Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Landscape of genomic alterations in cervical carcinomas

Abstract

Cervical cancer is responsible for 10–15% of cancer-related deaths in women worldwide1,2. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established3. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS4,5,6,7 as well as several copy-number alterations in the pathogenesis of cervical carcinomas8,9. Here we report whole-exome sequencing analysis of 115 cervical carcinoma–normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour–normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Relationship of mutational spectrum and rates with clinicopathological characteristics in cervical carcinoma.
Figure 2: Novel recurrent somatic mutations in cervical carcinoma.
Figure 3: Relationships between HPV integration, copy-number amplifications and gene expression in cervical carcinoma.

Accession codes

Data deposits

Sequence data used for this analysis are available in dbGaP under accession phs000600.

References

  1. Jemal, A. et al. Global cancer statistics. CA Cancer J. Clin. 61, 69–90 (2011)

    PubMed  Google Scholar 

  2. International Agency for Research on Cancer. A review of human carcinogen: biological agents. in IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol. 100B (International Agency for Research on Cancer, 2012)

  3. zur Hausen, H. Papillomaviruses in the causation of human cancers — a brief historical account. Virology 384, 260–265 (2009)

    CAS  PubMed  Google Scholar 

  4. Crook, T. et al. Clonal p53 mutation in primary cervical cancer: association with human-papillomavirus-negative tumours. Lancet 339, 1070–1073 (1992)

    CAS  PubMed  Google Scholar 

  5. McIntyre, J. B. et al. PIK3CA mutational status and overall survival in patients with cervical cancer treated with radical chemoradiotherapy. Gynecol. Oncol. 128, 409–414 (2013)

    CAS  PubMed  Google Scholar 

  6. Kang, S. et al. Inverse correlation between RASSF1A hypermethylation, KRAS and BRAF mutations in cervical adenocarcinoma. Gynecol. Oncol. 105, 662–666 (2007)

    CAS  PubMed  Google Scholar 

  7. Wingo, S. N. et al. Somatic LKB1 mutations promote cervical cancer progression. PLoS ONE 4, e5137 (2009)

    ADS  PubMed  PubMed Central  Google Scholar 

  8. Narayan, G. & Murty, V. V. Integrative genomic approaches in cervical cancer: implications for molecular pathogenesis. Future Oncol. 6, 1643–1652 (2010)

    CAS  PubMed  Google Scholar 

  9. Vazquez-Mena, O. et al. Amplified genes may be overexpressed, unchanged, or downregulated in cervical cancer cell lines. PLoS ONE 7, e32667 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Arteaga, C. L. & Baselga, J. Impact of genomics on personalized cancer medicine. Clin. Cancer Res. 18, 612–618 (2012)

    CAS  PubMed  Google Scholar 

  11. Cibulskis, K. et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nature Biotechnol. 31, 213–219 (2013)

    CAS  Google Scholar 

  12. Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lohr, J. G. et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc. Natl Acad. Sci. USA 109, 3879–3884 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Greulich, H. et al. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc. Natl Acad. Sci. USA 109, 14476–14481 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bose, R. et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov. 3, 224–237 (2012)

    PubMed  PubMed Central  Google Scholar 

  16. Arvind, R. et al. A mutation in the common docking domain of ERK2 in a human cancer cell line, which was associated with its constitutive phosphorylation. Int. J. Oncol. 27, 1499–1504 (2005)

    CAS  PubMed  Google Scholar 

  17. De Luca, A., Maiello, M. R., D’Alessio, A., Pergameno, M. & Normanno, N. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin. Ther. Targets 16 (Suppl. 2). S17–S27 (2012)

    CAS  PubMed  Google Scholar 

  18. Le Gallo, M. et al. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nature Genet. 44, 1310–1315 (2012)

    CAS  PubMed  Google Scholar 

  19. Agrawal, N. et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333, 1154–1157 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen, J., Ghazawi, F. M. & Li, Q. Interplay of bromodomain and histone acetylation in the regulation of p300-dependent genes. Epigenetics 5, 509–515 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Smith, T. F., Gaitatzes, C., Saxena, K. & Neer, E. J. The WD repeat: a common architecture for diverse functions. Trends Biochem. Sci. 24, 181–185 (1999)

    CAS  PubMed  Google Scholar 

  22. Tong, K. I. et al. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol. Cell. Biol. 26, 2887–2900 (2006)

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012)

