MAN2A1 predicts prognosis and progression through cancer-related pathways in colorectal cancer
Original Article

MAN2A1 predicts prognosis and progression through cancer-related pathways in colorectal cancer

Yangzi Wang, Jianmin Zhao, Guoxiang Fu, Caixia Sheng, Jia Zhu, Tingting Zhong, Fang Yang^, Zhinong Jiang^

Department of pathology, Sir Run Run Shaw Hospital Affiliated to Zhejiang University, Hangzhou, China

Contributions: (I) Conception and design: Y Wang; (II) Administrative support: Z Jiang, F Yang; (III) Provision of study materials or patients: J Zhao, G Fu; (IV) Collection and assembly of data: C Sheng, J Zhu; (V) Data analysis and interpretation: T Zhong; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

^ORCID: Fang Yang, 0000-0003-0688-5690; Zhinong Jiang, 0000-0003-4040-0407.

Correspondence to: Zhinong Jiang, MD, PhD. Sir Run Run Shaw Hospital, Affiliated to Zhejiang University, East Qingchun Road 3, Hangzhou 310016, China. Email: 3200039@zju.edu.cn; Fang Yang. Department of pathology, Sir Run Run Shaw Hospital, Affiliated to Zhejiang University, East Qingchun Road 3, Hangzhou 310016, China. Email: xiaoyangpumc@zju.edu.cn.

Background: Colorectal cancer (CRC) is a common malignant tumor leading to poor prognosis and high mortality. Mannosidase alpha class 2A member 1 (MAN2A1) turns to oncogene through fusing Fer tyrosine kinase (FER) and associates with multiple cancer occurrence. In order to determine whether MAN2A1 can promote tumorigenesis and metastasis in CRC, we conducted a series of studies.

Methods: We obtained gene expression and clinical data of CRC from The Cancer Genome Atlas (TCGA) databases. RNA raw counts data was merged by Python. Batch processing of univariate Cox regression analysis was performed to preliminary identify the genes associated with prognosis. Differentially expressed genes (DEGs) between lymph node metastasis (LNM) patients and non-LNM patients were identified via edgR in Sangerbox tool. Protein-protein interactive (PPI) network was constructed using Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software. Kaplan-Meier (KM) survival of CRC patients was analyzed by Sangerbox tool. Clinicopathologic characteristics of CRC patients were analyzed by SPSS statistics software. Differences in RNA expression levels of genes were validated in our cohort by real-time polymerase chain reaction (RT-PCR). Analyses of Signaling pathways and gene ontology were explored by gene set enrichment analysis (GSEA).

Results: We first obtained 4,455 genes associated with the prognosis of CRC, and 998 of these genes were also DEGs in CRC between metastatic CRC tissues and in situ tissues. Therein, MAN2A1 expression was downregulated in LNM CRC compared with CRC in situ, also downregulated in CRC compared with adjacent normal tissues, and high gene expression levels of MAN2A1 was associated with better survival.

Conclusions: Our study suggested that MAN2A1 could be a potential biomarker significantly related to prognosis and LNM of CRC patients.

Keywords: Colorectal cancer (CRC); biomarker; bioinformatics analysis

Submitted Mar 11, 2022. Accepted for publication Aug 01, 2022.

doi: 10.21037/tcr-22-629

Introduction

Colorectal cancer (CRC) is a common digestive system carcinoma, CRC is the third commonly diagnosed malignant tumor and the fourth malignancy leading to death (1). Approximately 44% of CRC patients were diagnosed with stage Ⅰ-Ⅱ, and the 5-year survival rate of stage Ⅰ and stage Ⅱ was 91% and 82% respectively (2). However, 35% of patients were diagnosed with metastatic disease and 50% of patients diagnosed with non-metastatic CRC ended up manifesting with metastatic disease, leading to low survival rates (3-5).

With the development of molecular biology and bioinformatics, differentially expressed genes (DEGs) between metastatic tumor and in situ tumor can be identified. These DEGs are relevant to the pathological stage, metastatic and prognosis of patients (6). The wide application of various bioinformatics tools also make efforts to predict the possible mechanisms of genes (7,8).

