title: Whole-genome sequencing of an aggressive BRAF wild-type papillary thyroid cancer identified EML4-ALK translocation as a therapeutic target.
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.
authors.affiliation: Translational Genomics Research Institute, 445 N. Fifth St, Phoenix, AZ, 85004, USA, mdemeure@tgen.org.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Demeure
authors.forename: Meraj
authors.initials: M
authors.lastname: Aziz
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenberg
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gurley
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Bussey
authors.forename: John D
authors.initials: JD
authors.lastname: Carpten
mesh_terms: D000284:Administration, Oral; D000077548:Anaplastic Lymphoma Kinase; D002277:Carcinoma / Q000235:genetics* / Q000556:secondary / Q000601:surgery; D002291:Carcinoma, Papillary; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics*; D002874:Chromosome Mapping; D000077547:Crizotinib; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000235:genetics*; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000187:drug effects / Q000235:genetics; D011720:Pyrazoles / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics*; D018570:Risk Assessment; D012697:Serine Endopeptidases / Q000187:drug effects / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary / Q000601:surgery; D013965:Thyroidectomy / Q000379:methods; D013997:Time Factors; D014057:Tomography, X-Ray Computed / Q000379:methods; D014178:Translocation, Genetic / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C415585:EML4 protein, human; D012697:Serine Endopeptidases