L Capelli1, E Petracci2, V Quagliuolo3, L Saragoni4, P Colombo5, P Morgagni6, D Calistri1, A Tomezzoli7, M Di Cosmo8, F Roviello9, C Vindigni10, A Coniglio11, V Villanacci12, M Catarci13, L Coppola14, S Alfieri15, R Ricci16, C Capella17, S Rausei18, D Gulino2, D Amadori19, P Ulivi20. 1. Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014 Meldola, Italy. 2. Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. 3. Department of General Oncologic Surgery, Humanitas Research Hospital IRCCS, Rozzano Milan, Italy. 4. Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy. 5. Department of Pathology, Humanitas Research Hospital IRCCS, Rozzano Milan, Italy. 6. Gastroenterological and Mininvasive General Surgery Unit, Morgagni Pierantoni Hospital, Forlì, Italy. 7. Pathology Unit, Borgo Trento Hospital, Verona, Italy. 8. General and Upper GI Surgery, University of Verona, Verona, Italy. 9. General Surgery and Surgical Oncology Units, University of Siena, Siena, Italy. 10. Unit of Pathology, Azienda Ospedaliera Universitaria Senese, Siena, Italy. 11. Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. 12. Department of Pathology, University and Spedali Civili of Brescia, Brescia, Italy. 13. General and Oncologic Surgery Unit, San Filippo Neri Hospital, Roma, Italy. 14. Pathology Unit, San Filippo Neri Hospital, Roma, Italy. 15. Department of Digestive Surgery, Catholic University, A. Gemelli Hospital, Roma, Italy. 16. Department of Pathology, Catholic University, A. Gemelli Hospital, Roma, Italy. 17. Department of Human Morphology, Circolo e Fondazione Macchi Hospital, Varese, Italy. 18. General Surgery Unit, Circolo e Fondazione Macchi Hospital, Varese, Italy. 19. Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. 20. Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014 Meldola, Italy. Electronic address: paola.ulivi@irst.emr.it.
Abstract
BACKGROUND: Gastric gastrointestinal stromal tumors (GISTs) represent a subgroup of GISTs with a better prognosis than those located in other areas. In this retrospective study we performed a molecular characterization of a large series of patients with gastric GISTs in relation to clinical-pathological characteristics and prognosis. METHODS: DNA was extracted from paraffin-embedded sections from 221 gastric GIST patients submitted to surgery. Exons 9, 11, 13 and 17 of KIT, exons 12 and 18 of PDGFRA and exons 11 and 15 of BRAF were analyzed by direct sequencing. Cox regression analysis adjusted for clinical-pathological factors was performed to evaluate KIT and PDGFRA mutations in relation to the composite endpoint of relapse or death. RESULTS: KIT and PDGFRA mutations were observed in 119 (53.8%) and 56 (25.3%) patients, respectively, whereas 46 (20.8%) patients had wild type (wt) disease. Univariable analyses showed that a high Miettinen risk category and the presence of ulceration and KIT deletions were associated with increased risk of relapse or death (p < 0.001; p = 0.0389 and p = 0.002, respectively). After adjusting for Miettinen risk score, KIT deletions remained an independent prognostic factor (HRadj = 2.65, 95% CI [1.15-6.13], p = 0.023). Moreover, KIT deletions in exon 11 codons 557, 558 or 559 were associated with a higher risk of relapse or death than wt tumors (HRadj = 3.29 95% CI [1.64-6.64], p = 0.001). CONCLUSIONS: KIT deletions in exon 11, especially those involving codons 557, 558 or 559, were correlated with a more aggressive gastric GIST phenotype and increased risk of relapse or death.
BACKGROUND: Gastric gastrointestinal stromal tumors (GISTs) represent a subgroup of GISTs with a better prognosis than those located in other areas. In this retrospective study we performed a molecular characterization of a large series of patients with gastric GISTs in relation to clinical-pathological characteristics and prognosis. METHODS: DNA was extracted from paraffin-embedded sections from 221 gastric GISTpatients submitted to surgery. Exons 9, 11, 13 and 17 of KIT, exons 12 and 18 of PDGFRA and exons 11 and 15 of BRAF were analyzed by direct sequencing. Cox regression analysis adjusted for clinical-pathological factors was performed to evaluate KIT and PDGFRA mutations in relation to the composite endpoint of relapse or death. RESULTS:KIT and PDGFRA mutations were observed in 119 (53.8%) and 56 (25.3%) patients, respectively, whereas 46 (20.8%) patients had wild type (wt) disease. Univariable analyses showed that a high Miettinen risk category and the presence of ulceration and KIT deletions were associated with increased risk of relapse or death (p < 0.001; p = 0.0389 and p = 0.002, respectively). After adjusting for Miettinen risk score, KIT deletions remained an independent prognostic factor (HRadj = 2.65, 95% CI [1.15-6.13], p = 0.023). Moreover, KIT deletions in exon 11 codons 557, 558 or 559 were associated with a higher risk of relapse or death than wt tumors (HRadj = 3.29 95% CI [1.64-6.64], p = 0.001). CONCLUSIONS:KIT deletions in exon 11, especially those involving codons 557, 558 or 559, were correlated with a more aggressive gastric GIST phenotype and increased risk of relapse or death.