title: Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1.
abstract: Patients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTC and 18 ATC), and 55 RAIR, FDG-PET-positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 versus 12%; P = 0.002) in primary PDTC, whereas BRAF was more common than RAS (39 versus 13%; P = 0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9 of 10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5 of 6 patients were discordant for mutations of PIK3CA or AKT1. AKT1_G49A was found in 9 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR, FDG-PET-positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites because these mutations arise during progression, an important consideration for therapies directed at phosphoinositide 3-kinase effectors.
authors.affiliation: Human Oncology and Pathogenesis Program and Departments of Medicine and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Ricarte-Filho
authors.forename: Mabel
authors.initials: M
authors.lastname: Ryder
authors.forename: Dhananjay A
authors.initials: DA
authors.lastname: Chitale
authors.forename: Michael
authors.initials: M
authors.lastname: Rivera
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Manickam
authors.initials: M
authors.lastname: Janakiraman
authors.forename: David
authors.initials: D
authors.lastname: Solit
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Knauf
authors.forename: R Michael
authors.initials: RM
authors.lastname: Tuttle
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Ghossein
authors.forename: James A
authors.initials: JA
authors.lastname: Fagin
mesh_terms: D001483:Base Sequence; D018265:Carcinoma, Papillary, Follicular / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D018450:Disease Progression; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D009154:Mutation / Q000502:physiology; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D011877:Radionuclide Imaging; D013964:Thyroid Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D017211:Treatment Failure
chemical_list: D007457:Iodine Radioisotopes; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C494918:AKT1 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt