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.