Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients - A GIRCG study.
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.
Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014 Meldola, Italy.
L
L
Capelli
Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
E
E
Petracci
Department of General Oncologic Surgery, Humanitas Research Hospital IRCCS, Rozzano Milan, Italy.
V
V
Quagliuolo
Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy.
L
L
Saragoni
Department of Pathology, Humanitas Research Hospital IRCCS, Rozzano Milan, Italy.
P
P
Colombo
Gastroenterological and Mininvasive General Surgery Unit, Morgagni Pierantoni Hospital, Forlì, Italy.
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P
Morgagni
Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Maroncelli 40, 47014 Meldola, Italy.
D
D
Calistri
Pathology Unit, Borgo Trento Hospital, Verona, Italy.
A
A
Tomezzoli
General and Upper GI Surgery, University of Verona, Verona, Italy.
M
M
Di Cosmo
General Surgery and Surgical Oncology Units, University of Siena, Siena, Italy.
F
F
Roviello
Unit of Pathology, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
C
C
Vindigni
Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
A
A
Coniglio
Department of Pathology, University and Spedali Civili of Brescia, Brescia, Italy.
V
V
Villanacci
General and Oncologic Surgery Unit, San Filippo Neri Hospital, Roma, Italy.
M
M
Catarci
Pathology Unit, San Filippo Neri Hospital, Roma, Italy.
L
L
Coppola
Department of Digestive Surgery, Catholic University, A. Gemelli Hospital, Roma, Italy.
S
S
Alfieri
Department of Pathology, Catholic University, A. Gemelli Hospital, Roma, Italy.
R
R
Ricci
Department of Human Morphology, Circolo e Fondazione Macchi Hospital, Varese, Italy.
C
C
Capella
General Surgery Unit, Circolo e Fondazione Macchi Hospital, Varese, Italy.
S
S
Rausei
Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
D
D
Gulino
Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
D
D
Amadori
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.
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Ulivi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005091:Exons / Q000235:genetics; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D011379:Prognosis; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D047368:Tumor Burden; D055815:Young Adult
D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
BRAF; GISTs; KIT; Mutation; PDGFRA; Prognostic factors