Phosphatidylinositol 3-kinase/Akt and Ras/Raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer

Libero Santarpia, Adel K. El-Naggar, Gilbert J. Cote, Jeffrey N. Myers, Steven I. Sherman

Research output: Contribution to journalArticle

138 Citations (Scopus)

Abstract

Context: Anaplastic thyroid carcinoma (ATC) can occur in the setting of differentiated thyroid carcinoma (DTC), which suggests a continuum in malignant progression from DTC to ATC. The Ras/Raf-MAPK and the phosphatidylinositol 3-kinase/Akt signaling pathways play critical roles in DTC tumorigenesis, but their roles in the pathogenesis of ATC are poorly defined. Objective: Our objective was to explore the potential contributions of these two pathways in ATC pathogenesis. Design, Setting, and Subjects: The mutational status of BRAF, PIK3CA, PTEN, and RAS genes was analyzed in genomic DNA from microdissected tumor specimens of 36 cases of ATC, and in 16 samples of paired-matched lymph node metastases. PIK3CA copy number gain was assessed by real-time quantitative PCR. We performed immunohistochemistry for phospho-ERK and phospho-AKT in 26 cases of ATC. Results: DTC was present in half of the cases. BRAF V600E mutation was identified in nine of 36 (25%) ATCs; seven cases had identical mutations in both the ATC and DTC components. PIK3CA kinase domain mutations were found in five (14%) ATCs, one of which had mutations in both differentiated and anaplastic areas. RAS and PTEN mutations were each found in two (6%) ATCs. PIK3CA gain copy number was found notably increased in 14 (39%) ATCs. Conclusions: BRAF mutations appear to play a role in the tumorigenesis of a subset of ATCs, and the majority of lymph node metastases. PIK3CA alterations occur preferentially in the later stages of ATC and were the most relevant events during thyroid cancer progression. The activation of both pathways suggests an important role in ATC dedifferentiation.

Original languageEnglish
Pages (from-to)278-284
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume93
Issue number1
DOIs
Publication statusPublished - Jan 2008

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Phosphatidylinositol 3-Kinase
Mitogen-Activated Protein Kinases
Tumors
Phosphotransferases
Genes
Chemical activation
Thyroid Neoplasms
Mutation
DNA
Carcinogenesis
Lymph Nodes
Neoplasm Metastasis
Immunohistochemistry
Anaplastic Thyroid Carcinoma
Critical Pathways
Real-Time Polymerase Chain Reaction

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

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Phosphatidylinositol 3-kinase/Akt and Ras/Raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. / Santarpia, Libero; El-Naggar, Adel K.; Cote, Gilbert J.; Myers, Jeffrey N.; Sherman, Steven I.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 93, No. 1, 01.2008, p. 278-284.

Research output: Contribution to journalArticle

Santarpia, Libero ; El-Naggar, Adel K. ; Cote, Gilbert J. ; Myers, Jeffrey N. ; Sherman, Steven I. / Phosphatidylinositol 3-kinase/Akt and Ras/Raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. In: Journal of Clinical Endocrinology and Metabolism. 2008 ; Vol. 93, No. 1. pp. 278-284.
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abstract = "Context: Anaplastic thyroid carcinoma (ATC) can occur in the setting of differentiated thyroid carcinoma (DTC), which suggests a continuum in malignant progression from DTC to ATC. The Ras/Raf-MAPK and the phosphatidylinositol 3-kinase/Akt signaling pathways play critical roles in DTC tumorigenesis, but their roles in the pathogenesis of ATC are poorly defined. Objective: Our objective was to explore the potential contributions of these two pathways in ATC pathogenesis. Design, Setting, and Subjects: The mutational status of BRAF, PIK3CA, PTEN, and RAS genes was analyzed in genomic DNA from microdissected tumor specimens of 36 cases of ATC, and in 16 samples of paired-matched lymph node metastases. PIK3CA copy number gain was assessed by real-time quantitative PCR. We performed immunohistochemistry for phospho-ERK and phospho-AKT in 26 cases of ATC. Results: DTC was present in half of the cases. BRAF V600E mutation was identified in nine of 36 (25{\%}) ATCs; seven cases had identical mutations in both the ATC and DTC components. PIK3CA kinase domain mutations were found in five (14{\%}) ATCs, one of which had mutations in both differentiated and anaplastic areas. RAS and PTEN mutations were each found in two (6{\%}) ATCs. PIK3CA gain copy number was found notably increased in 14 (39{\%}) ATCs. Conclusions: BRAF mutations appear to play a role in the tumorigenesis of a subset of ATCs, and the majority of lymph node metastases. PIK3CA alterations occur preferentially in the later stages of ATC and were the most relevant events during thyroid cancer progression. The activation of both pathways suggests an important role in ATC dedifferentiation.",
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AU - Myers, Jeffrey N.

