Whole-genome sequencing of an aggressive BRAF wild-type papillary thyroid cancer identified EML4-ALK translocation as a therapeutic target

World J Surg. 2014 Jun;38(6):1296-305. doi: 10.1007/s00268-014-2485-3.


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.

Publication types

  • Case Reports

MeSH terms

  • Administration, Oral
  • Anaplastic Lymphoma Kinase
  • Carcinoma / genetics*
  • Carcinoma / secondary
  • Carcinoma / surgery
  • Carcinoma, Papillary
  • Cell Cycle Proteins / drug effects
  • Cell Cycle Proteins / genetics*
  • Chromosome Mapping
  • Crizotinib
  • Follow-Up Studies
  • Genetic Predisposition to Disease
  • Humans
  • Lung Neoplasms / diagnostic imaging
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / secondary
  • Male
  • Microtubule-Associated Proteins / drug effects
  • Microtubule-Associated Proteins / genetics*
  • Middle Aged
  • Molecular Targeted Therapy / methods
  • Mutation
  • Neoplasm Invasiveness / pathology
  • Neoplasm Recurrence, Local / diagnostic imaging
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / genetics
  • Proto-Oncogene Proteins B-raf / drug effects
  • Proto-Oncogene Proteins B-raf / genetics
  • Pyrazoles / administration & dosage*
  • Pyridines / administration & dosage*
  • Receptor Protein-Tyrosine Kinases / drug effects
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Risk Assessment
  • Serine Endopeptidases / drug effects
  • Serine Endopeptidases / genetics*
  • Thyroid Cancer, Papillary
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / pathology
  • Thyroid Neoplasms / secondary
  • Thyroid Neoplasms / surgery
  • Thyroidectomy / methods
  • Time Factors
  • Tomography, X-Ray Computed / methods
  • Translocation, Genetic / genetics
  • Treatment Outcome


  • Cell Cycle Proteins
  • Microtubule-Associated Proteins
  • Pyrazoles
  • Pyridines
  • Crizotinib
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • EML4 protein, human
  • Serine Endopeptidases