Array CGH analysis in primary gastrointestinal stromal tumors: cytogenetic profile correlates with anatomic site and tumor aggressiveness, irrespective of mutational status.
Gastrointestinal stromal tumors (GISTs) comprise a biologically diverse group of neoplasms with respect to activating mutations in either KIT or PDGFRA, histology, anatomical site of origin, and clinical aggressiveness. In this study, we applied the high resolution array-based comparative genomic hybridization (array-CGH) technology to 66 primary GISTs (40 gastric and 26 nongastric, 48 with KIT and 18 with PDGFRA mutations) for identification of novel high-level alterations and for characterization of genotype-related genomic changes. All cases had genomic imbalances with the highest occurrence of 14q (73%), 1p (62%), 22q (59%), 15q (38%), and 13q (29%) losses. Our data indicate that loss of chromosome 14 and/or 22 is an early change in GIST tumorigenesis irrespective of tumor genotype. Furthermore, DNA copy number changes showed a site dependent pattern. These included lower incidence of losses at 14q (87% vs. 35%), and higher frequency of losses at 1p (45% vs. 85%) and 15q (17% vs. 69%) in nongastric versus gastric site (P<0.001 for all). However, in the multivariate analysis with adjustment to tumor risk stratification, only the 14q loss site-dependent pattern of distribution retained its significance. These findings suggest that loss of 14q is a relatively less frequent genetic event in the development of nongastric GISTs, the lack of which is most likely substituted by the accumulation of 1p/15q and other changes. The novel minimal overlapping regions of deletion at 1p (1p36.32-1p35.2, 1p34.1, and 1p22.1-1p21.3), 13q (13q14.11-q14.2 and 13q32.3-q33.1), and 15q23 were delineated, which point to chromosomal regions that may harbor genes relevant to the development of these neoplasms.
Wozniak
Agnieszka
A
Department of Human Genetics, Catholic University of Leuven, Leuven, Belgium.
Sciot
Raf
R
Guillou
Louis
L
Pauwels
Patrick
P
Wasag
Bartosz
B
Stul
Michel
M
Vermeesch
Joris Robert
JR
Vandenberghe
Peter
P
Limon
Janusz
J
Debiec-Rychter
Maria
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D020732:Cytogenetic Analysis; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018628:Gene Dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism
D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha