title: The genomic and transcriptomic landscape of anaplastic thyroid cancer: implications for therapy.
abstract: BACKGROUND
  Anaplastic thyroid carcinoma is the most undifferentiated form of thyroid cancer and one of the deadliest of all adult solid malignancies. Here we report the first genomic and transcriptomic profile of anaplastic thyroid cancer including those of several unique cell lines and outline novel potential drivers of malignancy and targets of therapy.
  
  
  METHODS
  We describe whole genomic and transcriptomic profiles of 1 primary anaplastic thyroid tumor and 3 authenticated cell lines. Those profiles augmented by the transcriptomes of 4 additional and unique cell lines were compared to 58 pairs of papillary thyroid carcinoma and matched normal tissue transcriptomes from The Cancer Genome Atlas study.
  
  
  RESULTS
  The most prevalent mutations were those of TP53 and BRAF; repeated alterations of the epigenetic machinery such as frame-shift deletions of HDAC10 and EP300, loss of SMARCA2 and fusions of MECP2, BCL11A and SS18 were observed. Sequence data displayed aneuploidy and large regions of copy loss and gain in all genomes. Common regions of gain were however evident encompassing chromosomes 5p and 20q. We found novel anaplastic gene fusions including MKRN1-BRAF, FGFR2-OGDH and SS18-SLC5A11, all expressed in-frame fusions involving a known proto-oncogene. Comparison of the anaplastic thyroid cancer expression datasets with the papillary thyroid cancer and normal thyroid tissue transcriptomes suggested several known drug targets such as FGFRs, VEGFRs, KIT and RET to have lower expression levels in anaplastic specimens compared with both papillary thyroid cancers and normal tissues, confirming the observed lack of response to therapies targeting these pathways. Further integrative data analysis identified the mTOR signaling pathway as a potential therapeutic target in this disease.
  
  
  CONCLUSIONS
  Anaplastic thyroid carcinoma possessed heterogeneous and unique profiles revealing the significance of detailed molecular profiling of individual tumors and the treatment of each as a unique entity; the cell line sequence data promises to facilitate the more accurate and intentional drug screening studies for anaplastic thyroid cancer.
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. kkasaian@bcgsc.ca.
authors.forename: Katayoon
authors.initials: K
authors.lastname: Kasaian
authors.affiliation: Department of Surgery, St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia, Canada. SMWiseman@providencehealth.bc.ca.
authors.forename: Sam M
authors.initials: SM
authors.lastname: Wiseman
authors.affiliation: Department of Pathology and Laboratory Medicine, St. Paul's Hospital and University of British Columbia, Vancouver, British Columbia, Canada. BWalker@providencehealth.bc.ca.
authors.forename: Blair A
authors.initials: BA
authors.lastname: Walker
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. jschein@bcgsc.ca.
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Schein
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. yzhao@bcgsc.ca.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. mhirst@bcgsc.ca.
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. rmoore@bcgsc.ca.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Moore
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. amungall@bcgsc.ca.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mungall
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. mmarra@bcgsc.ca.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. mmarra@bcgsc.ca.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. sjones@bcgsc.ca.|Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. sjones@bcgsc.ca.|Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada. sjones@bcgsc.ca.|, 570 West 7th Ave, Vancouver, British Columbia, V5Z 4S6, Canada. sjones@bcgsc.ca.
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
mesh_terms: D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics*; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D023281:Genomics / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D000090063:Proto-Oncogene Mas; D017422:Sequence Analysis, DNA; D000077273:Thyroid Cancer, Papillary; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics*