Integrated transcriptomic analysis of distance-related field cancerization in rectal cancer patients.

Honglin Guo,Zhixiang Zhou,Ping Li,Weigen Zeng,Kaitai Zhang,Shujun Cheng,Xuexin Yu,Lin Feng

doi:10.18632/oncotarget.17864

Abstract

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.

Highlights

Colorectal cancer (CRC) is the third most common cancer in both men and women [1]
Global gene expression profile analysis of field cancerization in rectal cancer patients To illustrate distance-related Field cancerization (FC), we collected tumor tissues and paired normal tissues from specimens surgically resected from 32 rectal cancer patients
Given the impact of mitochondrion genome mutations on FC, we focused on fatty acid metabolic process-associated genes, which reflect the function of the mitochondrion, and evaluated their prognostic value in the colorectal cancer (CRC) dataset from The Cancer Genome Atlas (TCGA) (Figure 4)

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer in both men and women [1]. It is commonly accepted that CRC develops through a multistep carcinogenesis process from normal colorectal epithelium to adenoma, which progresses to cancer, accompanied by the accumulation of molecular alterations [2]. The molecular changes that give rise to the cancer can occur long before the morphological abnormality of the tissue Studies of such early molecular alterations could provide valuable information in risk assessment, early cancer detection and monitoring of progression in cancer management. The aberrant molecular alterations and environmental modifications are present throughout the organ that gives rise to the tumor [4]. This phenomenon has been studied in several epithelial tumors, including non-small cell lung cancer [5, 6], colorectal cancer [7, 8], breast cancer [9], head and neck cancer [10] and prostate cancer [11, 12]

Methods

Results

Conclusion