Abstract

Nasopharyngeal carcinoma (NPC) has extremely skewed ethnic and geographic distributions, is poorly understood at the genetic level and is in need of effective therapeutic approaches. Here we determined the mutational landscape of 128 cases with NPC using whole-exome and targeted deep sequencing, as well as SNP array analysis. These approaches revealed a distinct mutational signature and nine significantly mutated genes, many of which have not been implicated previously in NPC. Notably, integrated analysis showed enrichment of genetic lesions affecting several important cellular processes and pathways, including chromatin modification, ERBB-PI3K signaling and autophagy machinery. Further functional studies suggested the biological relevance of these lesions to the NPC malignant phenotype. In addition, we uncovered a number of new druggable candidates because of their genomic alterations. Together our study provides a molecular basis for a comprehensive understanding of, and exploring new therapies for, NPC.

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Acknowledgements

We thank M.-S. Zeng (Sun Yat-sen University Cancer Center), T. Chan (Memorial Sloan-Kettering Cancer Center), Z.J. Zang (National Cancer Centre Singapore) and P. Tan for generously sharing materials as well as relevant facilities. This work is supported by US National Institutes of Health grant R01CA026038-35 (H.P.K.), the National Research Foundation Singapore and the Singapore Ministry of Education under the Research Centres of Excellence initiative (H.P.K.) and the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award to H.P.K. This work is also supported by The Terry Fox Foundation International Run Program through funds raised by the Terry Fox Singapore Run to the National University Cancer Institute, Singapore (NCIS).

Author information

Author notes

    • De-Chen Lin
    •  & Xuan Meng

    These authors contributed equally to this work.

    • Henry Yang
    • , Seishi Ogawa
    • , Kwok Seng Loh
    •  & H Phillip Koeffler

    These authors jointly directed this work.

Affiliations

  1. Cancer Science Institute of Singapore, National University of Singapore, Singapore.

    • De-Chen Lin
    • , Xuan Meng
    • , Masaharu Hazawa
    • , Ana Maria Varela
    • , Liang Xu
    • , Li-Zhen Liu
    • , Ling-Wen Ding
    • , Arjun Sharma
    • , Boon Cher Goh
    • , Soo Chin Lee
    • , Henry Yang
    •  & H Phillip Koeffler
  2. Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California, USA.

    • De-Chen Lin
    •  & H Phillip Koeffler
  3. Department of Medicine, School of Medicine, National University of Singapore, Singapore.

    • Xuan Meng
  4. Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

    • Yasunobu Nagata
    • , Yusuke Sato
    •  & Seishi Ogawa
  5. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

    • Yasunobu Nagata
    • , Yusuke Sato
    •  & Seishi Ogawa
  6. Department of Haematology-Oncology, National University Cancer Institute, Singapore.

    • Boon Cher Goh
    •  & Soo Chin Lee
  7. Department of Pathology, National University Health System, Singapore.

    • Bengt Fredrik Petersson
  8. Department of Otolaryngology, National University Hospital Singapore, Singapore.

    • Feng Gang Yu
    •  & Kwok Seng Loh
  9. Department of Immunology, National University of Singapore, Singapore.

    • Paul Macary
    •  & Min Zin Oo
  10. Department of Microbiology, National University of Singapore, Singapore.

    • Chan Soh Ha
  11. National University Cancer Institute, National University Hospital Singapore, Singapore.

    • H Phillip Koeffler

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Contributions

D.-C.L. and H.P.K. designed the study and wrote the manuscript. D.-C.L., X.M., M.H., Y.N., Y.S., A.M.V., L.X., L.-W.D. and A.S. performed experiments. C.S.H., B.F.P., B.C.G., S.C.L., F.G.Y. and K.S.L. coordinated sample collection and processing. D.-C.L., Y.N., Y.S., L.-Z.L., H.Y. and S.O. performed bioinformatical analysis. D.-C.L., X.M., Y.N., P.M., M.Z.O., B.C.G., S.C.L., F.G.Y., H.Y., S.O., K.S.L. and H.P.K. analyzed and discussed the data.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to De-Chen Lin.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–5 and Supplementary Tables 4,5 and 7–10.

Excel files

  1. 1.

    Supplementary Table 1

    (a) Coverage analysis of whole exome sequencing (Discovery Cohort and 5 NPC cell lines). (b) Coverage analysis of targeted sequencing (Prevalence Cohort).

  2. 2.

    Supplementary Table 2

    (a) Clinical parameters of NPCs analyzed with whole exome sequencing and SNP-array (Discovery Cohort). (b) Clinical parameters of NPCs analyzed with targeted sequencing (Prevalence Cohort).

  3. 3.

    Supplementary Table 3

    (a) Summary of somatic mutations of 56 NPCs analyzed with whole exome sequencing. (b) Summary of probable somatic mutations in NPC cell lines. (c) Summary of somatic mutations of 66 NPCs analyzed with targeted sequencing

  4. 4.

    Supplementary Table 6

    Genes for targeted capture in Prevalence Cohort

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DOI

https://doi.org/10.1038/ng.3006

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