  24. Pamer, E. & Cresswell, P. Mechanisms of MHC class I-restricted antigen processing. Annu. Rev. Immunol. 16, 323–358 (1998)

    CAS  PubMed  Google Scholar 

  25. Neve, R. M., Ylstra, B., Chang, C. H., Albertson, D. G. & Benz, C. C. ErbB2 activation of ESX gene expression. Oncogene 21, 3934–3938 (2002)

    CAS  PubMed  Google Scholar 

  26. Wentzensen, N., Vinokurova, S. & von Knebel Doeberitz, M. Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. Cancer Res. 64, 3878–3884 (2004)

    CAS  PubMed  Google Scholar 

  27. Kraus, I. et al. The majority of viral-cellular fusion transcripts in cervical carcinomas cotranscribe cellular sequences of known or predicted genes. Cancer Res. 68, 2514–2522 (2008)

    CAS  PubMed  Google Scholar 

  28. Schmitz, M., Driesch, C., Jansen, L., Runnebaum, I. B. & Durst, M. Non-random integration of the HPV genome in cervical cancer. PLoS ONE 7, e39632 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tang, K. W., Alaei-Mahabadi, B., Samuelsson, T., Lindh, M. & Larsson, E. The landscape of viral expression and host gene fusion and adaptation in human cancer. Nature Commun. 4, 2513 (2013)

    ADS  Google Scholar 

  30. Peter, M. et al. Frequent genomic structural alterations at HPV insertion sites in cervical carcinoma. J. Pathol. 221, 320–330 (2010)

    CAS  PubMed  Google Scholar 

  31. Gnirke, A. et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nature Biotechnol. 27, 182–189 (2009)

    CAS  Google Scholar 

  32. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25, 1754–1760 (2009)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009)

    PubMed  PubMed Central  Google Scholar 

  34. Stransky, N. et al. The mutational landscape of head and neck squamous cell carcinoma. Science 333, 1157–1160 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  35. Banerji, S. et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486, 405–409 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee, R. S. et al. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J. Clin. Invest. 122, 2983–2988 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Berger, M. F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chapman, M. A. et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467–472 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cibulskis, K. et al. ContEst: estimating cross-contamination of human samples in next-generation sequencing data. Bioinformatics 27, 2601–2602 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Forbes, S. A. et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 39, D945–D950 (2011)

    CAS  PubMed  Google Scholar 

  41. DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nature Genet. 43, 491–498 (2011)

    CAS  PubMed  Google Scholar 

  42. McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Carter, S. L. et al. Absolute quantification of somatic DNA alterations in human cancer. Nature Biotechnol. 30, 413–421 (2012)

    CAS  Google Scholar 

  44. Erlich, H. HLA DNA typing: past, present, and future. Tissue Antigens 80, 1–11 (2012)

    CAS  PubMed  Google Scholar 

  45. Ward, J. H., Jr Hierarchical grouping to optimize an objective function. J. Am. Stat. Assoc. 58, 236–244 (1963)

    MathSciNet  Google Scholar 

  46. Trapnell, C. et al. Differential analysis of gene regulation at transcript resolution with RNA-seq. Nature Biotechnol. 31, 46–63 (2012)

    Google Scholar 

  47. Bass, A. J. et al. Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nature Genet. 43, 964–968 (2011)

    CAS  PubMed  Google Scholar 

  48. Pleasance, E. D. et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191–196 (2010)

    ADS  CAS  PubMed  Google Scholar 

  49. Wilkerson, M. D. & Hayes, D. N. ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics 26, 1572–1573 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Cañadas, M. P. et al. Comparison of the f-HPV typing and Hybrid Capture II assays for detection of high-risk HPV genotypes in cervical samples. J. Virol. Methods 183, 14–18 (2012)

    PubMed  Google Scholar 

  51. Walline, H. M. et al. High-risk human papillomavirus detection in oropharyngeal, nasopharyngeal, and, oral cavity cancers: comparison of multiple methods. JAMA Otolaryngol. Head Neck Surg. http://dx.doi.org/10.1001/jamaoto.2013.5460. (31 October 2013)

  52. Yang, H. et al. Sensitive detection of human papillomavirus in cervical, head/neck, and schistosomiasis-associated bladder malignancies. Proc. Natl Acad. Sci. USA 102, 7683–7688 (2005)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kostic, A. D. et al. PathSeq: software to identify or discover microbes by deep sequencing of human tissue. Nature Biotechnol. 29, 393–396 (2011)

