Comprehensive genomic characterization of head and neck squamous cell carcinomas

Cancer Genome Atlas Network

Abstract

The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.

Conflict of interest statement

The author declare no competing financial interests.

Figures

Figure 1. DNA copy number alterations.
Figure 1. DNA copy number alterations.
a, Copy number alterations by anatomic site and HPV status for squamous cancers. Lung squamous cell carcinoma (LUSC, n = 358) and cervical squamous cell carcinoma (CESC, n = 114). b, Unsupervised analysis of copy number alteration of HNSCC (n = 279) with associated characteristics. The rectangle indicates chromosome 7 amplifications in the purple cluster. NA, not available. PowerPoint slide
Figure 2. Significantly mutated genes in HNSCC.
Figure 2. Significantly mutated genes in HNSCC.
Genes (rows) with significantly mutated genes (identified using the MutSigCV algorithim; q < 0.1) ordered by q value; additional genes with trends towards significance are also shown. Samples (columns, n = 279) are arranged to emphasize mutual exclusivity among mutations. Left, mutation percentage in TCGA. Right, mutation percentage in COSMIC (‘upper aerodigestive tract’ tissue). Top, overall number of mutations per megabase. Colour coding indicates mutation type. PowerPoint slide
Figure 3. Candidate therapeutic targets and driver…
Figure 3. Candidate therapeutic targets and driver oncogenic events.
Alteration events for key genes are displayed by sample (n = 279). TSG, tumour suppressor gene. PowerPoint slide
Figure 4. Integrated analysis of genomic alterations.
Figure 4. Integrated analysis of genomic alterations.
a, b, Samples (n = 279) are displayed in columns and grouped by gene expression (a) or methylation (b) subtype (sub.). Unadjusted two-sided Fisher’s exact test P values assess the association of each genomic alteration. Methylation probe location of CpG islands, shores and shelves are shown on the left of b. Annotation shows HPV status and subtype (16, 33 and 35). CN, copy number. PowerPoint slide
Figure 5. Deregulation of signalling pathways and…
Figure 5. Deregulation of signalling pathways and transcription factors.
Key affected pathways, components and inferred functions, are summarized in the main text and Supplementary Information section 7 for n = 279 samples. The frequency (%) of genetic alterations for HPV(−) and HPV(+) tumours are shown separately within sub-panels and highlighted. Also see Supplementary Fig. 7.15. Pathway alterations include homozygous deletions, focal amplifications and somatic mutations. Activated and inactivated pathways/genes, and activating or inhibitory symbols are based on predicted effects of genome alterations and/or pathway functions. PowerPoint slide

References

    1. Ferlay J, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer. 2010;127:2893–2917.
    1. Ang KK, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N. Engl. J. Med. 2010;363:24–35.
    1. Stransky N, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333:1157–1160.
    1. Agrawal N, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011;333:1154–1157.
    1. The Cancer Genome Atlas Research Network Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519–525.
    1. Oganesyan G, et al. Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature. 2006;439:208–211.
    1. Karim R, et al. Human papillomavirus (HPV) upregulates the cellular deubiquitinase UCHL1 to suppress the keratinocyte’s innate immune response. PLoS Pathog. 2013;9:e1003384.
    1. Eliopoulos AG, et al. CD40-induced growth inhibition in epithelial cells is mimicked by Epstein–Barr Virus-encoded LMP1: involvement of TRAF3 as a common mediator. Oncogene. 1996;13:2243–2254.
    1. Imbeault M, et al. Acquisition of host-derived CD40L by HIV-1 in vivo and its functional consequences in the B-cell compartment. J. Virol. 2011;85:2189–2200.
    1. Ni CZ, et al. Molecular basis for CD40 signaling mediated by TRAF3. Proc. Natl Acad. Sci. USA. 2000;97:10395–10399.
    1. Chung GT, et al. Constitutive activation of distinct NF-κB signals in EBV-associated nasopharyngeal carcinoma. J. Pathol. 2013;231:311–322.
    1. Annunziata CM, et al. Frequent engagement of the classical and alternative NF-κB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell. 2007;12:115–130.
    1. Ciriello G, et al. Emerging landscape of oncogenic signatures across human cancers. Nature Genet. 2013;45:1127–1133.
    1. Smeets SJ, et al. Genetic classification of oral and oropharyngeal carcinomas identifies subgroups with a different prognosis. Cellular Oncol. 2009;31:291–300.
    1. Mayo MW, et al. Requirement of NF-κB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science. 1997;278:1812–1815.
    1. Sok JC, et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin. Cancer Res. 2006;12:5064–5073.
    1. Kong-Beltran M, et al. Somatic mutations lead to an oncogenic deletion of met in lung cancer. Cancer Res. 2006;66:283–289.
    1. Popescu NC, DiPaolo JA, Amsbaugh SC. Integration sites of human papillomavirus 18 DNA sequences on HeLa cell chromosomes. Cytogenet. Cell Genet. 1987;44:58–62.
    1. Forbes, S. A. et al. The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr. Protoc. Hum. Genet. Chapter 10, Unit 10.11 (2008)
    1. Sherry ST, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29:308–311.
    1. Morris LG, et al. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nature Genet. 2013;45:253–261.
    1. Haraguchi K, et al. Ajuba negatively regulates the Wnt signaling pathway by promoting GSK-3β-mediated phosphorylation of β-catenin. Oncogene. 2008;27:274–284.
    1. Nagai Y, et al. The LIM protein Ajuba is required for ciliogenesis and left-right axis determination in medaka. Biochem. Biophys. Res. Commun. 2010;396:887–893.
    1. Sun G, Irvine KD. Ajuba family proteins link JNK to Hippo signaling. Sci. Signal. 2013;6:ra81.
    1. Reddy BV, Irvine KD. Regulation of Hippo signaling by EGFR-MAPK signaling through Ajuba family proteins. Dev. Cell. 2013;24:459–471.
    1. Kalan S, Matveyenko A, Loayza D. LIM protein Ajuba participates in the repression of the ATR-mediated DNA damage response. Front. Genet. 2013;4:95.
    1. Nola S, et al. Ajuba is required for Rac activation and maintenance of E-cadherin adhesion. J. Cell Biol. 2011;195:855–871.
    1. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature499, 43–49 (2013)
    1. Fickie MR, et al. Adults with Sotos syndrome: review of 21 adults with molecularly confirmed NSD1 alterations, including a detailed case report of the oldest person. Am. J. Med. Genet. A. 2011;155:2105–2111.
    1. Wang GG, Cai L, Pasillas MP, Kamps MP. NUP98–NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nature Cell Biol. 2007;9:804–812.
    1. Quintana RM, et al. A transposon-based analysis of gene mutations related to skin cancer development. J. Invest. Dermatol. 2013;133:239–248.
    1. Chung CH, et al. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell. 2004;5:489–500.
    1. Walter V, et al. Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes. PLoS ONE. 2013;8:e56823.
    1. Lu SL, et al. Loss of transforming growth factor-β type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev. 2006;20:1331–1342.
    1. Oberst A, Green DR. It cuts both ways: reconciling the dual roles of caspase 8 in cell death and survival. Nature Rev. Mol. Cell Biol. 2011;12:757–763.
    1. Park SJ, et al. Opposite role of Ras in tumor necrosis factor-α-induced cell cycle regulation: competition for Raf kinase. Biochem. Biophys. Res. Commun. 2001;287:1140–1147.
    1. Byers LA, et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin. Cancer Res. 2013;19:279–290.
    1. Wong JV, Dong P, Nevins JR, Mathey-Prevot B, You L. Network calisthenics: control of E2F dynamics in cell cycle entry. Cell Cycle. 2011;10:3086–3094.
    1. Sanhaji M, et al. Polo-like kinase 1 inhibitors, mitotic stress and the tumor suppressor p53. Cell Cycle. 2013;12:1340–1351.
    1. Morishita A, et al. HMGA2 is a driver of tumor metastasis. Cancer Res. 2013;73:4289–4299.
    1. Bancroft CC, et al. Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF-κB and AP-1 activation and IL-8 and VEGF expression in human head and neck squamous cell carcinoma lines. Int. J. Cancer. 2002;99:538–548.
    1. Yang X, et al. ΔNp63 versatilely regulates a broad NF-κB gene program and promotes squamous epithelial proliferation, migration, and inflammation. Cancer Res. 2011;71:3688–3700.
    1. Keating PJ, et al. Frequency of down-regulation of individual HLA-A and -B alleles in cervical carcinomas in relation to TAP-1 expression. Br. J. Cancer. 1995;72:405–411.
    1. Esteban F, et al. Lack of MHC class I antigens and tumour aggressiveness of the squamous cell carcinoma of the larynx. Br. J. Cancer. 1990;62:1047–1051.
    1. Dotto GP. Crosstalk of Notch with p53 and p63 in cancer growth control. Nature Rev. Cancer. 2009;9:587–595.

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