In this study, we screened colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ) datasets from The Cancer Genome Atlas (TCGA) databases to identify DEGs between lymph node metastasis (LNM) patients and non-LNM patients which also associated with prognosis. In addition, we constructed a protein-protein interactive (PPI) network and used Cytoscape molecular complex detection (MCODE) plus to find hub genes. We explored these hub genes, found the association between Mannosidase alpha class 2A member 1 (MAN2A1) expression level and prognosis of CRC patients, and verified RNA expression level in CRC patients of our cohort. Therefore, we identified MAN2A1 as a candidate gene for biomarker related to diagnosis and prognosis of CRC patients. We present the following article in accordance with the REMARK reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-629/rc).

Methods

Tumor samples and ethics approval

The fresh tumor specimens and corresponding adjacent normal tissues were obtained from CRC patients who underwent surgery at Sir Run Run Shaw Hospital, affiliated to Zhejiang University, from 2018 to 2020. These tissues were stored at −80 ℃ at once after surgery (Table 1). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Ethics Committee of Sir Run Run Shaw Hospital, affiliated to Zhejiang University approved all study protocols (approval ID. 20200619-34). Individual consent for this retrospective study was waived.

Table 1

Demographic and clinical manifestation of 26 participants

Variables Data
Total number 26
   Age (years), mean ± SD 61.08±12.46
   Minimum 37
   Maximum 80
Gender, n (%)
   Male 13 (50.00)
   Female 13 (50.00)
Regional lymph node invasion, n (%)
   No 10 (38.46)
   Yes 16 (61.54)

SD, standard deviation.

Data acquisition

We downloaded CRC transcriptome profiles from TCGA database through the Genomic Data Commons (GDC) Portal. The public data included RNA-seq profiles of 272 CRC lymph node metastatic tissues (N1, N2) and 368 non-metastatic tissues (N0).

Identification of intersection genes

We merged RNA raw counts data by Python to analyze the RNA-seq data and converted gene ID to gene symbol (Homo sapiens). Then, batch processing of univariate Cox regression analysis was performed to identify genes associated with prognosis of CRC (P≤0.05). The DEGs were identified with edgeR package in Sangerbox tool (P≤0.05). Venn diagram was used to identify intersection genes of the above conditions.

PPI network

The interaction of the intersection genes were analyzed with Search Tool for the Retrieval of Interacting Genes (STRING, http://string-db.org) (9). Then, Cytoscape (http://www.cytoscape.org/) software was used for establishing PPI network. In addition, Cytoscape MCODE plus was used to analyze modules and got hub genes (10).

Enrichment analysis

To identified the biological significance of the intersection genes, the KEGG Orthology Based Annotation System (KOBAS) 3.0 (11) and Database for Annotation, Visualization, and Integrated Discovery (DAVID) online tools (12,13) were used for enrichment analysis. The DAVID was used to reveal Gene Ontology (GO) (P≤0.05), KOBAS 3.0 was used to reveal (Kyoto Encyclopedia of Genes and Genomes) KEGG pathways (corrected P value ≤0.05).

Detect MAN2A1 mRNA expression

Total RNA was isolated from the tissues using RNeasy Mini Kit (QIAGEN, Dusseldorf, Germany). The concentration and purity of RNA were detected with the NanoDrop 2000 spectrophotometer. Total RNA (1000 ng) was converted to complementary DNA (cDNA) by RevertAid First Strand cDNA Synthesis Kit (MA, USA, thermo scientific). We used LightCycler96 to conduct real-time polymerase chain reaction (RT-PCR) by SYBR Green (Nanjing, China, Vazyme). We used two-step amplification reaction as follows: 25 ℃ for 5 min for preincubation, then 42 ℃ for 60 min and 70 ℃ for 5 min. GAPDH expression was utilized as an endogenous control. Quantitative analysis was calculated by the 2−ΔCt method. Primers were designed as follows: MAN2A1 forward, 5'-AAGTCAGCGCAGTTTGGGAT-3' and reverse 5'-CCACAGACTGTCCTTCTATTCCC-3'.

Gene set enrichment analysis (GSEA)

GSEA is a computational mathematics method to interpret gene expression data and demonstrate differences between two biological group (14,15). GSEA 4.1.0 software was used to analyze the biological functions of MAN2A1 in CRC. CRC patients were divided into two groups according to MAN2A1 expression levels. We used the Molecular Signatures Database (16,17) (MsigDB, https://www.gseamsigdb.org/gsea/msigdb/) to analyze KEGG pathways and GO terms to explore the potential biological mechanism and function of MAN2A1, GSEA parameters were repeating the analysis 2000 times at a time and default weighted enrichment statistics. false discovery rate (FDR) q‐value ≤0.05 was set as cut-off criteria.

Statistical analysis

Sangerbox (http://vip.sangerbox.com/) is a comprehensive bioinformatics analysis tool that can carry out bioinformatics analysis and visualize results (18). Kaplan-Meier (KM) Survival analysis of MAN2A1 was performed by sangerbox tool. The clinicopathologic features of MAN2A1 were evaluated with chi-squared, univariate, and logistic regression method by SPSS. Patients’ overall survival (OS)-related clinical characteristics in TCGA was analyzed by Cox regression via SPSS.

Results

Identification of hub genes in CRC

We drew a flow chart of research design (Figure 1). We downloaded expression profiles and clinical data of COAD and READ from TCGA and identified 4,455 genes associated with prognosis in CRC by cox analysis in batch mode (P≤0.05), identified 5,887 genes differentially expressed between metastatic CRC tissues and in situ tissues by edgR in Sangerbox tool (P≤0.05). Finally, we got 998 potential aim genes met the above requirements shown in the intersection of Venn diagram (Figure 2A). PPI network was constructed by STRING and cytoscape software for the 998 potential aim genes, composed of 551 up-regulated genes and 447 down-regulated genes (Figure 2B). Then we utilized MCODE plus to find 196 hub genes (central nodes), including 63 up-regulated genes and 133 down-regulated genes (Figure 2C, Table S1).

Figure 1 Flow chart of research design. TCGA, The Cancer Genome Atlas; CRC, colorectal cancer; COAD, colon adenocarcinoma; READ, rectum adenocarcinoma; MCODE, molecular complex detection; MAN2A1, mannosidase alpha class 2A member 1.
Figure 2 Identify 196 hub genes of CRC. (A) Identify 998 potential aim genes by Venn diagram. (B) The PPI network of the 998 DEGs in CRC. (C) Modules to get hub genes (orange circles signify up-regulated DEGs and blue circles denoted down-regulated DEGs). CRC, colorectal cancer; PPI, protein-protein interactive; DEG, differentially expressed gene.

GO and signaling pathway enrichment analysis

We analyzed the potential aim genes via the KOBAS online software and identified 28 significant enrichment pathways, indicating they were enriched in metabolic pathways, pathways in cancer, human papillomavirus interaction, endocytosis, P53 signaling pathway and so on (Figure 3A). And the DAVID online software was used to identify 113 significant enrichment GO terms, including biological process (BP), molecular function (MF), and cellular components (CC). The top 20 GO terms are depicted in Figure 3B-3D.

Figure 3 The significantly enriched KEGG pathways and top 20 GO. (A) KEGG pathways; (B) biological process; (C) molecular function; (D) cellular components. KEGG, Kyoto Encyclopedia of Genes and Genomes; GO, Gene Ontology; FDR, false discovery rate.

The expression of MAN2A1 in CRC

We found that the expression of MAN2A1 in CRC and metastatic CRC have not been reported. In addition, the relation between MAN2A1 expression and CRC survival was still controversial. Consequently, we explored the expression of MAN2A1 between metastatic CRC and non-metastatic CRC in TCGA database and found that MAN2A1 was lower expressed in metastatic CRC (Figure 4A). We also found the expression of MAN2A1 in TCGA and our own CRC tissues was down-expressed than adjacent normal tissues cohort (n=26, 16 of 26 were metastatic patients, 10 of 26 were nonmetastatic patients) (Figure 4B,4C).

Figure 4 MAN2A1 expression in CRC tissue. (A) MAN2A1 expression in metastatic CRC samples and non-metastatic CRC samples in TCGA database. (B) The expression level of MAN2A1 in CRC tissues and normal tissues in TCGA database. (C) The expression level of MAN2A1 in CRC tissues and adjacent normal tissues of all CRC samples in our cohort. *, P<0.05; **, P<0.01; ***, P<0.001. TPM, transcripts per million; CRC, colorectal cancer; TCGA, The Cancer Genome Atlas.

