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Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape.
Bruce, Jeff P; To, Ka-Fai; Lui, Vivian W Y; Chung, Grace T Y; Chan, Yuk-Yu; Tsang, Chi Man; Yip, Kevin Y; Ma, Brigette B Y; Woo, John K S; Hui, Edwin P; Mak, Michael K F; Lee, Sau-Dan; Chow, Chit; Velapasamy, Sharmila; Or, Yvonne Y Y; Siu, Pui Kei; El Ghamrasni, Samah; Prokopec, Stephenie; Wu, Man; Kwan, Johnny S H; Liu, Yuchen; Chan, Jason Y K; van Hasselt, C Andrew; Young, Lawrence S; Dawson, Christopher W; Paterson, Ian C; Yap, Lee-Fah; Tsao, Sai-Wah; Liu, Fei-Fei; Chan, Anthony T C; Pugh, Trevor J; Lo, Kwok-Wai.
Afiliación
  • Bruce JP; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • To KF; Department of Anatomical and cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Lui VWY; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Chung GTY; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Chan YY; Department of Anatomical and cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Tsang CM; Department of Anatomical and cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Yip KY; Department of Anatomical and cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Ma BBY; Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Woo JKS; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Hui EP; Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Mak MKF; Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Lee SD; Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Chow C; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Velapasamy S; Sir Y.K. Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Or YYY; Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Siu PK; Department of Anatomical and cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • El Ghamrasni S; Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Prokopec S; Department of Anatomical and cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Wu M; Department of Anatomical and cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Kwan JSH; Department of Anatomical and cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Liu Y; Department of Anatomical and cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Chan JYK; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • van Hasselt CA; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Young LS; Department of Anatomical and cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Dawson CW; Department of Anatomical and cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Paterson IC; School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Yap LF; Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Tsao SW; Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • Liu FF; Warwick Medical School, University of Warwick, Coventry, UK.
  • Chan ATC; Warwick Medical School, University of Warwick, Coventry, UK.
  • Pugh TJ; Department of Oral & Craniofacial Sciences and Oral Cancer Research and Coordinating Centre, University of Malaya, Kuala Lumpur, Malaysia.
  • Lo KW; Department of Oral & Craniofacial Sciences and Oral Cancer Research and Coordinating Centre, University of Malaya, Kuala Lumpur, Malaysia.
Nat Commun ; 12(1): 4193, 2021 07 07.
Article en En | MEDLINE | ID: mdl-34234122
Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.
Asunto(s)
Infecciones por Virus de Epstein-Barr/inmunología; Herpesvirus Humano 4/genética; Carcinoma Nasofaríngeo/inmunología; Neoplasias Nasofaríngeas/inmunología; Escape del Tumor/genética; Animales; Antineoplásicos/farmacología; Antineoplásicos/uso terapéutico; Carcinogénesis/efectos de los fármacos; Carcinogénesis/genética; Carcinogénesis/inmunología; Línea Celular Tumoral; Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética; Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética; Infecciones por Virus de Epstein-Barr/genética; Infecciones por Virus de Epstein-Barr/terapia; Infecciones por Virus de Epstein-Barr/virología; Femenino; Regulación Viral de la Expresión Génica/inmunología; Herpesvirus Humano 4/inmunología; Herpesvirus Humano 4/patogenicidad; Interacciones Huésped-Patógeno/genética; Interacciones Huésped-Patógeno/inmunología; Humanos; Metionina Adenosiltransferasa/antagonistas & inhibidores; Metionina Adenosiltransferasa/metabolismo; Ratones; FN-kappa B/metabolismo; Carcinoma Nasofaríngeo/genética; Carcinoma Nasofaríngeo/terapia; Carcinoma Nasofaríngeo/virología; Neoplasias Nasofaríngeas/genética; Neoplasias Nasofaríngeas/terapia; Neoplasias Nasofaríngeas/virología; Nasofaringe/inmunología; Nasofaringe/patología; Nasofaringe/cirugía; Nasofaringe/virología; Receptor Tipo II de Factor de Crecimiento Transformador beta/genética; Receptor Tipo II de Factor de Crecimiento Transformador beta/metabolismo; Eliminación de Secuencia; Transducción de Señal/efectos de los fármacos; Transducción de Señal/genética; Transducción de Señal/inmunología; Escape del Tumor/efectos de los fármacos; Secuenciación Completa del Genoma; Ensayos Antitumor por Modelo de Xenoinjerto
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Nasofaríngeas / Herpesvirus Humano 4 / Escape del Tumor / Infecciones por Virus de Epstein-Barr / Carcinoma Nasofaríngeo Tipo de estudio: Prognostic_studies Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Nasofaríngeas / Herpesvirus Humano 4 / Escape del Tumor / Infecciones por Virus de Epstein-Barr / Carcinoma Nasofaríngeo Tipo de estudio: Prognostic_studies Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido