Int J Stem Cells.  2023 May;16(2):215-233. 10.15283/ijsc22188.

Alterations and Co-Occurrence of C-MYC, N-MYC, and L-MYC Expression are Related to Clinical Outcomes in Various Cancers

• Lee M
• Seok J
• Saha SK
• Cho S
• Jeong Y
• Gil M
• Kim A
• Shin HY
• Bae H
• Do JT
• Kim YB
• Cho SG

• KMID: 2542834
• DOI: http://doi.org/10.15283/ijsc22188

Abstract

Background and Objectives
MYC, also known as an oncogenic reprogramming factor, is a multifunctional transcription factor that maintains induced pluripotent stem cells (iPSCs). Although MYC is frequently upregulated in various cancers and is correlated with a poor prognosis, MYC is downregulated and correlated with a good prognosis in lung adenocarcinoma. MYC and two other MYC family genes, MYCN and MYCL, have similar structures and could contribute to tumorigenic conversion both in vitro and in vivo.
Methods and Results
We systematically investigated whether MYC family genes act as prognostic factors in various human cancers. We first evaluated alterations in the expression of MYC family genes in various cancers using the Oncomine and The Cancer Genome Atlas (TCGA) database and their mutation and copy number alterations using the TCGA database with cBioPortal. Then, we investigated the association between the expression of MYC family genes and the prognosis of cancer patients using various prognosis databases. Multivariate analysis also confirmed that co-expression of MYC/MYCL/MYCN was significantly associated with the prognosis of lung, gastric, liver, and breast cancers.
Conclusions
Taken together, our results demonstrate that the MYC family can function not only as an oncogene but also as a tumor suppressor gene in various cancers, which could be used to develop a novel approach to cancer treatment.

Keyword

MYC; Cancer,; Bioinformatics; Clinical outcomes

Figure

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  Fig. 1 MYC family structure and expression analysis in various types of cancer. (A) Architecture of MYC family. Generic representation of a mammalian MYC protein, indicating the transcriptional activation domain, MYC boxes (I, II, III), which are strictly conserved in MYC family genes and play an important role in binding to various transcriptional coactivators, canonical nuclear localization sequence (NLS), and region involved in DNA binding as basic helix-loop-helix (bHLH)/leucine zipper (LZ) domain. All trees of MYC genes are known to originate from different chromosomes (the red text denotes the chromosome number from which they are transcribed). MYC protein contains 439 amino acids. MYCN and MYCL proteins slightly differ in length (464 and 364 amino acids, respectively). (B) The comparison indicated the number of datasets with MYC family mRNA overexpression (red) and under-expression (blue) in cancer versus normal tissue. The threshold was designed using the following parameters: p-value of 1e-4, fold-change of 2, and gene ranking of 10%. (C) The MYC family gene expression in various cancers was determined using RT–PCR. (D) Protein expression levels of MYC family in various cancers using western blot analysis. MYC: myelocytomatosis oncogene.

• 

  Fig. 2 MYC mRNA expression and prognosis analysis in different types of cancer. (A) MYC expression was analyzed in various types of cancers using Oncomine database. The plots show the expression of MYC in various types of cancer. (B) MYC expression was analyzed using the Oncomine database and is represented as a box plot in brain, colon, prostate, breast, and blood cancers relative to their normal tissues. (C) MYC expression was analyzed using TCGA data via GEPIA and is represented as a box plot in breast, colon, lymphoma, brain, and kidney cancers (red box plot) relative to their normal tissues (grey box plot) with a threshold of p-value<0.05. (D) The prognostic value of MYC was analyzed using the Prognoscan database and is represented as the hazard ratio. (E) Survival curve comparing patients with high (red) and low (blue/green) expression was plotted using the PrognoScan, GEPIA, and SurvExpress databases. The survival curves indicated the relationship between patient survival probability and MYC expression in various cancers, with a threshold of Cox p-value<0.05. ODG: oligodendroglioma, MG: malignant glioma, NOS: not otherwise specified, CLL: chronic lymphocytic leukemia, BRCA: breast invasive carcinoma, COAD: colon adenocarcinoma, DLBC: lymphoid neoplasm diffuses large B-cell lymphoma, LGG: brain lower grade glioma, KIRP: kidney renal papillary cell carcinoma, HR: hazard ratio, TCGA: the cancer genome atlas, GSE: gene set enrichment.

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  Fig. 3 MYC mutation and alteration frequency analysis in various types of cancer. (A) Mutation diagram of MYC in different types of cancer across protein domains. One hotspot (P74A/L/Q/R/S/T) represented the predominant mutations in the N-terminus of MYC (upper panel). Alteration frequencies of MYC mutation in various types of cancer (lower panel). (B) Interacting nodes display MYC protein interactions with other related proteins downloaded from STRING v10.5. (C) Copy number alterations of MYC-interacting genes and cancer subtypes were determined using cBioPortal (http://www.cbioportal.org). The alteration frequency of a five-gene signature (MYC, BCL2, TP53, MYB, JUN) (left panel) and alteration frequency of a seven-gene signature (MYC, BCL2, TP53, MYB, JUN, CDK4, CDKN1A, CDKN2A) are presented for various cancer subtypes (right panel). Only the types of cancer containing >100 samples and an alteration frequency of >50% are shown. Prostate cancer tends to amplify MYC frequently. (D) We used the Oncoprint feature of cBioPortal (http://www.cbioportal.org) to determine the copy number alteration frequency of each genes (BCL2, TP53, MYB, and JUN) in MYC within the prostate cancer subtype (upper panel); the percentages of the copy number alteration of each genes (MYC, BCL2, TP53, MYB, JUN, CDK4, CDKN1A, and CDKN2A) are presented in prostate cancer (lower panel). (E) Network view of MYC neighborhood in prostate cancer was downloaded from cBioPortal. MYC is a seed gene (indicated by a thick border), and all other genes were automatically found to be altered in prostate cancer. Darker red indicates an increased frequency of alterations (defined as mutations, copy number amplifications, or homozygous deletions) in prostate cancer. MYC: myelocytomatosis oncogene, MYB: myeloblastosis oncogene, TP53: tumor protein p53, BCL2: B-cell CLL/lymphoma 2, JUN: Jun proto-oncogene, CDK4: cyclin-dependent kinase 4, CDKN1A: cyclin-dependent kinase in- hibitor 1A, CDKN2A: cyclin-dependent kinase inhibitor 2A, STRING: search tool for recurring instances of neighboring genes, TCGA: the cancer genome atlas.

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  Fig. 4 MYCL mRNA expression and prognosis analysis in different types of cancer. (A) MYCL expression was analyzed in various types of cancer using the Oncomine database. The plots show the expression of MYCL in various types of cancer. (B) MYCL expression was analyzed using the Oncomine database and is represented as a box plot in lung, ovarian, brain, lymphoma, and pancreatic cancers relative to their normal tissues. (C) MYCL expression was analyzed using TCGA data via GEPIA and is represented as a box plot in lung, ovarian, brain, and pancreatic cancers (red box plot) relative to their normal tissues (grey box plot) with a threshold of p-value<0.05. (D) The prognostic value of MYCL was analyzed using the Prognoscan database and is represented as the hazard ratio. (E) The survival curve comparing patients with high (red) and low (black/blue/green) expression was plotted using the Kaplan-Meier Plotter, R2, and SurvExpress databases. Survival curves indicated the relationship between patient survival and MYCL expression in various cancers with a threshold of Cox p-value<0.05. LCs: lung cancers, LAC: lung adeno-carcinoma, OSC: ovarian serous cystadenocarcinoma, AOG: anaplastic oligodendroglioma, NKC: natural killer cell, TL: T-lymphocyte, TLNKC: T-lymphocyte and natural killer cell, CHL: classical Hodgkin’s lymphoma, BLCA: bladder urothelial carcinoma, LUSC: lung squamous cell carcinoma, OV: ovarian serous cystadenocarcinoma, LGG: brain lower grade glioma, PAAD: pancreatic adenocarcinoma, GB: glioblastoma, HR: hazard ratio, TCGA: the cancer genome atlas, GSE: gene set enrichment, GEPIA: gene expression profiling interactive analysis.

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  Fig. 5 MYCL mutation and alteration frequency analysis in various types of cancer. (A) Mutation diagram of MYCL in different types of cancer across protein domains. One hotspot (A303V) represented the predominant mutations in the MYCL HLH domain (upper panel). Alteration frequencies of MYCL mutation are shown in various types of cancer (lower panel). (B) Interacting nodes display MYCL protein interactions with other related proteins, retrieved from STRING v10.5. (C) The copy number alterations of MYCL-interacting genes and cancer subtypes were determined using cBioPortal (http://www.cbioportal.org). The alteration frequencies of a five-gene signature (MYCL, TP53, RLF, PPLE, COL9A2) (left panel) and a seven-gene signature (MYCL, TP53, RLF, PPLE, COL9A2, IER5, GLI4) were determined in various cancer subtypes (right panel). Only the types of cancer containing >100 samples and an alteration frequency of >50% are shown. (D) Ovarian cancer tends to amplify MYCL frequently. We used the Oncoprint feature of cBioPortal (http://www.cbioportal.org) to determine the copy number alteration frequencies of each genes (TP53, RLF, PPLE, and COL9A2) in MYCL within ovarian cancer subtypes (upper panel); the percentages of alterations of each genes (MYCL, TP53, RLF, PPLE, COL9A2, IER5, and GLI4) is presented in ovarian cancer (lower panel). (E) Network view of the MYCL neighborhood in ovarian cancer was downloaded from cBioPortal. MYCL is a seed gene (indicated by a thick border), and all other genes were automatically found to be altered in ovarian cancer. Darker red indicates an increased frequency of alterations (defined as mutations, copy number amplifications, or homozygous deletions) in ovarian cancer. TCGA: the cancer genome atlas, STRING: search tool for recurring instances of neighboring genes.

