Mutational Profile of Advanced Primary and Metastatic Radioactive Iodine-Refractory Thyroid Cancers Reveals Distinct Pathogenetic Roles forBRAF, PIK3CA, andAKT1

Abstract

Patients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodinerefractory (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. [Cancer Res 2009;69(11):4885-93]

Phase II Efficacy and Pharmacogenomic Study of Selumetinib (AZD6244; ARRY-142886) in Iodine-131 Refractory Papillary Thyroid Carcinoma with or without Follicular Elements

“…When present, PIK3CA/AKT1 mutations would suggest coactivation of MAPK and PI3K in disease progression. Experimental compounds targeting effectors in the PI3K/AKT/mTOR pathway are being developed and could be considered in combination with a MEK inhibitor to improve response rates in future studies of thyroid cancer (41). …”

An update on molecular biology of thyroid cancers

“…Several human tumor studies proposed that activation and nuclear localization of Akt1 is involved in the invasiveness and metastasis of FTC induced by the PI3K/Akt pathway [83]. This proposal-was supported by the detection of Akt1 mutations in metastatic thyroid cancers [84]. On the other hand, excision of Akt1 was shown to delay and prevent tumor development, angiogenesis, and movement of FTC to distant sites in TR␤PV mice [85].…”

BRAF mutation assessment in papillary thyroid cancer: are we ready to use it in clinical practice?

“…Accordingly, the impact of BRAF mutation on clinical outcome has been extensively exploited in a variety of cancers, often resulting in controversial or unsettled findings. A T-to-A transversion at nucleotide 1799, which results in a valine to glutamate substitution at residue 600 (BRAF V600E ), is by far the most common mutation in differentiated thyroid cancer (DTC) [2]; however, it has been found as well in a fraction of poorly differentiated (PDTC) (10-15 %) and anaplastic thyroid carcinomas (ATC) (10-44 %) [4,5]. The BRAF V600E mutation's high prevalence and detection easiness have facilitated the understanding of its pathogenetic, diagnostic, prognostic, and therapeutic roles in thyroid tumors.…”