Skip to main content

Advertisement

SpringerLink
Log in

Whole-genome Sequencing of an Aggressive BRAF Wild-type Papillary Thyroid Cancer Identified EML4–ALK Translocation as a Therapeutic Target

  • Published:
World Journal of Surgery Aims and scope Submit manuscript

Abstract

Background

Recent advances in the treatment of cancer have focused on targeting genomic aberrations with selective therapeutic agents. In radioiodine resistant aggressive papillary thyroid cancers, there remain few effective therapeutic options. A 62-year-old man who underwent multiple operations for papillary thyroid cancer and whose metastases progressed despite standard treatments provided tumor tissue.

Methods

We analyzed tumor and whole blood DNA by whole genome sequencing, achieving 80× or greater coverage over 94 % of the exome and 90 % of the genome. We determined somatic mutations and structural alterations.

Results

We found a total of 57 somatic mutations in 55 genes of the cancer genome. There was notably a lack of mutations in NRAS and BRAF, and no RET/PTC rearrangement. There was a mutation in the TRAPP oncogene and a loss of heterozygosity of the p16, p18, and RB1 tumor suppressor genes. The oncogenic driver for this tumor is a translocation involving the genes for anaplastic lymphoma receptor tyrosine kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4). The EML4–ALK translocation has been reported in approximately 5 % of lung cancers, as well as in pediatric neuroblastoma, and is a therapeutic target for crizotinib.

Conclusions

This is the first report of the whole genomic sequencing of a papillary thyroid cancer in which we identified an EML4–ALK translocation of a TRAPP oncogene mutation. These findings suggest that this tumor has a more distinct oncogenesis than BRAF mutant papillary thyroid cancer. Whole genome sequencing can elucidate an oncogenic context and expose potential therapeutic vulnerabilities in rare cancers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Cole MP, Jones CTA, Todd IDH (1971) A new anti-oestrogenic agent in late breast cancer: an early appraisal of ICI46474. Br J Cancer 25:270–275

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Rose C, Thorpe SM, Leber J et al (1980) Therapeutic effect of tamoxifen related to estrogen receptor level. Recent Results Cancer Res 71:131–141

    Google Scholar 

  3. Hawk WA, Hazard JB (1976) The many appearances of papillary carcinoma of the thyroid. Cleve Clin Q 43:207–216

    Article  CAS  PubMed  Google Scholar 

  4. Jalisi S, Ainsworth T, LaValley M (2010) Prognostic outcomes of tall cell variant papillary thyroid cancer: a meta-analysis. J Thyroid Res 2010:1–4

    Article  Google Scholar 

  5. Ghossein R, Livolsi VA (2008) Papillary thyroid cancer tall cell variant. Thyroid 18:1179–1181

    Article  CAS  PubMed  Google Scholar 

  6. Soda M, Choi YL, Enomoto M et al (2007) Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer. Nature 448:561–567

    Article  CAS  PubMed  Google Scholar 

  7. Shaw AT, Kim D-W, Nakagawa K et al (2013) Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368:2385–2394

    Article  CAS  PubMed  Google Scholar 

  8. Dmanac R, Sparks AB, Callow MJ et al (2013) Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science 327:78–81

    Article  Google Scholar 

  9. Liu X, Tesfai J, Evrard YA et al (2203) c-Myc transformation domain recruits the human STAGA complex and requires TRRAP and GCN5 acetylase activity for transcription activation. J Biol Chem 278:20405–20412

    Article  Google Scholar 

  10. Ard PG, Chatterjee C, Kunjibettu S et al (2002) Transcriptional regulation of the mdm2 oncogene by p53 requires TRRAP acetyltransferase complexes. Mol Cell Biol 22:5650–5661

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Wei X, Walia V, Lin JC et al (2011) Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat Genet 43:442–446

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Avaniyapuram KM, Chongfei Y, Mingzhao X (2012) Mutational analysis of the GNA11, MMP27, FGD1, TRRAP and GRM3 genes in thyroid cancer. Oncol Lett 6:437–441

    Google Scholar 

  13. Guan K-L, Jenkins CW, Li Y et al (1994) Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev 8:2939–2952

    Article  CAS  PubMed  Google Scholar 

  14. Iyer G, Hanrahan AJ, Milowsky MI et al (2012) Genome sequencing identifies a basis for everolimus sensitivity. Science 338:221–223

