The Principles of Clinical Cytogenetics - Extra Materials - Springer

Cytogenetics of Solid Tumors 433
Fig. 4. Noncomplex karyotype in a gastrointestinal stromal tumor with loss of chromosome 14 as an isolated
chromosomal abnormality.
Gastrointestinal Stromal Tumors
Most gastrointestinal stromal tumors (GISTs) contain activating mutations of the KIT or PDGFRA
oncogenes (98–100). These mutations have been targeted with spectacular success using the KIT
inhibitor, imatinib mesylate (STI571, Gleevec) (101,102). In addition, germline (inherited) KIT mutations
are responsible for rare syndromes of familial, multifocal GISTs (103). Both the germline and
somatic KIT aberrations are point mutations that are not evident at the cytogenetic level of resolution.
However, most GISTs also have one or more chromosomal deletions (100,104), and the cytogenetic
profile in GISTs is different from that in histological mimics such as leiomyoma and leiomyosarcoma
(see Table 1). The cytogenetic aberrations in GISTs appear to be secondary events and it is
likely that KIT mutations initiate the neoplastic process in many GISTs, whereas cytogenetic aberrations
are important in the biological and clinical progression of those tumors. Benign GISTs can have
normal karyotypes or isolated losses of 14q and 22q. Borderline malignant GISTs invariably have
loss of 14q, which is often accompanied by loss of 1p, 9p, 11p, or 22q (see Fig. 4). Highly malignant
GISTs usually contain at least three of the above-mentioned chromosomal deletions, although their
karyotypes are nonetheless simpler than those in most cancers that are histological GIST mimics.
Molecular cytogenetic screening by comparative genomic hybridization (CGH) (see Chapter 17) has
also revealed correlations between increasing numbers of chromosomal aberrations and aggressive
clinicopathological behavior. El-Rifai et al. reported such correlations in 95 GISTs, including 24
benign, 36 malignant primary, and 35 metastatic tumors (105). The mean number of demonstrable
chromosomal aberrations were 2.6, 7.5, and 9.0, respectively, in the benign, malignant primary, and
metastatic GISTs. Deletions of chromosome arms 1p, 14q, and 22q were found in both benign and