Prognostic value of MAN2A1 expression in CRC

We evaluated the prognostic value of MAN2A1 in TCGA CRC dataset by performing KM survival analysis. The results showed that high expression of MAN2A1 was associated with better OS (Figure 5, P=0.0019). Univariate cox analysis was used to analyze independent prognostic value of MAN2A1, and the results showed that high expression of age (P=0.001), invasion depth (P=0.005), LNM (P<0.001), distant metastasis (P<0.001), and Tumor Node Metastasis (TNM) stage (P<0.001) corresponded with poor OS in CRC patients, whereas MAN2A1 (P=0.013), radiation treatment (P=0.047) corresponded with favorable OS in CRC patients (Table 2).

Figure 5 The prognosis value of MAN2A1 expression in CRC. High expression of MAN2A1 indicated better survival of patients. HR, hazard ratio; CRC, colorectal cancer.

Table 2

COX analysis of the associations between MAN2A1 expression and clinicopathologic features of CRC patients in TCGA database

Parameter Univariate analysis
P value HR 95% CI
Age (≥65 vs. <65), years 0.001** 1.984 1.34–2.938
Gender (female vs. male) 0.847 0.966 0.682–1.370
Invasion depth (T3 & T4 vs. T1 & T2) 0.005 2.444 1.314–4.547
Lymph node metastasis (yes vs. no) <0.001*** 2.509 1.749–3.599
Distant metastasis (yes vs. no) <0.001*** 3.766 2.551–5.561
TNM stage (stages III & IV vs. Stages I & II) <0.001*** 2.832 1.936–4.143
MAN2A1 expression (high vs. low) 0.013 0.637 0.446–0.909
Pharmacological treatment (yes vs. no) 0.731 1.089 0.670–1.770
Radiation treatment (yes vs. no) 0.047 0.592 0.353–0.992

**, P<0.01; ***, P<0.001. CRC, colorectal cancer; TCGA, The Cancer Genome Atlas; HR, hazard ratio; TNM, Tumor Node Metastasis.

The association of MAN2A1 expression and clinicopathologic characteristics in CRC

The expression level of MAN2A1 was associated with the prognosis in CRC patients. The expression of MAN2A1 was significantly related to LNM (P=0.05), and TNM stage (P=0.02) (Table 3). Whereas age, gender, radiation treatment, pharmacological treatment, invasion depth, and distant metastasis were not correlate with MAN2A1 expression (Table 3). Logistic regression analysis results showed that the expression of MAN2A1 was associated with LNM [yes vs. no, odd ratio (OR): 0.725, 95% CI: 0.526–1.001, P=0.05], distant metastasis (yes vs. no, OR: 0.634, 95% CI: 0.396–1.015, P=0.058), and TNM stage (stages III and IV vs. stages I and II, OR: 0.684, 95% CI: 0.494–0.947, P=0.022) (Table 4).

Table 3

Chi-square analysis of the association between MAN2A1 expression value and clinicopathologic characteristics of CRC patients in TCGA database

Variables Total Low expression High expression χ2 P
Age, years 0.902 0.342
   <65 249 127 122
   ≥65 368 202 166
Gender 0.772 0.380
   Female 288 159 129
   Male 329 170 159
Radiation treatment 1.970 0.160
   Yes 128 72 56
   No 393 193 200
Pharmacological treatment 0.835 0.361
   Yes 124 66 58
   No 395 195 200
TNM stage 5.426 0.02*
   Stage I 105 55 50
   Stage II 226 108 118
   Stage III 179 101 78
   Stage IV 88 56 32
Invasion depth 0.012 0.914
   T1 20 10 10
   T2 105 57 48
   T3 420 228 192
   T4 70 32 38
Lymph node metastasis 3.827 0.05*
   Yes 264 153 111
   No 350 175 175
Distant metastasis 3.640 0.056
   Yes 88 56 32
   No 464 244 220

*, P<0.05. CRC, colorectal cancer; TCGA, The Cancer Genome Atlas.

Table 4

Logistic regression analysis of the association between MAN2A1 expression value and clinical characteristics of CRC patients in TCGA database

Logistic regression analysis P HR 95% CI
Lymph node metastasis (yes vs. no) 0.05* 0.725 0.526–1.001
Distant metastasis (yes vs. no) 0.058 0.634 0.396–1.015
TNM stage (stages III & IV vs. stages I & II) 0.022* 0.684 0.494–0.947

*, P<0.05. CRC, colorectal cancer; TCGA, The Cancer Genome Atlas; HR, hazard ratio; TNM, Tumor Node Metastasis.

KEGG and GO pathway enrichment analysis by GSEA

The top 20 signaling pathways enriched in the MAN2A1 high-expression group were showed in Table 5. Enriched top pathways such as WNT signaling pathway, ubiquitin mediated proteolysis, CRC, pathways in cancer, prostate cancer, TGF beta signaling pathway, MAPK signaling pathway, ERBB signaling pathway and apoptosis were associated with cancer occurrence (Table 5). Gene Ontology contains biological process, cellular components, and molecular function. The enriched top 5 for each category are shown in Figure 6. The enriched biological process were post embryonic development, positive regulation of cell cycle process, peptidyl serine modification, hormone mediated signaling pathway and cerebellar cortex formation. The enriched cellular components were apical part of cell, golgi associated vesicle, golgi stack, golgi apparatus subcompartment and pml body. The enriched molecular functions were ubiquitin like protein transferase activity, ubiquitin like protein ligase activity, phosphoric ester hydrolase activity, adenosine-triphosphate (ATP) hydrolysis activity and phosphatase activity.

Table 5

Signaling pathways enriched in the MAN2A1 high-expression group

Signaling pathway NES NOM p-value FDR q-value
KEGG_wnt signaling pathway 2.361 ≤0.001 0.003
KEGG_long term potentiation 2.328 ≤0.001 0.001
KEGG_oocyte meiosis 2.296 ≤0.001 9.30E-04
KEGG_ubiquitin mediated proteolysis 2.281 ≤0.001 6.98E-04
KEGG_neurotrophin signaling pathway 2.259 ≤0.001 0.001
KEGG_GNRH signaling pathway 2.228 ≤0.001 0.001
KEGG_progesterone mediated oocyte maturation 2.223 ≤0.001 9.62E-04
KEGG_colorectal cancer 2.223 ≤0.001 8.42E-04
KEGG_pathways in cancer 2.211 ≤0.001 7.48E-04
KEGG_prostate cancer 2.201 ≤0.001 6.73E-04
KEGG_TGF beta signaling pathway 2.195 ≤0.001 6.12E-04
KEGG_lysine degradation 2.193 ≤0.001 5.61E-04
KEGG_MAPK signaling pathway 2.184 ≤0.001 5.18E-04
KEGG_ERBB signaling pathway 2.176 ≤0.001 7.73E-04
KEGG_apoptosis 2.176 ≤0.001 7.22E-04
KEGG_melanogenesis 2.174 ≤0.001 7.41E-04
KEGG_butanoate metabolism 2.171 ≤0.001 6.97E-04
KEGG_phosphatidylinositol signaling system 2.171 ≤0.001 6.58E-04
KEGG_P53 signaling pathway 2.169 ≤0.001 6.24E-04
KEGG_beta alanine metabolism 2.161 ≤0.001 7.03E-04

NES, normalized enrichment score; NOM, nominal; FDR, false discovery rate.

Figure 6 Top 5 biological process, cellular components, and molecular functions were respectively enriched in the MAN2A1 high-expression group. NES, normalized enrichment score; FDR, false discovery rate.

Discussion

As the World Health Organization (WHO) reported, the incidence and mortality rate of CRC ranks third in the United States (19). Previous studies have shown kinds of mechanisms of CRC, including chromosomal instability (20,21), microsatellite instability, oncogenes signaling pathways, metabolic alterations (22,23), abnormal immune response (24-26) etc. Numerous genes have been considered as prognostic predictors and potential therapeutic targets of CRC, the genes associated with CRC metastasis are in same significance.

