Gene Expression Monotonicity across Bladder Cancer Stages Informs on the Molecular Pathogenesis and Identifies a Prognostic Eight-Gene Signature
Despite advancements in molecular classification, tumor stage and grade still remain the most relevant prognosticators used by clinicians to decide on patient management. Here, we leverage publicly available data to characterize bladder cancer (BLCA)’s stage biology based on increased sample sizes,...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-05-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/10/2542 |
| _version_ | 1797501010526076928 |
|---|---|
| author | Rafael Stroggilos Maria Frantzi Jerome Zoidakis Marika Mokou Napoleon Moulavasilis Emmanouil Mavrogeorgis Anna Melidi Manousos Makridakis Konstantinos Stravodimos Maria G. Roubelakis Harald Mischak Antonia Vlahou |
| author_facet | Rafael Stroggilos Maria Frantzi Jerome Zoidakis Marika Mokou Napoleon Moulavasilis Emmanouil Mavrogeorgis Anna Melidi Manousos Makridakis Konstantinos Stravodimos Maria G. Roubelakis Harald Mischak Antonia Vlahou |
| author_sort | Rafael Stroggilos |
| collection | DOAJ |
| description | Despite advancements in molecular classification, tumor stage and grade still remain the most relevant prognosticators used by clinicians to decide on patient management. Here, we leverage publicly available data to characterize bladder cancer (BLCA)’s stage biology based on increased sample sizes, identify potential therapeutic targets, and extract putative biomarkers. A total of 1135 primary BLCA transcriptomes from 12 microarray studies were compiled in a meta-cohort and analyzed for monotonal alterations in pathway activities, gene expression, and co-expression patterns with increasing stage (Ta–T1–T2–T3–T4), starting from the non-malignant tumor-adjacent urothelium. The TCGA-2017 and IMvigor-210 RNA-Seq data were used to validate our findings. Wnt, MTORC1 signaling, and MYC activity were monotonically increased with increasing stage, while an opposite trend was detected for the catabolism of fatty acids, circadian clock genes, and the metabolism of heme. Co-expression network analysis highlighted stage- and cell-type-specific genes of potentially synergistic therapeutic value. An eight-gene signature, consisting of the genes <i>AKAP7</i>, <i>ANLN</i>, <i>CBX7</i>, <i>CDC14B</i>, <i>ENO1</i>, <i>GTPBP4</i>, <i>MED19</i>, and <i>ZFP2</i>, had independent prognostic value in both the discovery and validation sets. This novel eight-gene signature may increase the granularity of current risk-to-progression estimators. |
| first_indexed | 2024-03-10T03:12:07Z |
| format | Article |
| id | doaj.art-ee8334f40e2445e1b6d990f810e1a144 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T03:12:07Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ee8334f40e2445e1b6d990f810e1a1442023-11-23T10:24:39ZengMDPI AGCancers2072-66942022-05-011410254210.3390/cancers14102542Gene Expression Monotonicity across Bladder Cancer Stages Informs on the Molecular Pathogenesis and Identifies a Prognostic Eight-Gene SignatureRafael Stroggilos0Maria Frantzi1Jerome Zoidakis2Marika Mokou3Napoleon Moulavasilis4Emmanouil Mavrogeorgis5Anna Melidi6Manousos Makridakis7Konstantinos Stravodimos8Maria G. Roubelakis9Harald Mischak10Antonia Vlahou11Systems Biology Center, Biomedical Research Foundation of the Academy of Athens, Soranou Efessiou 4, 11527 Athens, GreeceMosaiques Diagnostics GmbH, 30659 Hannover, GermanySystems Biology Center, Biomedical Research Foundation of the Academy of Athens, Soranou Efessiou 4, 11527 Athens, GreeceMosaiques Diagnostics GmbH, 30659 Hannover, Germany1st Department of Urology, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, GreeceSystems Biology Center, Biomedical Research Foundation of the Academy of Athens, Soranou Efessiou 4, 11527 Athens, GreeceSystems Biology Center, Biomedical Research Foundation of the Academy of Athens, Soranou Efessiou 4, 11527 Athens, GreeceSystems Biology Center, Biomedical Research Foundation of the Academy of Athens, Soranou Efessiou 4, 11527 Athens, Greece1st Department of Urology, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, GreeceLaboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceMosaiques Diagnostics GmbH, 30659 Hannover, GermanySystems Biology Center, Biomedical Research Foundation of the Academy of Athens, Soranou Efessiou 4, 11527 Athens, GreeceDespite advancements in molecular classification, tumor stage and grade still remain the most relevant prognosticators used by clinicians to decide on patient management. Here, we leverage publicly available data to characterize bladder cancer (BLCA)’s stage biology based on increased sample sizes, identify potential therapeutic targets, and extract putative biomarkers. A total of 1135 primary BLCA transcriptomes from 12 microarray studies were compiled in a meta-cohort and analyzed for monotonal alterations in pathway activities, gene expression, and co-expression patterns with increasing stage (Ta–T1–T2–T3–T4), starting from the non-malignant tumor-adjacent urothelium. The TCGA-2017 and IMvigor-210 RNA-Seq data were used to validate our findings. Wnt, MTORC1 signaling, and MYC activity were monotonically increased with increasing stage, while an opposite trend was detected for the catabolism of fatty acids, circadian clock genes, and the metabolism of heme. Co-expression network analysis highlighted stage- and cell-type-specific genes of potentially synergistic therapeutic value. An eight-gene signature, consisting of the genes <i>AKAP7</i>, <i>ANLN</i>, <i>CBX7</i>, <i>CDC14B</i>, <i>ENO1</i>, <i>GTPBP4</i>, <i>MED19</i>, and <i>ZFP2</i>, had independent prognostic value in both the discovery and validation sets. This novel eight-gene signature may increase the granularity of current risk-to-progression estimators.https://www.mdpi.com/2072-6694/14/10/2542bladder cancer stagetranscriptomicsmeta-analysismolecular alterationsprognostic signatureurothelial carcinoma |
| spellingShingle | Rafael Stroggilos Maria Frantzi Jerome Zoidakis Marika Mokou Napoleon Moulavasilis Emmanouil Mavrogeorgis Anna Melidi Manousos Makridakis Konstantinos Stravodimos Maria G. Roubelakis Harald Mischak Antonia Vlahou Gene Expression Monotonicity across Bladder Cancer Stages Informs on the Molecular Pathogenesis and Identifies a Prognostic Eight-Gene Signature Cancers bladder cancer stage transcriptomics meta-analysis molecular alterations prognostic signature urothelial carcinoma |
| title | Gene Expression Monotonicity across Bladder Cancer Stages Informs on the Molecular Pathogenesis and Identifies a Prognostic Eight-Gene Signature |
| title_full | Gene Expression Monotonicity across Bladder Cancer Stages Informs on the Molecular Pathogenesis and Identifies a Prognostic Eight-Gene Signature |
| title_fullStr | Gene Expression Monotonicity across Bladder Cancer Stages Informs on the Molecular Pathogenesis and Identifies a Prognostic Eight-Gene Signature |
| title_full_unstemmed | Gene Expression Monotonicity across Bladder Cancer Stages Informs on the Molecular Pathogenesis and Identifies a Prognostic Eight-Gene Signature |
| title_short | Gene Expression Monotonicity across Bladder Cancer Stages Informs on the Molecular Pathogenesis and Identifies a Prognostic Eight-Gene Signature |
| title_sort | gene expression monotonicity across bladder cancer stages informs on the molecular pathogenesis and identifies a prognostic eight gene signature |
| topic | bladder cancer stage transcriptomics meta-analysis molecular alterations prognostic signature urothelial carcinoma |
| url | https://www.mdpi.com/2072-6694/14/10/2542 |
| work_keys_str_mv | AT rafaelstroggilos geneexpressionmonotonicityacrossbladdercancerstagesinformsonthemolecularpathogenesisandidentifiesaprognosticeightgenesignature AT mariafrantzi geneexpressionmonotonicityacrossbladdercancerstagesinformsonthemolecularpathogenesisandidentifiesaprognosticeightgenesignature AT jeromezoidakis geneexpressionmonotonicityacrossbladdercancerstagesinformsonthemolecularpathogenesisandidentifiesaprognosticeightgenesignature AT marikamokou geneexpressionmonotonicityacrossbladdercancerstagesinformsonthemolecularpathogenesisandidentifiesaprognosticeightgenesignature AT napoleonmoulavasilis geneexpressionmonotonicityacrossbladdercancerstagesinformsonthemolecularpathogenesisandidentifiesaprognosticeightgenesignature AT emmanouilmavrogeorgis geneexpressionmonotonicityacrossbladdercancerstagesinformsonthemolecularpathogenesisandidentifiesaprognosticeightgenesignature AT annamelidi geneexpressionmonotonicityacrossbladdercancerstagesinformsonthemolecularpathogenesisandidentifiesaprognosticeightgenesignature AT manousosmakridakis geneexpressionmonotonicityacrossbladdercancerstagesinformsonthemolecularpathogenesisandidentifiesaprognosticeightgenesignature AT konstantinosstravodimos geneexpressionmonotonicityacrossbladdercancerstagesinformsonthemolecularpathogenesisandidentifiesaprognosticeightgenesignature AT mariagroubelakis geneexpressionmonotonicityacrossbladdercancerstagesinformsonthemolecularpathogenesisandidentifiesaprognosticeightgenesignature AT haraldmischak geneexpressionmonotonicityacrossbladdercancerstagesinformsonthemolecularpathogenesisandidentifiesaprognosticeightgenesignature AT antoniavlahou geneexpressionmonotonicityacrossbladdercancerstagesinformsonthemolecularpathogenesisandidentifiesaprognosticeightgenesignature |