Chromosome copy number changes carry prognostic information independent of KIT/PDGFRA point mutations in gastrointestinal stromal tumors.
BACKGROUND
Oncogenic point mutations in KIT or PDGFRA are recognized as the primary events responsible for the pathogenesis of most gastrointestinal stromal tumors (GIST), but additional genomic alterations are frequent and presumably required for tumor progression. The relative contribution of such alterations for the biology and clinical behavior of GIST, however, remains elusive.


METHODS
In the present study, somatic mutations in KIT and PDGFRA were evaluated by direct sequencing analysis in a consecutive series of 80 GIST patients. For a subset of 29 tumors, comparative genomic hybridization was additionally used to screen for chromosome copy number aberrations. Genotype and genomic findings were cross-tabulated and compared with available clinical and follow-up data.


RESULTS
We report an overall mutation frequency of 87.5%, with 76.25% of the tumors showing alterations in KIT and 11.25% in PDGFRA. Secondary KIT mutations were additionally found in two of four samples obtained after imatinib treatment. Chromosomal imbalances were detected in 25 out of 29 tumors (86%), namely losses at 14q (88% of abnormal cases), 22q (44%), 1p (44%), and 15q (36%), and gains at 1q (16%) and 12q (20%). In addition to clinico-pathological high-risk groups, patients with KIT mutations, genomic complexity, genomic gains and deletions at either 1p or 22q showed a significantly shorter disease-free survival. Furthermore, genomic complexity was the best predictor of disease progression in multivariate analysis.


CONCLUSIONS
In addition to KIT/PDGFRA mutational status, our findings indicate that secondary chromosomal changes contribute significantly to tumor development and progression of GIST and that genomic complexity carries independent prognostic value that complements clinico-pathological and genotype information.
Silva
Mara
M
Department of Genetics, Portuguese Oncology Institute - Porto, Rua Dr, António Bernardino Almeida, 4200-072 Porto, Portugal.
Veiga
Isabel
I
Ribeiro
Franclim R
FR
Vieira
Joana
J
Pinto
Carla
C
Pinheiro
Manuela
M
Mesquita
Bárbara
B
Santos
Catarina
C
Soares
Marta
M
Dinis
José
J
Santos
Lúcio
L
Lopes
Paula
P
Afonso
Mariana
M
Lopes
Carlos
C
Teixeira
Manuel R
MR
D000328:Adult; D000368:Aged; D000782:Aneuploidy; D002877:Chromosomes, Human; D055028:Comparative Genomic Hybridization; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000175:diagnosis* / Q000473:pathology*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D057089:Pathology, Molecular / Q000379:methods*; D017354:Point Mutation; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D017422:Sequence Analysis, DNA
D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha
Science. 1998 Jan 23;279(5350):577-80
9438854
Genes Chromosomes Cancer. 2010 Feb;49(2):91-8
19847891
Clin Cancer Res. 2006 Jul 1;12(13):3961-70
16818693
Am J Pathol. 2000 Mar;156(3):791-5
10702394
Lab Invest. 2005 Feb;85(2):237-47
15580284
Lancet. 2007 May 19;369(9574):1731-41
17512858
J Pathol. 2007 Mar;211(4):463-70
17226762
Int J Cancer. 2003 Oct 10;106(6):887-95
12918066
Hum Pathol. 2008 Oct;39(10):1411-9
18774375
Genes Chromosomes Cancer. 2007 Mar;46(3):261-76
17171690
Cancer Genet Cytogenet. 2002 May;135(1):1-22
12072198
Science. 2003 Jan 31;299(5607):708-10
12522257
Mol Cell Biol. 2007 Jan;27(1):267-82
17060458
Gastroenterology. 2005 Feb;128(2):270-9
15685537
Cancer Res. 2000 Jul 15;60(14):3899-903
10919666
Mol Cell Probes. 1992 Apr;6(2):145-52
1355266
Am J Pathol. 2002 Jan;160(1):15-22
11786393
Cytometry. 1998 Mar 1;31(3):163-73
9515715
J Clin Pathol. 2008 Feb;61(2):203-8
17827398
Science. 1992 Oct 30;258(5083):818-21
1359641
Histopathology. 2008 Sep;53(3):245-66
18312355
Genes Chromosomes Cancer. 2007 Jun;46(6):564-76
17330260
Ann Diagn Pathol. 2007 Feb;11(1):27-33
17240304
Trends Genet. 1989 Dec;5(12):391
2623762
Cancer. 2008 Oct 1;113(7):1532-43
18671247
Hum Pathol. 2002 May;33(5):459-65
12094370
Histopathology. 2006 Jan;48(1):83-96
16359540
Int J Oncol. 2006 Jun;28(6):1361-7
16685437
J Clin Pathol. 2005 Jun;58(6):634-9
15917417
J Clin Oncol. 2004 Sep 15;22(18):3813-25
15365079
N Engl J Med. 2002 Feb 28;346(9):683-93
11870247
J Clin Pathol. 2006 Jun;59(6):557-63
16731599
J Clin Oncol. 2005 Sep 1;23(25):6190-8
16135486
Hum Pathol. 2002 May;33(5):484-95
12094373
J Mol Diagn. 2004 Aug;6(3):197-204
15269295
Hematol Oncol Clin North Am. 2000 Jun;14(3):517-35
10909038
J Natl Compr Canc Netw. 2007 Jul;5 Suppl 2:S1-29; quiz S30
17624289
Annu Rev Pathol. 2008;3:557-86
18039140