title: Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing.
abstract: Anaplastic thyroid carcinoma (ATC) is a frequently lethal malignancy that is often unresponsive to available therapeutic strategies. The tumorigenesis of ATC and its relationship to the widely prevalent well-differentiated thyroid carcinomas are unclear. We have analyzed 22 cases of ATC as well as 4 established ATC cell lines using whole-exome sequencing. A total of 2674 somatic mutations (121/sample) were detected. Ontology analysis revealed that the majority of variants aggregated in the MAPK, ErbB and RAS signaling pathways. Mutations in genes related to malignancy not previously associated with thyroid tumorigenesis were observed, including mTOR, NF1, NF2, MLH1, MLH3, MSH5, MSH6, ERBB2, EIF1AX and USH2A; some of which were recurrent and were investigated in 24 additional ATC cases and 8 ATC cell lines. Somatic mutations in established thyroid cancer genes were detected in 14 of 22 (64%) tumors and included recurrent mutations in BRAF, TP53 and RAS-family genes (6 cases each), as well as PIK3CA (2 cases) and single cases of CDKN1B, CDKN2C, CTNNB1 and RET mutations. BRAF V600E and RAS mutations were mutually exclusive; all ATC cell lines exhibited a combination of mutations in either BRAF and TP53 or NRAS and TP53. A hypermutator phenotype in two cases with >8 times higher mutational burden than the remaining mean was identified; both cases harbored unique somatic mutations in MLH mismatch-repair genes. This first comprehensive exome-wide analysis of the mutational landscape of ATC identifies novel genes potentially associated with ATC tumorigenesis, some of which may be targets for future therapeutic intervention.
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Department of Surgery.
authors.forename: John W
authors.initials: JW
authors.lastname: Kunstman
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Department of Oncology-Pathology and.
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute and.
authors.forename: Gerald
authors.initials: G
authors.lastname: Goh
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Department of Surgery.
authors.forename: Taylor C
authors.initials: TC
authors.lastname: Brown
authors.affiliation: Department of Oncology-Pathology and.
authors.forename: Adam
authors.initials: A
authors.lastname: Stenman
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Department of Surgery.
authors.forename: James M
authors.initials: JM
authors.lastname: Healy
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Department of Surgery.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Rubinstein
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute and.
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Oncology-Pathology and.
authors.forename: Nimrod
authors.initials: N
authors.lastname: Kiss
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute and.
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.affiliation: Department of Genetics.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Manju L
authors.initials: ML
authors.lastname: Prasad
authors.affiliation: Department of Oncology-Pathology and.
authors.forename: Anders
authors.initials: A
authors.lastname: Höög
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital CCK, SE-171 76 Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Zedenius
authors.affiliation: Department of Oncology-Pathology and.
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Department of Surgery.
authors.forename: Reju
authors.initials: R
authors.lastname: Korah
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute and.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Yale Endocrine Neoplasia Laboratory, Department of Surgery, tobias.carling@yale.edu.
authors.forename: Tobias
authors.initials: T
authors.lastname: Carling
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D048493:Proto-Oncogene Proteins B-raf