title: Frequency and clinicopathologic profile of PIK3CA mutant GISTs: molecular genetic study of 529 cases.
abstract: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors usually driven by the mutational activation of receptor tyrosine kinases, KIT, or PDGFRA. Oncogenic activation of phosphatidylinositide-3-kinase (PI3K), a downstream effector in the KIT signaling pathway, has been identified in different types of cancer, with the PI3K 110α subunit encoded by PIK3CA being a common mutational target. In this study, the mutational hotspot in the PIK3CA kinase domain encoded by exon 20 was evaluated in 529 imatinib-naive GISTs using PCR amplification and Sanger sequencing. Eight mutations (two co-existing in one tumor) were identified. Subsequently, The cobas PIK3CA Mutation Test was employed to evaluate mutational hotspots in exons 1, 4, 7, and 9 in 119 PIK3CA exon 20-wild type tumors. In two cases, mutations in exons 1 and 9 were identified. In one GIST, previously undetected by Sanger sequencing, the exon 20 mutation was discovered. Altogether, eight primary and two metastatic GISTs carried PIK3CA mutations. The size of primary PIK3CA-mutant GISTs was ≥14 cm (mean size 17 cm), and mitotic activity varied from 0 to 72 per 50HPF (mean 5/50HPF). Follow-up data showed short survival in 6 of 7 studied cases. Detection of PIK3CA mutations in large or metastatic KIT-mutant GISTs may suggest that PIK3CA-mutant clones have a proliferative advantage during disease progression. Tyrosine kinase inhibitors have been successfully used in GIST treatment. However, resistance frequently develops due to secondary KIT mutations or activation of downstream to KIT signaling pathways, such as the PI3K/AKT/mTOR pathway. PIK3CA mutations similar to the ones detected in GISTs have been shown to cause such activation. Therefore, genotyping of PIK3CA in GISTs might help to pinpoint primary and metastatic tumors with the potential to develop resistance to tyrosine kinase inhibitors and guide therapy with PI3K inhibitors.
authors.affiliation: Laboratory of Pathology, National Cancer Institute (NCI), Bethesda, MD, USA.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Lasota
authors.affiliation: Laboratory of Pathology, National Cancer Institute (NCI), Bethesda, MD, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Felisiak-Golabek
authors.affiliation: Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Wasag
authors.affiliation: Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Kowalik
authors.affiliation: Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zięba
authors.affiliation: Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Chłopek
authors.affiliation: Laboratory of Pathology, National Cancer Institute (NCI), Bethesda, MD, USA.
authors.forename: Zeng-Feng
authors.initials: ZF
authors.lastname: Wang
authors.affiliation: Laboratory of Pathology, National Cancer Institute (NCI), Bethesda, MD, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Coates
authors.affiliation: Department of Surgical Pathology, Holycross Cancer Center, Kielce, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Kopczynski
authors.affiliation: Department of Clinical Oncology, Holycross Cancer Center, Kielce, Poland.|Faculty of Health Sciences, The Jan Kochanowski University, Kielce, Poland.
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Gozdz
authors.affiliation: HUSLab, University of Helsinki, Helsinki, Finland.
authors.forename: Maarit
authors.initials: M
authors.lastname: Sarlomo-Rikala
authors.affiliation: Laboratory of Pathology, National Cancer Institute (NCI), Bethesda, MD, USA.
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human