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BMC Cancer
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Colorectal Cancer | Research

Aberrant methylation in neurofunctional gene serves as a hallmark of tumorigenesis and progression in colorectal cancer

Authors: Xuan Li, Du Cai, Yaoyi Huang, Yumo Xie, Dingcheng Shen, Ze Yuan, Xiaoxia Liu, Meijin Huang, Yanxin Luo, Huichuan Yu, Xiaolin Wang

Published in: BMC Cancer | Issue 1/2023

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Abstract

Background

DNA methylation is one of the most promising biomarkers in predicting the prognosis of colorectal cancer (CRC). We aimed to develop a DNA methylation biomarker that could evaluate the prognosis of CRC.

Methods

A promising DNA methylation biomarker was developed by hypermethylated genes in cancer tissue that were identified from Illumina EPIC methylation arrays. A cohort comprising 30 pairs of snap-frozen tumor tissue and adjacent normal tissue was used for correlation analysis between the methylation and expression status of the marker. The other cohort comprising 254 formalin-fixed paraffin-embedded (FFPE) tumor tissue from 254 CRC patients was used for prognosis analysis.

Results

Regulating synaptic membrane exocytosis 2 (RIMS2) was hypermethylated and lowly expressed in CRC comparing to adjacent normal tissue. Hypermethylation of RIMS2 in CRC was correlated with less frequent KRAS mutant and high differentiation. RIMS2 promoter methylation showed independent predictive value for survival outcome (P = 0.015, HR 1.992, 95% CI [(1.140–3.48)]), and a combination of RIMS2 methylation with KRAS status could predict prognosis better.

