Comprehensive Analysis of Differentially Expressed Long Noncoding RNA-mRNA in the Adenoma-Carcinoma Sequence of DNA Mismatch Repair Proficient Colon Cancer.

Wenkun Li,Chunmei Guo,Yadan Wang,Wu Lin,Canghai Wang,Nan Wei,Kuiliang Liu,Hong Liu,Yueqiong Lao,Yun Wang,Qian Li,Nanshan Li,Jing Wu,Jiang Ge,Guojun Jiang,Sumanta Chatterjee

doi:10.1155/2021/9977695

Abstract

DNA proficient mismatch repair colon cancer (pMMR CC) is the most common subtype of sporadic CC. We aimed to investigate the role of long noncoding RNAs (lncRNAs) in pMMR CC carcinogenesis. In the present study, we conducted transcriptomic analysis of lncRNAs-mRNAs in five low-grade intraepithelial neoplasia (LGIN), five high-grade intraepithelial neoplasia (HGIN), four pMMR CC, and five normal control (NC) tissues. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway, and coexpression network analyses were performed to elucidate the functions of lncRNAs and mRNAs as well as their interactions. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate five dysregulated lncRNAs in a large set of colon tissues. Receiver-operating characteristic (ROC) curves were employed to evaluate the performance of the candidate lncRNAs. A set of 5783 differentially expressed lncRNAs and 4483 differentially expressed mRNAs were detected among the LGIN, HGIN, pMMR CC, and NC samples. These differentially expressed lncRNAs and mRNAs were assigned to 275 significant GO terms and 179 significant KEGG enriched pathways. qRT-PCR confirmed that the expression of five selected lncRNAs (ENST00000521815, ENST00000603052, ENST00000609220, NR_026543, and ENST00000545920) were consistent with the microarray data. ROC analysis showed that four lncRNAs (ENST00000521815, ENST00000603052, ENST00000609220, and NR_026543) had larger area under the ROC curve (AUC) values compared to serum carcinoembryonic antigens, thereby distinguishing NC from pMMR CC. In conclusion, several lncRNAs play various roles in the adenoma-carcinoma sequence and may serve as potential biomarkers for the early diagnosis of pMMR CC.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, comprising over 1.8 million new cases in 2018 [1]
About two-thirds of CRC cases arise with unknown contributions from germline factors or a significant family history of cancer or inflammatory bowel disease, defined as sporadic CRC. ree major genetic mechanisms underlie the pathogenesis of sporadic CRC [7], namely, chromosomal instability (CIN), microsatellite instability (MSI), and the epigenomic CpG island methylator phenotype (CIMP)
A total of 244 sporadic colonic tissues, including 63 adenomas of low-grade intraepithelial neoplasia (LGIN), 32 adenomas of high-grade intraepithelial neoplasia (HGIN), 66 proficient mismatch repair colon cancer (pMMR CC), eight defective mismatch repair (dMMR) CC, and 75 normal control (NC) samples from adjacent (≥10 cm) hyperplastic or inflammatory polyps were sampled at Beijing Shijitan Hospital (Beijing, China) from 2018 to 2019. e samples were immediately placed in RNAlater solution

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, comprising over 1.8 million new cases in 2018 [1]. More than 70% of CRC cases are located in the colon, which is called colon cancer (CC) [2]. According to the latest data, CRC ranks fifth in both incidence and mortality among cancers in China [3]. CRC is a heterogeneous disease with a progressive accumulation of genetic and epigenetic alterations [4,5,6]. About two-thirds of CRC cases arise with unknown contributions from germline factors or a significant family history of cancer or inflammatory bowel disease, defined as sporadic CRC. Ree major genetic mechanisms underlie the pathogenesis of sporadic CRC [7], namely, chromosomal instability (CIN), microsatellite instability (MSI), and the epigenomic CpG island methylator phenotype (CIMP). CIN, the first described and the most common pathway, accounts for 80%–85% of sporadic CRC [8]. CIN CRCs are nonhypermutated with DNA proficient mismatch repair (pMMR) functions [7]. e mechanism responsible for CIN is different from that responsible for MSI and CIMP

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Conclusion