    CAS  Google Scholar 

  54. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  55. Harris, R. S. & Liddament, M. T. Retroviral restriction by APOBEC proteins. Nature Rev. Immunol. 4, 868–877 (2004)

    CAS  Google Scholar 

  56. Roberts, S. A. et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nature Genet. 45, 970–976 (2013)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was conducted as part of the Slim Initiative for Genomic Medicine in the Americas, a project funded by the Carlos Slim Health Institute in Mexico. This work was also partially supported by the Rebecca Ridley Kry Fellowship of the Damon Runyon Cancer Research Foundation (A.I.O.); MMRF Research Fellow Award (A.I.O.); Helse Vest, Research Council of Norway, Norwegian Cancer Society and Harald Andersens legat (H.B.S.); CONACyT grant SALUD-2008-C01-87625 and UANL PAICyT grant CS1038-1 (H.A.B.-S.); and CONACyT grant 161619 (J.M.-Z.). We also thank B. Edvardsen, K. Dahl-Michelsen, Å. Mokleiv, K. Madisso, T. Njølstad and E. Valen for technical and programmatic assistance; the staff of the Broad Institute Genomics Platform for their assistance in processing samples and generating the sequencing data used in the analyses; the Instituto Mexicano del Seguro Social (IMSS) for their Support; and L. Gaffney of Broad Institute Communications for figure layout and design.

Author information

Authors and Affiliations

Authors

Contributions

A.I.O., L.L., S.S.F., C.S.P., H.B.S. and M.M. wrote the manuscript with help from co-authors. A.I.O., L.L., K.C., C.S. and G.G. performed whole exome and genome sequencing data analysis. A.I.O., I.I., V.T., K.V.-S., A.S.G., S.R.-C., C.R.E., S.S.F. and C.S.P. performed RNA sequencing data analysis. A.I.O., S.S.F., C.S.P. and T.J.P. performed HPV integration analyses. A.I.O. and A.D.C. performed copy-number analyses. A.I.O., F.D., B.K., R.W. and H.G. performed functional experiments on MAPK1. B.B., N.B.G., G.S.G.-M. and C.P.C. facilitated and performed pathology review. O.K.V., H.M.W. and T.E.C. performed HPV status determination. L.A., E.N. and M.L.C. facilitated project management. L.L., I.I.-R., V.T., K.V.-S., A.S.G., S.R.-C., I.P.R.-S. and C.R.E. performed sequencing data validation. M.E.-C., M.K.H., E.W., E.A.H., C.K. and M.L.G.-R. performed specimen processing, biobanking and data management. K.W., L.B., L.D.V.-C., G.M., J.V., C.R., A.C. and H.B.S. collected patient materials and clinical information. A.I.O., L.L. and D.S.N. performed biostatistical and epidemiological analyses. A.I.O., L.L., S.S.F., C.S.P., I.I.-R., T.J.P., A.D.C., V.T., A.A.W., M.W.R., F.D., M.S.L., C.S., S.L.C., A.M., H.B.S. and M.M. contributed text, figures (including Supplementary Information) and analytical tools. A.H.-M., C.R.E., L.A.A., S.B.G., H.A.B.-S., J.M.-Z., G.G., H.B.S. and M.M. provided leadership for the project. All authors contributed to the final manuscript. Lead authors A.I.O. and L.L. and senior authors M.M. and H.B.S. contributed equally to this work.

Corresponding authors

Correspondence to Helga B. Salvesen or Matthew Meyerson.

Ethics declarations

Competing interests

M.M. holds equity in, and consults for, Foundation Medicine.

Supplementary information

Supplementary Information

This file contains Supplementary Notes 1-15 with additional references (see Contents for more details), Supplementary Figures 1-30 and Supplementary Tables 1-11, 13 and 15-21 (see separate files for tables 12 and 14). (PDF 5727 kb)

Supplementary Table 12

This zipped file contains the correlation between RNASeq-derived gene expression and WES-derived copy number across 16898 genes, as well as the full complement of the raw values for these two parameters for 79 tumors with RNASeq data. (ZIP 30025 kb)

Supplementary Table 14

This file contains details of HPV typing and viral integration analyses. (XLSX 56 kb)

PowerPoint slides

Source data

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ojesina, A., Lichtenstein, L., Freeman, S. et al. Landscape of genomic alterations in cervical carcinomas. Nature 506, 371–375 (2014). https://doi.org/10.1038/nature12881

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature12881

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer