Molecular patterns and mechanisms of tumorigenesis in HPV-associated and HPV-independent sinonasal squamous cell carcinoma
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Le résumé fourni par la source
ABSTRACT Mechanisms of tumorigenesis in sinonasal squamous cell carcinoma (SNSCC) remain poorly described due to its rare nature. A subset of SNSCC are associated with the human papillomavirus (HPV); however, it is unknown whether HPV is a driver of HPV-associated SNSCC tumorigenesis or merely a neutral bystander. We hypothesized that performing the first large high-throughput sequencing study of SNSCC would reveal molecular mechanisms of tumorigenesis driving HPV-associated and HPV-independent SNSCC and identify targetable pathways. High-throughput sequencing was performed on 64 patients with HPV-associated and HPV-independent sinonasal carcinomas. Mutation annotation, viral integration, copy number, and pathway-based analyses were performed. Analysis of HPV-associated SNSCC revealed similar mutational patterns observed in HPV-associated cervical and head and neck squamous cell carcinoma, including lack of TP53 mutations and the presence of known hotspot mutations in PI3K and FGFR3. Further similarities included enrichment of APOBEC mutational signature, viral integration at known hotspot locations, and frequent mutations in epigenetic regulators. HPV-associated SNSCC-specific recurrent mutations were also identified including KMT2C , UBXN11 , AP3S1 , MT-ND4 , and MT-ND5 . Mutations in KMT2D and FGFR3 were associated with decreased overall survival. We developed the first known HPV-associated SNSCC cell line and combinatorial small molecule inhibition of YAP/TAZ and PI3K pathways synergistically inhibited tumor cell clonogenicity. In conclusion, HPV-associated SNSCC and HPV-independent SNSCC are driven by molecularly distinct mechanisms of tumorigenesis. Combinatorial blockade of YAP/TAZ and vertical inhibition of the PI3K pathway may be useful in targeting HPV-associated SNSCC whereas targeting MYC and horizontal inhibition of RAS/PI3K pathways for HPV-independent SNSCC. One Sentence Summary This study solidifies HPV as a driver of HPV-associated SNSCC tumorigenesis, identifies molecular mechanisms distinguishing HPV-associated and HPV-independent SNSCC, and elucidates YAP/TAZ and PI3K blockade as key targets for HPV-associated SNSCC.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Molecular patterns and mechanisms of tumorigenesis in HPV-associated and HPV-independent sinonasal squamous cell carcinoma
- Date Crossref
- 18/06/2024
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Johns Hopkins University Department of Otolaryngology - Head and Neck Surgery pays non établi dans la noticeUniversité ou école supérieure
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Johns Hopkins Medicine pays non établi dans la noticeÉtablissement de santé
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National Institutes of Health pays non établi dans la noticeOrganisme public
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National Cancer Institute Center for Cancer Research pays non établi dans la noticeOrganisme public
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Center for Cancer Research pays non établi dans la noticeStructure de recherche
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Cancer Institute (WIA) pays non établi dans la noticeÉtablissement de santé
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University of California San Diego Department of Otolaryngology - Head and Neck Surgery pays non établi dans la noticeUniversité ou école supérieure
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Sidney Kimmel Comprehensive Cancer Center pays non établi dans la noticeStructure de recherche
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Harvard University pays non établi dans la noticeUniversité ou école supérieure
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University of Baltimore pays non établi dans la noticeUniversité ou école supérieure
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Bethesda pays non établi dans la noticeInstitution
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Department of Otolaryngology - Head and Neck Surgery pays non établi dans la noticeOrganisation à but non lucratif
Department of Otolaryngology - Head and Neck Surgery — Johns Hopkins University, Johns Hopkins Medicine et National Institutes of Health, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.