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Hamatani K, Mukai M, Takahashi K et al (2012) Rearranged anaplastic lymphoma kinase (ALK) gene in adult-onset papillary thyroid cancer amongst atomic bomb survivors. Thyroid 22:1153–1159

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Ishida E, Nakamura M, Shimada K et al (2007) DNA hypermethylation status of multiple genes in papillary thyroid carcinomas. Pathobiology 74:344–352

    Article  CAS  PubMed  Google Scholar 

  17. Kjelllman P, Lagercrantz S, Höög A et al (2001) Gain of 1q and loss of 9q21.3-q32 are associated with a less favorable prognosis in papillary thyroid carcinoma. Genes Chromosom Cancer 32:43–49

    Article  Google Scholar 

  18. Ball E, Bond J, Franc B et al (2007) An immunohistochemical study of p16(INK4a) expression in multistep thyroid tumourigenesis. Eur J Cancer 43:194–201

    Article  CAS  PubMed  Google Scholar 

  19. van Veelen W, Kompmaker R, Gloerich M et al (2009) P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma development. Int J Cancer 124:339–345

    Article  PubMed  Google Scholar 

  20. Morris SW, Kirstein MN, Valentine MB et al (1994) Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 263:1281–1284

    Article  CAS  PubMed  Google Scholar 

  21. Mosse YP, Balis FM, Lim MS et al (2012) Efficacy of crizotinib in children with relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and neuroblastoma: a Children’s Oncology Group phase I consortium study. Abstract presented at 2012 American Society of Clinical Oncology Annual Meeting, June 1–5, 2012, Chicago, IL [abstract 9500]

  22. Brose MS, Nutting C, Jarzab B et al (2013) Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: the phase III DECISION trial. J Clin Oncol 31(Suppl):4

    Google Scholar 

  23. Chapman PB, Hauschild A, Robert C et al (2011) Improved survival with vemurafenib in melanoma with BRAF mutations. N Engl J Med 364:2507–2516

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Doebele RC, Pilling AB, Aisner DL et al (2012) Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res 18:1472–1482

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Katayama R, Khan TM, Benes C et al (2011) Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4–ALK. Proc Natl Acad Sci USA 108:7535–7540

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Seto T, Kiura K, Nishio M et al (2013) CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1–2 study. Lancet Oncol 142013(14):590–598

    Article  Google Scholar 

  27. Mehra R, Camidge R, Sharma S et al (2012) First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. J Clin Oncol 30:3007

    Google Scholar 

  28. Sequist LC, Gettinger S, Senzer NM et al (2010) Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol 28:4953–4960

    Article  CAS  PubMed  Google Scholar 

  29. Sang J, Acquaviva J, Friedland JC et al (2013) Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer. Cancer Discov 3:430–443

    Article  CAS  PubMed  Google Scholar 

  30. Boland JM, Erdogan S, Vasmatzis G et al (2009) Anaplastic lymphoma kinase immunoreactivity correlates with ALK gene rearrangement and transcriptional up-regulation in non-small cell lung carcinomas. Hum Pathol 40:1152–1158

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Translational Genomics Research Institute, 445 N. Fifth St, Phoenix, AZ, 85004, USA

    Michael J. Demeure, Meraj Aziz, Kimberly J. Bussey & John D. Carpten

  2. Arizona Oncology, 2070 W Rudasill Rd, #130, Tucson, AZ, 85704, USA

    Richard Rosenberg

  3. Scottsdale Pathology Consultants, 9003 E. Shea Blvd, Scottsdale, AZ, 85258, USA

    Steven D. Gurley

  4. 9475 E. Ironwood Square, Suite 102, Scottsdale, AZ, 85258, USA

    Michael J. Demeure

Authors
  1. Michael J. Demeure
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meraj Aziz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard Rosenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steven D. Gurley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kimberly J. Bussey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John D. Carpten
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael J. Demeure.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Demeure, M.J., Aziz, M., Rosenberg, R. et al. Whole-genome Sequencing of an Aggressive BRAF Wild-type Papillary Thyroid Cancer Identified EML4–ALK Translocation as a Therapeutic Target. World J Surg 38, 1296–1305 (2014). https://doi.org/10.1007/s00268-014-2485-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00268-014-2485-3

Keywords

Search

Navigation