Frequency and clinicopathologic profile of PIK3CA mutant GISTs: molecular genetic study of 529 cases

• Published in: Modern pathology Vol. 29; no. 3; pp. 275 - 282
• Main Authors: Lasota, Jerzy, Felisiak-Golabek, Anna, Wasag, Bartosz, Kowalik, Artur, Zięba, Sebastian, Chłopek, Małgorzata, Wang, Zeng-Feng, Coates, Tiffany, Kopczynski, Janusz, Gozdz, Stanislaw, Sarlomo-Rikala, Maarit, Miettinen, Markku
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-03-2016; Elsevier Limited
• Subjects: 38/22; 38/23; 45/77; 692/420/755; 82/51; Adult; Aged; Aged, 80 and over; Base Sequence; Class I Phosphatidylinositol 3-Kinases; DNA Mutational Analysis; Drug Resistance, Neoplasm - genetics; Female; Gastrointestinal Neoplasms - genetics; Gastrointestinal Stromal Tumors - genetics; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Laboratory Medicine; Male; Medicine; Medicine & Public Health; Middle Aged; Mutation; original-article; Pathology; Phosphatidylinositol 3-Kinases - genetics; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/modpathol.2015.160

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.