Integrated transcriptomic analysis of distance-related field cancerization in rectal cancer patients
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Honglin Guo1,*, Weigen Zeng2,*, Lin Feng1, Xuexin Yu3, Ping Li1, Kaitai Zhang1, Zhixiang Zhou4 and Shujun Cheng1
1State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
2Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
3College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
4Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
*These authors contributed to the work equally and should be regarded as co-first authors
Zhixiang Zhou, email: firstname.lastname@example.org
Kaitai Zhang, email: email@example.com
Shujun Cheng, email: firstname.lastname@example.org
Keywords: field cancerization, CRC, fatty acid metabolism, ribosome biogenesis, CPT2
Received: March 01, 2017 Accepted: April 07, 2017 Published: May 15, 2017
Field cancerization (FC) occurs in various epithelial carcinomas, including colorectal cancer, which indicates that the molecular events in carcinogenesis might occur in normal tissues extending from tumors. However, the transcriptomic characteristics of FC in colorectal cancer (CRC) remain largely unexplored. To investigate the changes in gene expression associated with proximity to the tumor, we analyzed the global gene expression profiles of cancer tissues and histologically normal tissues taken at various distances from the tumor (1 cm, 5 cm and the proximal end of the resected sample) from 32 rectal cancer patients. Significantly differentially expressed genes related to the distance from the tumor were screened by linear mixed effects analysis using the lme4 package in R. The distance-related differentially expressed genes that were gradually up-regulated (n=302) or gradually down-regulated (n=568) from normal tissues to the tumor were used to construct protein-protein interaction (PPI) networks. Three subnetworks among the gradually up-regulated genes and four subnetworks among the gradually down-regulated genes were identified using the MCODE plugin in the Cytoscape software program. The most significantly enriched Gene Ontology (GO) biological process terms were “ribosome biogenesis”, “mRNA splicing via spliceosome”, and “positive regulation of leukocyte migration” for the gradually up-regulated subnetworks and “cellular calcium ion homeostasis”, “cell separation after cytokinesis”, “cell junction assembly”, and “fatty acid metabolic process” for the gradually down-regulated subnetworks. Combined with the previously constructed multistep carcinogenesis model used for the analysis, 50.59% of the genes in the subnetworks (43/85) displayed identical changes in expression from normal colon tissues to adenoma and colon cancer. We focused on the 7 genes associated with fatty acid metabolic processes in the distance-related down-regulated subnetwork. Survival analysis of patients in the CRC dataset from The Cancer Genome Atlas (TCGA) revealed that higher expression of these 7 genes, especially CPT2, ACAA2 and ACADM, was associated with better prognosis (p = 0.034, p = 0.00058, p = 0.039, p = 0.04). Cox proportional hazards regression analysis revealed that CPT2 was an independent prognostic factor (p = 0.004131). Our results demonstrate that field cancerization occurs in CRC and affects gene expression in normal tissues extending from the tumor, which may provide new insights into CRC oncogenesis and patient progression.
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