| Autor: |
Giuseppe Rospo, Annalisa Lorenzato, Nabil Amirouchene-Angelozzi, Alessandro Magrì, Carlotta Cancelliere, Giorgio Corti, Carola Negrino, Vito Amodio, Monica Montone, Alice Bartolini, Ludovic Barault, Luca Novara, Claudio Isella, Enzo Medico, Andrea Bertotti, Livio Trusolino, Giovanni Germano, Federica Di Nicolantonio, Alberto Bardelli |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
Genome Medicine, Vol 11, Iss 1, Pp 1-22 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
1756-994X |
| DOI: |
10.1186/s13073-019-0654-6 |
| Popis: |
Abstract Background Neoantigens that arise as a consequence of tumor-specific mutations can be recognized by T lymphocytes leading to effective immune surveillance. In colorectal cancer (CRC) and other tumor types, a high number of neoantigens is associated with patient response to immune therapies. The molecular processes governing the generation of neoantigens and their turnover in cancer cells are poorly understood. We exploited CRC as a model system to understand how alterations in DNA repair pathways modulate neoantigen profiles over time. Methods We performed whole exome sequencing (WES) and RNA sequencing (RNAseq) in CRC cell lines, in vitro and in vivo, and in CRC patient-derived xenografts (PDXs) to track longitudinally genomic profiles, clonal evolution, mutational signatures, and predicted neoantigens. Results The majority of CRC models showed remarkably stable mutational and neoantigen profiles; however, those carrying defects in DNA repair genes continuously diversified. Rapidly evolving and evolutionary stable CRCs displayed characteristic genomic signatures and transcriptional profiles. Downregulation of molecules implicated in antigen presentation occurred selectively in highly mutated and rapidly evolving CRC. Conclusions These results indicate that CRCs carrying alterations in DNA repair pathways display dynamic neoantigen patterns that fluctuate over time. We define CRC subsets characterized by slow and fast evolvability and link this phenotype to downregulation of antigen-presenting cellular mechanisms. Longitudinal monitoring of the neoantigen landscape could be relevant in the context of precision medicine. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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