The Principles of Clinical Cytogenetics - Extra Materials - Springer

Cytogenetics of Solid Tumors 427
cally contain numerous clonal and nonclonal chromosomal aberrations, are most often found in highly
malignant solid tumors. On the other hand, noncomplex karyotypes can be found in either benign or
malignant tumors. Therefore, the absence of cytogenetic complexity is not, in itself, a reassuring
finding. Although increased cytogenetic complexity generally correlates with increasing histological
grade, there is also considerable variability in cytogenetic complexity between different types of
solid tumor. Among the epithelial tumors, for example, breast carcinomas invariably have complex
karyotypes, whereas renal carcinomas generally have noncomplex karyotypes. Among the mesenchymal
tumors, osteosarcomas invariably have complex karyotypes, whereas equally malignant
Ewing’s sarcomas have noncomplex karyotypes.
The chromosome aberrations in solid tumors result in translocation, deletion, or amplification of
target genes. Translocations are particularly frequent in sarcomas, where they usually create fusions
of genes at the breakpoints of the participant chromosomes (22,23). Deletions are frequent in carcinomas,
where they likely result in loss of tumor suppressor genes. Amplifications, which are manifest
as intrachromosomal homogeneously staining regions or as extrachromosomal double minutes
(see also Chapter 15, Fig. 3) are seen occasionally in solid tumors of all types and can be of both
prognostic and therapeutic relevance (13,24).
DIAGNOSTIC AND PROGNOSTIC APPLICATIONS
Cytogenetic analyses have given extraordinary insights into the biology and pathogenesis of solid
tumors and, in some cases, these insights have then provided the basis for more accurate assessment
of diagnosis and prognosis. However, cytogenetic methods are not used routinely in the clinical
setting for all solid-tumor types. In some solid tumors, particularly those that are clinically benign,
there is no need for cytogenetic adjuncts, as the diagnosis and prognosis (with expectant cure after
adequate surgery) are straightforward. Other solid tumors, of which prostate cancer is a good example,
do not grow well in conventional tissue culture, and therefore routine karyotyping is not an option.
Widespread application of cytogenetics in such tumors awaits the identification of key genetic predictors,
which might be identified in tumor interphase cells by FISH methods. Still other solid tumors
have extremely complex karyotypes, and there has been little clinical advantage in cytogenetic analysis
of these, given the formidable task of describing the many abnormal chromosomes and given the
questionable clinical relevance of the individual chromosomal perturbations. The following sections
will highlight the applications of cytogenetics in mesenchymal and renal tumors, where the technical
challenges of the cytogenetic assays are surmountable and where the cytogenetic findings often provide
important diagnostic information.
MESENCYMAL TUMORS (SOFT TISSUE AND BONE TUMORS)
Ewing’s Sarcoma
Ewing’s sarcomas are highly aggressive bone and soft tissue tumors, in which the neoplastic cells
are generally of the small round cell type. Most Ewing’s sarcomas contain chromosome translocations
involving the Ewing’s sarcoma gene (EWS), which is located on the long arm of chromosome
22. These translocations involve a number of partner genes (see Table 1); the most common rearrangement
is t(11;22)(q24;q12) (see Fig. 1), which results in oncogenic fusion of the FLI1 gene on
chromosome 11 with the EWS gene (25–28). FLI1 encodes a transcription factor belonging to the
ETS family of transcription factors, and the oncogenic EWS-FLI1 fusion gene encodes an activated
version of this transcription factor. Other Ewing’s sacomas have variant translocations in which the
EWS gene is fused with other ETS family transcription factor genes (see Table 1) (29–33). The
Ewing’s gene translocations are apparently essential, because they are found in virtually all Ewing’s
sarcomas. These translocations are detected readily by conventional cytogenetic methods, even using
needle biopsy material, because Ewing’s sarcoma cells grow well in culture (2). The translocations