Copy-neutral loss of heterozygosity and chromosome gains and losses are frequent in gastrointestinal stromal tumors.
BACKGROUND
A KIT gain of function mutation is present in 70% of gastrointestinal stromal tumors (GISTs) and the wild-type (WT) allele is deleted in 5 to 15% of these cases. The WT KIT is probably deleted during GIST progression. We aimed to identify the mechanism of WT KIT loss and to determine whether other genes are involved or affected.


METHODS
Whole-genome SNP array analyses were performed in 22 GISTs with KIT exon 11 mutations, including 11 with WT loss, to investigate the mechanisms of WT allele deletion. CGH arrays and FISH were performed in some cases. Common genetic events were identified by SNP data analysis. The 9p21.3 locus was studied by multiplex quantification of genomic DNA.


RESULTS
Chromosome instability involving the whole chromosome/chromosome arm (whole C/CA) was detected in 21/22 cases. The GISTs segregated in two groups based on their chromosome number: polyGISTs had numerous whole C/CA gains (mean 23, range [9 to 43]/3.11 [1 to 5]), whereas biGISTs had fewer aberrations. Whole C/CA losses were also frequent and found in both groups. There were numerous copy-neutral losses of heterozygosity (cnLOH) of whole C/CA in both polyGIST (7/9) and biGIST (9/13) groups. cnLOH were frequent on 4q, 11p, 11q, 1p, 2q, 3p and 10, and never involved 12p, 12q, 20p, 20q or 19q. Other genetic alterations included segmental chromosome abnormalities, complete bi-allelic deletions (homozygous deletions) and, more rarely, amplifications. Nine of 11 GISTs with homozygous KIT exon 11 mutations had cnLOH of chromosome 4.


CONCLUSIONS
The cnLOH of whole C/CA is a frequent genetic alteration in GISTs and is closely associated with homozygous mutations of KIT and WT allele deletion.
EA4340, Versailles University, Boulogne-Billancourt, France. nelourenco@wanadoo.fr.|Digestive Oncology Unit, Saint Louis Hospital, APHP, Paris, France. nelourenco@wanadoo.fr.
Nelson
N
Lourenço
EA4340, Versailles University, Boulogne-Billancourt, France. zofia.helias@apr.aphp.fr.|Department of Pathology, Ambroise Paré Hospital, APHP, 9 Avenue Charles de Gaulle, Boulogne-Billancourt, France. zofia.helias@apr.aphp.fr.
Zofia
Z
Hélias-Rodzewicz
EA4340, Versailles University, Boulogne-Billancourt, France. jean-baptiste.bachet@psl.aphp.fr.|Digestive Oncology Unit, Pitié Salpétrière Hospital, APHP, Paris, France. jean-baptiste.bachet@psl.aphp.fr.
Jean-Baptiste
JB
Bachet
EA4340, Versailles University, Boulogne-Billancourt, France. brasab@hotmail.fr.
Sabrina
S
Brahimi-Adouane
Centre Henri Becquerel, INSERM U918, Université de Rouen, Rouen, France. fabrice.jardin@rouen.fnclcc.fr.
Fabrice
F
Jardin
Department of Pathology, Henri Mondor Hospital, APHP, Créteil, France. jeanne.tran-van-nhieu@hmn.aphp.fr.
Jeanne
J
Tran van Nhieu
EA4340, Versailles University, Boulogne-Billancourt, France. frederique.peschaud@apr.aphp.fr.|Department of Surgery, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France. frederique.peschaud@apr.aphp.fr.
Frédérique
F
Peschaud
Integragen, Evry, France. Emmanuel.Martin@integragen.com.
Emmanuel
E
Martin
EA4340, Versailles University, Boulogne-Billancourt, France. alain.beauchet@apr.aphp.fr.|Clinical Research Unit, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, France. alain.beauchet@apr.aphp.fr.
Alain
A
Beauchet
Bergonié Institut, INSERM U916, Bordeaux, France. F.Chibon@bordeaux.unicancer.fr.
Frédéric
F
Chibon
EA4340, Versailles University, Boulogne-Billancourt, France. jean-francois.emile@uvsq.fr.|Department of Pathology, Ambroise Paré Hospital, APHP, 9 Avenue Charles de Gaulle, Boulogne-Billancourt, France. jean-francois.emile@uvsq.fr.
Jean-François
JF
Emile
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002872:Chromosome Deletion; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D018450:Disease Progression; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D011123:Polyploidy
D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16