Multi-label transcriptional classification of colorectal cancer reflects tumor cell population heterogeneity
Abstract Background Transcriptional classification has been used to stratify colorectal cancer (CRC) into molecular subtypes with distinct biological and clinical features. However, it is not clear whether such subtypes represent discrete, mutually exclusive entities or molecular/phenotypic states w...
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Genome Medicine |
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| Online Access: | https://doi.org/10.1186/s13073-023-01176-5 |
| _version_ | 1827709208306384896 |
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| author | Silvia Cascianelli Chiara Barbera Alexandra Ambra Ulla Elena Grassi Barbara Lupo Diego Pasini Andrea Bertotti Livio Trusolino Enzo Medico Claudio Isella Marco Masseroli |
| author_facet | Silvia Cascianelli Chiara Barbera Alexandra Ambra Ulla Elena Grassi Barbara Lupo Diego Pasini Andrea Bertotti Livio Trusolino Enzo Medico Claudio Isella Marco Masseroli |
| author_sort | Silvia Cascianelli |
| collection | DOAJ |
| description | Abstract Background Transcriptional classification has been used to stratify colorectal cancer (CRC) into molecular subtypes with distinct biological and clinical features. However, it is not clear whether such subtypes represent discrete, mutually exclusive entities or molecular/phenotypic states with potential overlap. Therefore, we focused on the CRC Intrinsic Subtype (CRIS) classifier and evaluated whether assigning multiple CRIS subtypes to the same sample provides additional clinically and biologically relevant information. Methods A multi-label version of the CRIS classifier (multiCRIS) was applied to newly generated RNA-seq profiles from 606 CRC patient-derived xenografts (PDXs), together with human CRC bulk and single-cell RNA-seq datasets. Biological and clinical associations of single- and multi-label CRIS were compared. Finally, a machine learning-based multi-label CRIS predictor (ML2CRIS) was developed for single-sample classification. Results Surprisingly, about half of the CRC cases could be significantly assigned to more than one CRIS subtype. Single-cell RNA-seq analysis revealed that multiple CRIS membership can be a consequence of the concomitant presence of cells of different CRIS class or, less frequently, of cells with hybrid phenotype. Multi-label assignments were found to improve prediction of CRC prognosis and response to treatment. Finally, the ML2CRIS classifier was validated for retaining the same biological and clinical associations also in the context of single-sample classification. Conclusions These results show that CRIS subtypes retain their biological and clinical features even when concomitantly assigned to the same CRC sample. This approach could be potentially extended to other cancer types and classification systems. |
| first_indexed | 2024-03-10T17:17:41Z |
| format | Article |
| id | doaj.art-e6e006a00b2149d7bd6490d838c419a2 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-03-10T17:17:41Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-e6e006a00b2149d7bd6490d838c419a22023-11-20T10:26:54ZengBMCGenome Medicine1756-994X2023-05-0115111710.1186/s13073-023-01176-5Multi-label transcriptional classification of colorectal cancer reflects tumor cell population heterogeneitySilvia Cascianelli0Chiara Barbera1Alexandra Ambra Ulla2Elena Grassi3Barbara Lupo4Diego Pasini5Andrea Bertotti6Livio Trusolino7Enzo Medico8Claudio Isella9Marco Masseroli10Department of Electronics, Information and Bioengineering, Politecnico Di MilanoDepartment of Electronics, Information and Bioengineering, Politecnico Di MilanoDepartment of Oncology, University of TurinDepartment of Oncology, University of TurinDepartment of Oncology, University of TurinDepartment of Experimental Oncology, IEO, European Institute of Oncology IRCCSDepartment of Oncology, University of TurinDepartment of Oncology, University of TurinDepartment of Oncology, University of TurinDepartment of Oncology, University of TurinDepartment of Electronics, Information and Bioengineering, Politecnico Di MilanoAbstract Background Transcriptional classification has been used to stratify colorectal cancer (CRC) into molecular subtypes with distinct biological and clinical features. However, it is not clear whether such subtypes represent discrete, mutually exclusive entities or molecular/phenotypic states with potential overlap. Therefore, we focused on the CRC Intrinsic Subtype (CRIS) classifier and evaluated whether assigning multiple CRIS subtypes to the same sample provides additional clinically and biologically relevant information. Methods A multi-label version of the CRIS classifier (multiCRIS) was applied to newly generated RNA-seq profiles from 606 CRC patient-derived xenografts (PDXs), together with human CRC bulk and single-cell RNA-seq datasets. Biological and clinical associations of single- and multi-label CRIS were compared. Finally, a machine learning-based multi-label CRIS predictor (ML2CRIS) was developed for single-sample classification. Results Surprisingly, about half of the CRC cases could be significantly assigned to more than one CRIS subtype. Single-cell RNA-seq analysis revealed that multiple CRIS membership can be a consequence of the concomitant presence of cells of different CRIS class or, less frequently, of cells with hybrid phenotype. Multi-label assignments were found to improve prediction of CRC prognosis and response to treatment. Finally, the ML2CRIS classifier was validated for retaining the same biological and clinical associations also in the context of single-sample classification. Conclusions These results show that CRIS subtypes retain their biological and clinical features even when concomitantly assigned to the same CRC sample. This approach could be potentially extended to other cancer types and classification systems.https://doi.org/10.1186/s13073-023-01176-5Colorectal cancerMolecular subtypingComputational biologyTumor heterogeneity |
| spellingShingle | Silvia Cascianelli Chiara Barbera Alexandra Ambra Ulla Elena Grassi Barbara Lupo Diego Pasini Andrea Bertotti Livio Trusolino Enzo Medico Claudio Isella Marco Masseroli Multi-label transcriptional classification of colorectal cancer reflects tumor cell population heterogeneity Genome Medicine Colorectal cancer Molecular subtyping Computational biology Tumor heterogeneity |
| title | Multi-label transcriptional classification of colorectal cancer reflects tumor cell population heterogeneity |
| title_full | Multi-label transcriptional classification of colorectal cancer reflects tumor cell population heterogeneity |
| title_fullStr | Multi-label transcriptional classification of colorectal cancer reflects tumor cell population heterogeneity |
| title_full_unstemmed | Multi-label transcriptional classification of colorectal cancer reflects tumor cell population heterogeneity |
| title_short | Multi-label transcriptional classification of colorectal cancer reflects tumor cell population heterogeneity |
| title_sort | multi label transcriptional classification of colorectal cancer reflects tumor cell population heterogeneity |
| topic | Colorectal cancer Molecular subtyping Computational biology Tumor heterogeneity |
| url | https://doi.org/10.1186/s13073-023-01176-5 |
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