Conclusions

RIMS2 is frequently hypermethylated in CRC, which can silence the expression of RIMS2. RIMS2 methylation is a novel biomarker for predicting the prognosis of CRC.
Literature
1.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.CrossRefPubMed
2.
Xie Y, Shi L, He X, Luo Y. Gastrointestinal cancers in China, the USA, and Europe. Gastroenterol Rep. 2021;9:91–104.CrossRef
3.
Sveen A, Kopetz S, Lothe RA. Biomarker-guided therapy for colorectal cancer: strength in complexity. Nat Rev Clin Oncol. 2020;17:11–32.CrossRefPubMed
4.
Kocarnik JM, Shiovitz S, Phipps AI. Molecular phenotypes of colorectal cancer and potential clinical applications. Gastroenterol Rep. 2015;3:269–76.
5.
Zou Q, Wang X, Ren D, Hu B, Tang G, Zhang Y, et al. DNA methylation-based signature of CD8+ tumor-infiltrating lymphocytes enables evaluation of immune response and prognosis in colorectal cancer. J Immunother Cancer. 2021;9: e002671.CrossRefPubMedPubMedCentral
6.
Okugawa Y, Grady WM, Goel A. Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers. Gastroenterology. 2015;149:1204-1225.e12.CrossRefPubMed
7.
Chen Z, Huang Z, Luo Y, Zou Q, Bai L, Tang G, et al. Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer. J Transl Med. 2021;19:73.CrossRefPubMedPubMedCentral
8.
Dor Y, Cedar H. Principles of DNA methylation and their implications for biology and medicine. Lancet Lond Engl. 2018;392:777–86.CrossRef
9.
Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349:2042–54.CrossRefPubMed
10.
BLUEPRINT consortium. Quantitative comparison of DNA methylation assays for biomarker development and clinical applications. Nat Biotechnol. 2016;34:726–37.
11.
Vedeld HM, Goel A, Lind GE. Epigenetic biomarkers in gastrointestinal cancers: The current state and clinical perspectives. Semin Cancer Biol. 2018;51:36–49.CrossRefPubMed
12.
Wang Y, Südhof TC. Genomic definition of RIM proteins: evolutionary amplification of a family of synaptic regulatory proteins. Genomics. 2003;81:126–37.CrossRefPubMed
13.
Yasuda T, Shibasaki T, Minami K, Takahashi H, Mizoguchi A, Uriu Y, et al. Rim2α Determines Docking and Priming States in Insulin Granule Exocytosis. Cell Metab. 2010;12:117–29.CrossRefPubMed
14.
Acuna C, Liu X, Südhof TC. How to Make an Active Zone: Unexpected Universal Functional Redundancy between RIMs and RIM-BPs. Neuron. 2016;91:792–807.CrossRefPubMed
15.
Gebhart M, Juhasz-Vedres G, Zuccotti A, Brandt N, Engel J, Trockenbacher A, et al. Modulation of Cav1.3 Ca2+ channel gating by Rab3 interacting molecule. Mol Cell Neurosci. 2010;44:246–59.
16.
Dulubova I, Lou X, Lu J, Huryeva I, Alam A, Schneggenburger R, et al. A Munc13/RIM/Rab3 tripartite complex: from priming to plasticity? EMBO J. 2005;24:2839–50.CrossRefPubMedPubMedCentral
17.
Fukuda M. Distinct Rab binding specificity of Rim1, Rim2, rabphilin, and Noc2. Identification of a critical determinant of Rab3A/Rab27A recognition by Rim2. J Biol Chem. 2003;278:15373–80.
18.
Ozaki N, Shibasaki T, Kashima Y, Miki T, Takahashi K, Ueno H, et al. cAMP-GEFII is a direct target of cAMP in regulated exocytosis. Nat Cell Biol. 2000;2:805–11.CrossRefPubMed
19.
Ohara-Imaizumi M, Ohtsuka T, Matsushima S, Akimoto Y, Nishiwaki C, Nakamichi Y, et al. ELKS, a protein structurally related to the active zone-associated protein CAST, is expressed in pancreatic beta cells and functions in insulin exocytosis: interaction of ELKS with exocytotic machinery analyzed by total internal reflection fluorescence microscopy. Mol Biol Cell. 2005;16:3289–300.CrossRefPubMedPubMedCentral
20.
Mukasa A, Ueki K, Ge X, Ishikawa S, Ide T, Fujimaki T, et al. Selective expression of a subset of neuronal genes in oligodendroglioma with chromosome 1p loss. Brain Pathol Zurich Switz. 2004;14:34–42.CrossRef
21.
Tabariès S, McNulty A, Ouellet V, Annis MG, Dessureault M, Vinette M, et al. Afadin cooperates with Claudin-2 to promote breast cancer metastasis. Genes Dev. 2019;33:180–93.CrossRefPubMedPubMedCentral
22.
Shen D, Wang X, Wang H, Xu G, Xie Y, Zhuang Z, et al. Current Surveillance After Treatment is Not Sufficient for Patients With Rectal Cancer With Negative Baseline CEA. J Natl Compr Cancer Netw JNCCN. 2022;20:653-662.e3.CrossRefPubMed
23.
Yu H, Wang X, Bai L, Tang G, Carter KT, Cui J, et al. DNA methylation profile in CpG-depleted regions uncovers a high-risk subtype of early-stage colorectal cancer. J Natl Cancer Inst. 2023;115:52–61.CrossRefPubMed
24.
Luo Y, Kaz AM, Kanngurn S, Welsch P, Morris SM, Wang J, et al. NTRK3 is a potential tumor suppressor gene commonly inactivated by epigenetic mechanisms in colorectal cancer. PLoS Genet. 2013;9: e1003552.CrossRefPubMedPubMedCentral
25.
Eads CA, Danenberg KD, Kawakami K, Saltz LB, Blake C, Shibata D, et al. MethyLight: a high-throughput assay to measure DNA methylation. Nucleic Acids Res. 2000;28:E32.CrossRefPubMedPubMedCentral
26.
Yu H, Bai L, Tang G, Wang X, Huang M, Cao G, et al. Novel Assay for Quantitative Analysis of DNA Methylation at Single-Base Resolution. Clin Chem. 2019;65:664–73.CrossRefPubMed
27.
Vedeld HM, Merok M, Jeanmougin M, Danielsen SA, Honne H, Presthus GK, et al. CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers. Int J Cancer. 2017;141:967–76.CrossRefPubMedPubMedCentral
28.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods San Diego Calif. 2001;25:402–8.CrossRefPubMed
29.
30.
Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002;21:5427–40.CrossRefPubMed
31.
Kaeser PS, Deng L, Fan M, Südhof TC. RIM genes differentially contribute to organizing presynaptic release sites. Proc Natl Acad Sci U S A. 2012;109:11830–5.CrossRefPubMedPubMedCentral
32.
Weidenhofer J, Scott RJ, Tooney PA. Investigation of the expression of genes affecting cytomatrix active zone function in the amygdala in schizophrenia: effects of antipsychotic drugs. J Psychiatr Res. 2009;43:282–90.CrossRefPubMed
33.
Nielsen DA, Ji F, Yuferov V, Ho A, He C, Ott J, et al. Genome-wide association study identifies genes that may contribute to risk for developing heroin addiction. Psychiatr Genet. 2010;20:207–14.CrossRefPubMed
34.
35.
Dai J, Li Z-X, Zhang Y, Ma J-L, Zhou T, You W-C, et al. Whole Genome Messenger RNA Profiling Identifies a Novel Signature to Predict Gastric Cancer Survival. Clin Transl Gastroenterol. 2019;10: e00004.CrossRefPubMedPubMedCentral
36.
Lv T, Miao Y-F, Jin K, Han S, Xu T-Q, Qiu Z-L, et al. Dysregulated circular RNAs in medulloblastoma regulate proliferation and growth of tumor cells via host genes. Cancer Med. 2018;7:6147–57.CrossRefPubMedPubMedCentral
37.
Yang J, Hou Z, Wang C, Wang H, Zhang H. Gene expression profiles reveal key genes for early diagnosis and treatment of adamantinomatous craniopharyngioma. Cancer Gene Ther. 2018;25:227–39.CrossRefPubMed
38.
Maeda M, Yamashita S, Shimazu T, Iida N, Takeshima H, Nakajima T, et al. Novel epigenetic markers for gastric cancer risk stratification in individuals after Helicobacter pylori eradication. Gastric Cancer Off J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc. 2018;21:745–55.
39.
Chang Y-C, Su C-Y, Chen M-H, Chen W-S, Chen C-L, Hsiao M. Secretory RAB GTPase 3C modulates IL6-STAT3 pathway to promote colon cancer metastasis and is associated with poor prognosis. Mol Cancer. 2017;16:135.CrossRefPubMedPubMedCentral
40.
Luo Y, Ye G-Y, Qin S-L, Mu Y-F, Zhang L, Qi Y, et al. High expression of Rab3D predicts poor prognosis and associates with tumor progression in colorectal cancer. Int J Biochem Cell Biol. 2016;75:53–62.CrossRefPubMed
Metadata
Title
Aberrant methylation in neurofunctional gene serves as a hallmark of tumorigenesis and progression in colorectal cancer
Authors
Xuan Li
Du Cai
Yaoyi Huang
Yumo Xie
Dingcheng Shen
Ze Yuan
Xiaoxia Liu
Meijin Huang
Yanxin Luo
Huichuan Yu
Xiaolin Wang
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-10765-x

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