Evolving neoantigen profiles in colorectal cancers with DNA repair defects

Autor: Livio Trusolino, Federica Di Nicolantonio, Alberto Bardelli, Alice Bartolini, Enzo Medico, Alessandro Magrì, Ludovic Barault, Andrea Bertotti, Nabil Amirouchene-Angelozzi, Annalisa Lorenzato, Carola Negrino, Claudio Isella, Monica Montone, Vito Amodio, Giovanni Germano, Giorgio Corti, Giuseppe Rospo, Luca Novara, Carlotta Cancelliere
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
DNA Repair
lcsh:Medicine
Colorectal cancer
DNA repair
Immune response
Mutational signature
Neoantigen
Mice
SCID
Somatic evolution in cancer
Transcriptome
Mice
0302 clinical medicine
Mutation Rate
Mice
Inbred NOD
Genetics (clinical)
Exome sequencing
0303 health sciences
integumentary system
Phenotype
3. Good health
030220 oncology & carcinogenesis
Molecular Medicine
Female
Colorectal Neoplasms
lcsh:QH426-470
Antigen presentation
Context (language use)
Biology
Clonal Evolution
03 medical and health sciences
Downregulation and upregulation
Antigens
Neoplasm
Cell Line
Tumor
Genetics
Animals
Humans
Molecular Biology
030304 developmental biology
Research
lcsh:R
Carcinoma
Human genetics
digestive system diseases
lcsh:Genetics
030104 developmental biology
Cancer cell
Cancer research
Zdroj: Genome Medicine
Genome Medicine, Vol 11, Iss 1, Pp 1-22 (2019)
ISSN: 1756-994X
Popis: BackgroundNeoantigens that arise as a consequence of tumour-specific mutations can be recognized by T lymphocytes leading to effective immune surveillance. In colorectal cancer (CRC) and other tumour 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.MethodsWe performed Whole Exome Sequencing (WES) and RNA sequencing (RNAseq) in CRC cell lines,in vitroandvivo, and in CRC patient-derived xenografts (PDXs) to track longitudinally genomic profiles, clonal evolution, mutational signatures and predicted neoantigens.ResultsThe 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.ConclusionsThese results indicate that CRC 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: OpenAIRE
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