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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Journal of Translational Medicine 1/2018

Integrative analysis of the cancer genome atlas and cancer cell lines encyclopedia large-scale genomic databases: MUC4/MUC16/MUC20 signature is associated with poor survival in human carcinomas

Zeitschrift:
Journal of Translational Medicine > Ausgabe 1/2018
Autoren:
Nicolas Jonckheere, Isabelle Van Seuningen
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12967-018-1632-2) contains supplementary material, which is available to authorized users.

Abstract

Background

MUC4 is a membrane-bound mucin that promotes carcinogenetic progression and is often proposed as a promising biomarker for various carcinomas. In this manuscript, we analyzed large scale genomic datasets in order to evaluate MUC4 expression, identify genes that are correlated with MUC4 and propose new signatures as a prognostic marker of epithelial cancers.

Methods

Using cBioportal or SurvExpress tools, we studied MUC4 expression in large-scale genomic public datasets of human cancer (the cancer genome atlas, TCGA) and cancer cell line encyclopedia (CCLE).

Results

We identified 187 co-expressed genes for which the expression is correlated with MUC4 expression. Gene ontology analysis showed they are notably involved in cell adhesion, cell–cell junctions, glycosylation and cell signaling. In addition, we showed that MUC4 expression is correlated with MUC16 and MUC20, two other membrane-bound mucins. We showed that MUC4 expression is associated with a poorer overall survival in TCGA cancers with different localizations including pancreatic cancer, bladder cancer, colon cancer, lung adenocarcinoma, lung squamous adenocarcinoma, skin cancer and stomach cancer. We showed that the combination of MUC4, MUC16 and MUC20 signature is associated with statistically significant reduced overall survival and increased hazard ratio in pancreatic, colon and stomach cancer.

Conclusions

Altogether, this study provides the link between (i) MUC4 expression and clinical outcome in cancer and (ii) MUC4 expression and correlated genes involved in cell adhesion, cell–cell junctions, glycosylation and cell signaling. We propose the MUC4/MUC16/MUC20high signature as a marker of poor prognostic for pancreatic, colon and stomach cancers.
Zusatzmaterial
Additional file 1: Figure S1. MUC4 Oncoprint in Cancer Cell Line Encyclopedia. MUC4 alterations were explored in Cancer Cell Line Encyclopedia dataset using cBioPortal webtool. The oncoprint represents the amplification, deletion, up regulation or in frame mutation.
Additional file 2: Figure S2. MUC4 expression in normal tissues. MUC4 expression was analyzed with https://​gtexportal.​org. Expression is shown as log10 of RKPM (read per kilobases of transcript per million map reads). Boxplot are shown as median and 25/75% percentile. Outliers are represented as points.
Additional file 3: Table S1. Ontology of genes correlated with MUC4 expression. Gene list was retrieved from 881 samples of Cancer Cell Line Encyclopedia (Novartis/Broad, Nature 2012). 187 genes that are positively (n = 178) or negatively (n = 9) correlated with MUC4 expression were selected. Functional Annotation was performed using David Functional Annotation Tool.
Additional file 4: Figure S3. Interaction network of the proteins correlated with MUC4 expression. Interacting proteins were determined by String 10 tool and are represented by nodes. Edges represent a relationship between two nodes (known interaction from curated databases or experimentally determined; predicted interaction from gene neighborhood, gene fusion or co-occurrence; textmining; co-expression; protein homology). The obtained network was divided in 3 clusters by k-means clustering.
Additional file 5: Figure S4. Correlation of MUC4 expression and copy numbers of genes correlated with MUC4. The top genes were defined as genes harboring Pearson’s correlation higher than 0.5 with MUC4 expression. MUC4 mRNA expression and log2 copy number of ADGRF1, LCN2, MUC20, C1ORF116, STEAP4, SCEL, MUC16 were extracted using ( https://​portals.​broadinstitute.​org/​ccle).
Additional file 6: Table S2. Hazard-ratio and survival analysis of most significant genes clustered in GO term associated with MUC4 expression in TCGA tumor databases. Hazard ratio and p-value were determined using SurvExpress tool ( https://​bioinformatica.​mty.​itesm.​mx/​SurvExpress). Risk groups were sorted depending on the major GO term GO 0031424, GO 00071555, GO 0019897, GO 0016323 and GO 0016324 using the optimization algorithm (maximize) from the ordered prognostic.
Additional file 7: Table S3. Hazard-ratio and survival analysis of top genes associated with MUC4 expression in TCGA tumor databases. Hazard ratio and p-value were determined using SurvExpress tool ( https://​bioinformatica.​mty.​itesm.​mx/​SurvExpress). Risk groups were defined using the optimization algorithm (maximize) from the ordered prognostic. Selected genes ( ADGRF1, LCN2, MUC20, C1ORF116, SCEL, STEAP4) harbored Pearson’s correlation with MUC4 > 0.5.
Additional file 8: Figure S5. Overall survival of MUC4/MUC16/MUC20 high and low risk groups in cancer datasets available in TCGA. (A) Overall survival of MUC4/ MUC16/ MUC20 high and low risk groups in bladder cancer, colon cancer, lung adenocarcinoma, lung squamous adenocarcinoma, skin cancer and stomach cancer. High risk and low risk cohorts were determined by SurvExpress optimized algorithm. Log rang test and Hazard ratio were calculated to compare both cohorts. The numbers below horizontal axis represent the number of individuals not presenting the event of MUC4 high and low risk group along time. (B ) Overall survival of MUC4/ MUC16/ MUC20 high and low risk group in liver and acute myeloid leukemia (AML).
Additional file 9: Figure S6. MUC4- MUC16 and MUC4- MUC20 correlation of mRNA expression in 45 tumor tissues of GSE28735 PDAC dataset.
Additional file 10: Figure S7. MUC4, MUC16 and MUC20 expression in bladder, colorectal, lung, stomach, skin and ovarian cancer datasets. MUC4, MUC16 and MUC20 mRNA expression was evaluated in datasets to analyze whether the mRNA level differed between normal and tumor tissues. (A) GSE13507 contains 165 bladder cancer and 58 ANT samples. (B) GSE30219 contains 14 normal lung, 85 adenocarcinomas and 61 squamous cancer samples. (C) GSE40967 contains 566 colorectal cancers and 19 normal mucosae. (D) GSE27342 contains 80 tumors and 80 paired ANT tissues. (E) GSE4587 contains 2 normal, 2 melanomas and 2 metastatic melanomas. (F) GSE14407 contains 12 ovarian adenocarcinomas and 12 normal ovary samples. Statistical analyses were performed using paired t-test (*p<0.05, **p<0.01).
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