关研究尚不多见，且人们对其认知仅局限于局部。本研究针对23例连续入组患者的原发性sCRC肿瘤样本及其配对肝转移灶，通过同步评估编码mRNA与非编码RNA基因的整体基因表达谱（gene expression profile, GEP），解析sCRC肿瘤的分子异质性。

本研究纳入的sCRC患者肝转移灶，其基因转录本的失调谱与对应原发性结直肠癌病灶的失调谱基本一致。但同时亦发现部分转录本仅在肝转移灶中呈现表达失调，而在对应原发性肿瘤中表达水平维持正常，这提示相较于原发性肿瘤样本，转移性肿瘤细胞的基因组不稳定性有所增强。值得注意的是，在将肿瘤样本与非肿瘤结直肠组织进行归一化处理后，仅3个mRNA（即DEFB1、COL12A与PTGER3）及1个微小RNA（microRNA, miRNA）在肝转移灶与原发性肿瘤的对比中呈现显著表达失调。

在肝转移样本中特异性失调的经典信号通路包含多个与细胞间黏附及转移过程相关的基因（如IGF1R、PIK3CA、PTEN与EGFR）、内吞作用相关基因（如PDGFRA、SMAD2、ERBB3、PML与FGFR2）以及细胞周期相关基因（如SMAD2、CCND2、E2F5与MYC）。本研究结果同时凸显了转化生长因子β（transforming growth factor β, TGFβ）信号通路相关基因的激活，该通路由此成为结直肠癌肿瘤转移中发挥关键作用的候选基因靶点。

本研究共纳入23例存在可切除转移性病灶的结直肠癌患者（男性16例，女性7例；中位年龄66岁，年龄范围48~80岁），在获取所有受试者的知情同意后，收集了23例散发性结直肠腺癌组织样本与19例肝转移灶样本，共计42份标本。本研究的研究对象均为连续入组的转移性结直肠癌患者。