Analyzing Aberrant DNA Methylation in Colorectal Cancer Uncovered Intangible Heterogeneity of Gene Effects in the Survival Time of Patients

Overview

Journal Res Sq

Date 2023 Jul 3

PMID 37397988

Authors

Saeedeh Hajebi Khaniki

Farhad Shokoohi

Habibollah Esmaily

Mohammad Amin Kerachian

Affiliations

Soon will be listed here.

Abstract

Colorectal cancer (CRC) involves epigenetic alterations. Irregular gene-methylation alteration causes and advances CRC tumor growth. Detecting differentially methylated genes (DMGs) in CRC and patient survival time paves the way to early cancer detection and prognosis. However, CRC data including survival times are heterogeneous. Almost all studies tend to ignore the heterogeneity of DMG effects on survival. To this end, we utilized a sparse estimation method in the finite mixture of accelerated failure time (AFT) regression models to capture such heterogeneity. We analyzed a dataset of CRC and normal colon tissues and identified 3,406 DMGs. Analysis of overlapped DMGs with several Gene Expression Omnibus datasets led to 917 hypo- and 654 hyper-methylated DMGs. CRC pathways were revealed via gene ontology enrichment. Hub genes were selected based on Protein-Protein-Interaction network including , , , , and , regulating the Wnt signaling pathway. The relationship between identified DMGs/hub genes and patient survival time uncovered a two-component mixture of AFT regression model. The genes , , , , , , and and hub genes , , and were associated with survival time in the most aggressive form of the disease that can serve as potential diagnostic targets for early CRC detection.

References

Kerachian M, Javadmanesh A, Azghandi M, Mojtabanezhad Shariatpanahi A, Yassi M, Shams Davodly E . Crosstalk between DNA methylation and gene expression in colorectal cancer, a potential plasma biomarker for tracing this tumor. Sci Rep. 2020; 10(1):2813. PMC: 7028731. DOI: 10.1038/s41598-020-59690-0. View

He Y, Liu X, Gong R, Peng K, Liu R, Wang F . NK homeobox 2.2 functions as tumor suppressor in colorectal cancer due to DNA methylation. J Cancer. 2020; 11(16):4791-4800. PMC: 7330694. DOI: 10.7150/jca.43665. View

Xiao Q, Gan Y, Li Y, Fan L, Liu J, Lu P . MEF2A transcriptionally upregulates the expression of ZEB2 and CTNNB1 in colorectal cancer to promote tumor progression. Oncogene. 2021; 40(19):3364-3377. PMC: 8116210. DOI: 10.1038/s41388-021-01774-w. View

Barrow T, Klett H, Toth R, Bohm J, Gigic B, Habermann N . Smoking is associated with hypermethylation of the APC 1A promoter in colorectal cancer: the ColoCare Study. J Pathol. 2017; 243(3):366-375. PMC: 5647242. DOI: 10.1002/path.4955. View

Naumov V, Generozov E, Zaharjevskaya N, Matushkina D, Larin A, Chernyshov S . Genome-scale analysis of DNA methylation in colorectal cancer using Infinium HumanMethylation450 BeadChips. Epigenetics. 2013; 8(9):921-34. PMC: 3883769. DOI: 10.4161/epi.25577. View

Hu J, Zhao F, Huang B, Ran J, Chen M, Liu H . An Eight-CpG-based Methylation Classifier for Preoperative Discriminating Early and Advanced-Late Stage of Colorectal Cancer. Front Genet. 2021; 11:614160. PMC: 7838682. DOI: 10.3389/fgene.2020.614160. View

Marcucci G, Maharry K, Radmacher M, Mrozek K, Vukosavljevic T, Paschka P . Prognostic significance of, and gene and microRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: a Cancer and Leukemia Group B Study. J Clin Oncol. 2008; 26(31):5078-87. PMC: 2652095. DOI: 10.1200/JCO.2008.17.5554. View

Andrew A, Parker S, Anderson J, Rees J, Robinson C, Riddle B . Risk Factors for Diagnosis of Colorectal Cancer at a Late Stage: a Population-Based Study. J Gen Intern Med. 2018; 33(12):2100-2105. PMC: 6258633. DOI: 10.1007/s11606-018-4648-7. View

Katoh M, Katoh M . Molecular genetics and targeted therapy of WNT-related human diseases (Review). Int J Mol Med. 2017; 40(3):587-606. PMC: 5547940. DOI: 10.3892/ijmm.2017.3071. View

10.

Ge W, Cai W, Bai R, Hu W, Wu D, Zheng S . A novel 4-gene prognostic signature for hypermutated colorectal cancer. Cancer Manag Res. 2019; 11:1985-1996. PMC: 6407520. DOI: 10.2147/CMAR.S190963. View

11.

Liu Y, Guo C, Li F, Wu L . LncRNA LOXL1-AS1/miR-28-5p/SEMA7A axis facilitates pancreatic cancer progression. Cell Biochem Funct. 2019; 38(1):58-65. DOI: 10.1002/cbf.3449. View

12.

Wang S, Gao K, Deng D, Cai J, Xiao Z, He L . TLE4 promotes colorectal cancer progression through activation of JNK/c-Jun signaling pathway. Oncotarget. 2015; 7(3):2878-88. PMC: 4823078. DOI: 10.18632/oncotarget.6694. View

13.

McInnes T, Zou D, Rao D, Munro F, Phillips V, McCall J . Genome-wide methylation analysis identifies a core set of hypermethylated genes in CIMP-H colorectal cancer. BMC Cancer. 2017; 17(1):228. PMC: 5371203. DOI: 10.1186/s12885-017-3226-4. View

14.

Kinehara Y, Nagatomo I, Koyama S, Ito D, Nojima S, Kurebayashi R . Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells. JCI Insight. 2018; 3(24). PMC: 6338389. DOI: 10.1172/jci.insight.123093. View

15.

Issa J, Ottaviano Y, Celano P, Hamilton S, Davidson N, Baylin S . Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet. 1994; 7(4):536-40. DOI: 10.1038/ng0894-536. View

16.

Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J . Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995; 268(5215):1336-8. DOI: 10.1126/science.7761852. View

17.

Crump L, Wyatt G, Rutherford T, Richer J, Porter W, Lyons T . Hormonal Regulation of Semaphorin 7a in ER Breast Cancer Drives Therapeutic Resistance. Cancer Res. 2020; 81(1):187-198. PMC: 7878309. DOI: 10.1158/0008-5472.CAN-20-1601. View

18.

Rehman M, Tamagnone L . Semaphorins in cancer: biological mechanisms and therapeutic approaches. Semin Cell Dev Biol. 2012; 24(3):179-89. DOI: 10.1016/j.semcdb.2012.10.005. View

19.

Huang H, Fu J, Zhang L, Xu J, Li D, Onwuka J . Integrative Analysis of Identifying Methylation-Driven Genes Signature Predicts Prognosis in Colorectal Carcinoma. Front Oncol. 2021; 11:629860. PMC: 8231008. DOI: 10.3389/fonc.2021.629860. View

20.

Levine A, Oren M . The first 30 years of p53: growing ever more complex. Nat Rev Cancer. 2009; 9(10):749-58. PMC: 2771725. DOI: 10.1038/nrc2723. View