Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1 Journal Article

Authors: Ricarte-Filho, J. C.; Ryder, M.; Chitale, D. A.; Rivera, M.; Heguy, A.; Ladanyi, M.; Janakiraman, M.; Solit, D.; Knauf, J. A.; Tuttle, R. M.; Ghossein, R. A.; Fagin, J. A.
Article 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 iodinerefractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [ <sup>18</sup>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. ©2009 American Association for Cancer Research.
Keywords: adult; clinical article; aged; treatment failure; gene mutation; human cell; mutation; histopathology; advanced cancer; positron emission tomography; recurrent cancer; mass spectrometry; gene expression profiling; genotype; cell line, tumor; cancer resistance; oncogene; radioactive iodine; iodine radioisotopes; disease progression; 1-phosphatidylinositol 3-kinase; proto-oncogene proteins c-akt; fluorodeoxyglucose f 18; neoplasm metastasis; base sequence; thyroid cancer; thyroid neoplasms; mutation rate; dna mutational analysis; pik3ca gene; proto-oncogene proteins b-raf; akt1 gene; braf gene; carcinoma, papillary, follicular
Journal Title: Cancer Research
Volume: 69
Issue: 11
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2009-06-01
Start Page: 4885
End Page: 4893
Language: English
DOI: 10.1158/0008-5472.can-09-0727
PUBMED: 19487299
PROVIDER: scopus
PMCID: PMC2690720
Notes: --- - "Cited By (since 1996): 27" - "Export Date: 30 November 2010" - "CODEN: CNREA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. James A Fagin
    149 Fagin
  2. Jeffrey A Knauf
    57 Knauf
  3. Mabel M Ryder
    17 Ryder
  4. Adriana Heguy
    88 Heguy
  5. Ronald A Ghossein
    402 Ghossein
  6. David Solit
    658 Solit
  7. Robert M Tuttle
    439 Tuttle
  8. Michael Rivera
    35 Rivera
  9. Dhananjay Arun Chitale
    33 Chitale
  10. Marc Ladanyi
    1189 Ladanyi