AU - Sherman, Steven I.

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N2 - Context: Anaplastic thyroid carcinoma (ATC) can occur in the setting of differentiated thyroid carcinoma (DTC), which suggests a continuum in malignant progression from DTC to ATC. The Ras/Raf-MAPK and the phosphatidylinositol 3-kinase/Akt signaling pathways play critical roles in DTC tumorigenesis, but their roles in the pathogenesis of ATC are poorly defined. Objective: Our objective was to explore the potential contributions of these two pathways in ATC pathogenesis. Design, Setting, and Subjects: The mutational status of BRAF, PIK3CA, PTEN, and RAS genes was analyzed in genomic DNA from microdissected tumor specimens of 36 cases of ATC, and in 16 samples of paired-matched lymph node metastases. PIK3CA copy number gain was assessed by real-time quantitative PCR. We performed immunohistochemistry for phospho-ERK and phospho-AKT in 26 cases of ATC. Results: DTC was present in half of the cases. BRAF V600E mutation was identified in nine of 36 (25%) ATCs; seven cases had identical mutations in both the ATC and DTC components. PIK3CA kinase domain mutations were found in five (14%) ATCs, one of which had mutations in both differentiated and anaplastic areas. RAS and PTEN mutations were each found in two (6%) ATCs. PIK3CA gain copy number was found notably increased in 14 (39%) ATCs. Conclusions: BRAF mutations appear to play a role in the tumorigenesis of a subset of ATCs, and the majority of lymph node metastases. PIK3CA alterations occur preferentially in the later stages of ATC and were the most relevant events during thyroid cancer progression. The activation of both pathways suggests an important role in ATC dedifferentiation.

AB - Context: Anaplastic thyroid carcinoma (ATC) can occur in the setting of differentiated thyroid carcinoma (DTC), which suggests a continuum in malignant progression from DTC to ATC. The Ras/Raf-MAPK and the phosphatidylinositol 3-kinase/Akt signaling pathways play critical roles in DTC tumorigenesis, but their roles in the pathogenesis of ATC are poorly defined. Objective: Our objective was to explore the potential contributions of these two pathways in ATC pathogenesis. Design, Setting, and Subjects: The mutational status of BRAF, PIK3CA, PTEN, and RAS genes was analyzed in genomic DNA from microdissected tumor specimens of 36 cases of ATC, and in 16 samples of paired-matched lymph node metastases. PIK3CA copy number gain was assessed by real-time quantitative PCR. We performed immunohistochemistry for phospho-ERK and phospho-AKT in 26 cases of ATC. Results: DTC was present in half of the cases. BRAF V600E mutation was identified in nine of 36 (25%) ATCs; seven cases had identical mutations in both the ATC and DTC components. PIK3CA kinase domain mutations were found in five (14%) ATCs, one of which had mutations in both differentiated and anaplastic areas. RAS and PTEN mutations were each found in two (6%) ATCs. PIK3CA gain copy number was found notably increased in 14 (39%) ATCs. Conclusions: BRAF mutations appear to play a role in the tumorigenesis of a subset of ATCs, and the majority of lymph node metastases. PIK3CA alterations occur preferentially in the later stages of ATC and were the most relevant events during thyroid cancer progression. The activation of both pathways suggests an important role in ATC dedifferentiation.

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