Chromosomal aberrations in malignant gastrointestinal stromal tumors: correlation with c-KIT gene mutation

Gastrointestinal stromal tumors (GISTs) are distinctive, KIT positive mesen chymal neoplasms. The genetic alterations leading to the malignant behavior of these tumors are not well known. In this study, we looked for recurrent numerical chromosomal changes, which may be associated with malignant GIST s, using interphase fluorescence in situ hybridization (FISH). Fourteen mal ignant primary tumors and two intra-abdominal recurrences were analyzed. Ni ne benign tumors were studied for comparison. In all cases, the presence of mutations in exons 9, 11 and 13 of the KIT gene were evaluated. Sixteen ce ntromeric enumeration probes (CEP) for chromosomes 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 15, 16, 17, 18, and X and three locus specific probes (LSI) for 22q11.2 (BCR-locus). 13q14 (RB1-locus) and 14q32 (IgH-locus) were used. Th e most common changes seen in malignant GISTs were losses of 14q32 and 22q1 1, However, these changes were commonly detected in benign tumors and repre sent early changes related to the pathogenesis of GISTs. Losses of chromoso mes 1 and 9 were the only recurrent numerical changes seen exclusively in m alignant GISTs. Other recurrent numerical changes seen predominantly in mal ignant tumors were gain of chromosome 8 and losses of chromosomes 7 and 15. The concurrent loss of chromosome 7 and gain of chromosome 8 (in 4 cases) was never seen together with loss of chromosomes 9 or 15 and only once with loss of chromosome 1. Mutations in KIT were found in the majority of malig nant GISTs (64%) confirming a previously shown correlation between presence of such mutations and malignancy. KIT mutations were seen in four of five malignant GISTs with loss of chromosome 9, but only in one of four malignan t tumors with loss of chromosome 1. These observations may reflect the diff erent pathways leading to malignant transformation of GISTs. (C) 2001 Elsev ier Science Inc. All rights reserved.