The development of microarray technology and bioinformatics science provides an advanced method to solve clinical problems. In the present study, we screened TCGA-COAD and TCGA-READ datasets to identify genes significantly correlated with prognosis, and 4,455 genes were identified. The 4,455 genes were further analyzed to identify potential aim genes in both COAD and READ datasets, and we finally obtained 998 genes.

In addition, we constructed a PPI network with STRING online tools and analyzed with Cytoscape software. We also analyzed enrichment in GO and KEGG signaling pathways and found that they were enriched in 28 pathways, such as metabolic pathways, pathways in cancer, human papillomavirus interaction, endocytosis, P53 signaling pathway and so on which were relate to cancer occurrence and progress. Then, we used Cytoscape MCODE plus to analyze the 998 genes to get functional modules and identify hub genes based on topology to confirm densely connected regions. And find 196 hub genes (central nodes) that included 63 up-regulated genes and 133 down-regulated genes.

The metabolic reprogramming is related to the initiation, progression and metastasis of carcinomas, including CRC. Cancer cells usually need more nutrients, redox and energy to support their rapid proliferation and division. Cancer cells supply what they need through abnormal glycolysis, glutamine, glutaminolysis, serine and tryptophan metabolism, one-carbon metabolism and lipid metabolism (27). Previous studies have shown that the metabolic reprogramming is regulated by expression of oncogenic pathways and tumor suppressor genes, such as WNT signaling, KRAS signaling, PI3K/AKT/mTOR signaling, P53 signaling and so on (22,28).

In this study, we detected the expression of DEGs at the mRNA level afterwards and found MAN2A1 had lower expression levels in CRC than adjacent normal tissue; in addition, the expression of MAN2A1 was down-expressed in CRC tissues than normal tissues and down-expressed in metastatic CRC than non-metastatic CRC in TCGA. And the increasing expression of MAN2A1 was significantly negatively associated with CRC progression. Hence, we regarded MAN2A1 as a CRC-relevant gene.

MAN2A1 is a Golgi enzyme converting high mannose to complex type N-glycan for maturing membrane protein glycosylation (29,30). MAN2A1 fuses FER and turns to oncogene, previous analyses have shown that about 80% prostate cancer patients with MAN2A1-FER is positive associated with poor clinical outcome (31,32), other analysis has found that MAN2A1-FER fusion occur in liver cancer, esophageal cancer and other types malignancies (33). MAN2A1-FER fusion translocates FER kinase to Golgi apparatus, FER kinase activates and promote cancers through epidermal growth factor receptor (EGFR) signaling pathway (34-36).

In this study, via data mining in TCGA and validating in our cohort, we found MAN2A1 was significantly downregulated in CRC tissues than adjacent normal tissues and downregulated in metastatic CRC than non-metastatic CRC. These findings suggested that MAN2A1 might be inhibited in CRC cases. Furthermore, high expression of MAN2A1 was negatively and significantly related to TNM stage and LNM. The Kaplan-Meier survival analysis and COX analysis indicated that high expressed MAN2A1 was associated with better OS. Furthermore, GSEA analysis found MAN2A1 expression was related to wnt signaling pathway, CRC pathway, pathways in cancer, TGF beta signaling pathway, MAPK signaling pathway, P53 signaling pathway and so on. These results indicated that potential biological mechanism of MAN2A1 may be relate to CRC occurrence and progress. Nevertheless, the mechanisms of MAN2A1 in CRC need further study to explain. These results would be helpful for providing candidate targets for the diagnosis and prognosis for CRC patients, as well as new treatment strategy.

Acknowledgments

We sincerely thank the staff of Sir Run Run Shaw Hospital, affiliated to Zhejiang University for their laboratory and technical support.

Funding: The study was supported by the National Natural Science Foundation of China (No. 81773189).

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-629/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-629/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-629/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Ethics Committee of Sir Run Run Shaw Hospital, affiliated to Zhejiang University approved all study protocols (approval ID. 20200619-34). Individual consent for this retrospective study was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Wang Y, Zhao J, Fu G, Sheng C, Zhu J, Zhong T, Yang F, Jiang Z. MAN2A1 predicts prognosis and progression through cancer-related pathways in colorectal cancer. Transl Cancer Res 2022;11(10):3686-3697. doi: 10.21037/tcr-22-629

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