title: Mutation of the PIK3CA gene in anaplastic thyroid cancer.
abstract: The phosphatidylinositol 3'-kinase (PI3K) pathway is frequently activated in thyroid carcinomas through the constitutive activation of stimulatory molecules (e.g., Ras) and/or the loss of expression and/or function of the inhibitory PTEN protein that results in Akt activation. Recently, it has been reported that somatic mutations within the PI3K catalytic subunit, PIK3CA, are common (25-40%) among colorectal, gastric, breast, ovarian cancers, and high-grade brain tumors. Moreover, PIK3CA mutations have a tendency to cluster within the helical (exon 9) and the kinase (exon 20) domains. In this study, 13 thyroid cancer cell lines, 80 well-differentiated thyroid carcinomas of follicular (WDFC) and papillary (WDPC) type, and 70 anaplastic thyroid carcinomas (ATC) were investigated, by PCR-direct sequencing, for activating PIK3CA mutations at exons 9 and 20. Nonsynonymous somatic mutations were found in 16 ATC (23%), two WDFC (8%), and one WDPC (2%). In 18 of the 20 ATC cases showing coexisting differentiated carcinoma, mutations, when present, were restricted to the ATC component and located primarily within the kinase domain. Three cell lines of papillary and follicular lineage (K1, K2, and K5) were also found mutated. In addition, activation of Akt was observed in most of the ATC harboring PIK3CA mutations. These findings indicate that mutant PIK3CA is likely to function as an oncogene among ATC and less frequently well-differentiated thyroid carcinomas. The data also argue for a role of PIK3CA targeting in the treatment of ATC patients.
authors.affiliation: Institute of Molecular Pathology and Immunology of Porto University, Porto, Portugal. grostan@ipatimup.pt
authors.forename: Ginesa
authors.initials: G
authors.lastname: García-Rostán
authors.forename: Angela M
authors.initials: AM
authors.lastname: Costa
authors.forename: Isabel
authors.initials: I
authors.lastname: Pereira-Castro
authors.forename: Giuliana
authors.initials: G
authors.lastname: Salvatore
authors.forename: Radhames
authors.initials: R
authors.lastname: Hernandez
authors.forename: Mario J A
authors.initials: MJ
authors.lastname: Hermsem
authors.forename: Agustin
authors.initials: A
authors.lastname: Herrero
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.forename: Jose
authors.initials: J
authors.lastname: Cameselle-Teijeiro
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019943:Amino Acid Substitution; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002291:Carcinoma, Papillary / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004789:Enzyme Activation; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D020125:Mutation, Missense; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D051058:Oncogene Protein v-akt; D048493:Proto-Oncogene Proteins B-raf