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  Fig. 6 MYCN mRNA expression and prognosis analysis in different types of cancer. (A) MYCN mRNA expression was analyzed in various types of cancer using the Oncomine database. The plot shows the expression of MYCN in various types of cancer. (B) MYCL mRNA expression was analyzed using the Oncomine database and are represented as box plots in renal, leukemia, ovarian, and rectal cancers relative to their normal tissues. (C) MYCL mRNA expression was analyzed using TCGA data via GEPIA and is presented as box plots in leukemia and ovarian cancers (red box plot) relative to their normal tissues (grey box plot) with a threshold of p-value<0.05. (D) The prognostic value of MYCN was analyzed using the Prognoscan database and presented as the hazard ratio. (E) The survival curve comparing patients with high (red) and low (blue) expression was plotted using the PrognoScan, GEPIA, SurvExpress databases. The survival curves indicated the relationship between patient survival probability and MYCL expression in various types of cancer with a threshold of Cox p-value<0.05. CRC: clear cell renal cell carcinoma, TCALL: T-cell childhood acute lymphoblastic leukemia, OSCC: ovarian serous cystadenocarcinoma, LAML: acute myeloid leukemia, OV: ovarian serous cystadenocarcinoma, GEPIA: gene expression profiling interactive analysis, HR: hazard ratio, TCGA: the cancer genome atlas, GSE: gene set enrichment, GEPIA: gene expression profiling interactive analysis.

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  Fig. 7 MYCN mutation and alteration frequency analysis in various types of cancer. (A) Mutation diagram of MYCN in different types of cancer across protein domains. One hotspot (E47Gfs*8/P45Rfs*86) represented predominant mutations in the N-terminal domain of MYCN (upper panel). Alteration frequencies of MYCN mutation are shown in various types of cancer (lower panel). (B) Interacting nodes of MYCN protein with other related proteins are displayed, obtained using STRING v10.5. (C) The copy number alterations of MYCN-interacting genes in various cancer subtypes were determined using cBioPortal (http://www.cbioportal.org). The alteration frequencies of a five-gene signature (MYCN, NDRG1, NTRK1, PTEN, TP53) (left panel) and a seven-gene signature (MYCN, NDRG1, NTRK1, PTEN, TP53, CCND1, VEGFA) were determined in various cancer subtypes (right panel). Only the types of cancers containing >100 samples and an alteration frequency of >50% are shown. (D) NEP cancer tends to amplify MYCN frequently. We used the Oncoprint feature of cBioPortal (http://www.cbioportal.org) to determine the mutation and copy number alteration frequencies of each genes (NDRG1, NTRK1, PTEN, and TP53) in MYCN within the NEPC cancer subtype (upper panel); the percentages of alterations of each genes (MYCN, NDRG1, NTRK1, PTEN, TP53, CCND1, and VEGFA) is presented in NEPC cancer (lower panel). (E) The summary of predictive role of MYC family genes in different cancers is based on the consistent analyses of gene expression and clinical outcomes. NEP: neuroendocrine prostate, MYC: myelocytomatosis oncogene, O/T: oncogene and tumor suppressor, NDRG1: MYCN downstream regulated 1, NTRK1: neuro-trophic tyrosine kinase receptor type 1, PTEN: phosphatase and tensin homolog, TP53: tumor protein p53, CCND1: cyclin D1, VEGFA: vascular endothelial growth factor A, NEP: neuroendocrine prostate, STRING: search tool for recurring instances of neighboring genes.

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  Fig. 8 The relationship between the co-occurrence of MYC family genes and the clinical outcomes in various types of cancer. Multivariate survival analysis of MYC/MYCL, MYC/MYCN, and MYCL/MYCN was performed using data from Kaplan-Meier Plotter in lung (A), gastric (B), and liver (C) cancer. Multivariate survival analysis of MYC/MYCL/MYCN was performed using data from Kaplan-Meier Plotter in breast, lung, gastric, and liver cancer (D). All the survival curves were obtained using GraphPad Prism 7. A p-value<0.05 was considered signi-ficant. MYC: myelocytomatosis on-cogene.

Reference

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