The Principles of Clinical Cytogenetics - Extra Materials - Springer

Cytogenetics of Solid Tumors 431
clear cell sarcoma and true melanoma are quite different clinically. Whereas most melanomas are of
cutaneous origin, clear cell sarcomas generally present as isolated masses in deep soft tissues, without
apparent origin from skin. More than 75% of clear cell sarcomas contain a chromosomal rearrangement,
t(12;22)(q13;q12), that has never been reported in cutaneous melanoma and that hence
serves as a reliable marker in distinguishing these two tumor types. The (12;22) translocation fuses
the ATF1 gene on chromosome 12 with the EWS gene on chromosome 22 (69,70). ATF1 encodes a
transcription factor, and the biological implications of the translocation are probably similar to those
in Ewing’s sarcoma translocations, as discussed earlier.
Desmoplastic Small Round Cell Tumor
Desmoplastic small round cell tumors are aggressive and chemotherapy-resistant neoplasms that
arise usually from intraabdominal soft tissues (71). They are composed of undifferentiated malignant
small round cells within a striking desmoplastic reaction (71), and virtually all cases express an
EWS-WT1 fusion oncogene (72,73). The EWS-WT1 oncogene results from translocation between the
short arm of chromosome 11 and the long arm of chromosome 22, fusing the WT1 (Wilms tumor) and
EWS (Ewing’s) genes (74,75). The EWS-WT1 oncoprotein is a transcriptional regulator that
upregulates expression of platelet derived-growth factor-α (PDGFA) (76). PDGFA activates potent
mitogenic signaling pathways in fibroblasts (77), thereby likely contributing to the prominent desmoplastic
reaction.
Dermatofibrosarcoma Protuberans
Dermatofibrosarcoma protuberans (DFSP) are low-grade spindle cell tumors that can occasionally
progress to a more aggressive “fibrosarcomatous” phase. Most DFSP contain ring chromosomes
(see Fig. 3) comprised of sequences from chromosomes 17 and 22 (78,79). The ring chromosomes
contain multiple copies of a fusion gene, COL1A1-PDGFB, in which COL1A1 (a collagen gene) is
contributed by chromosome 17 and PDGFB (platelet derived growth factor beta gene) by chromosome
22 (80,81). Occasional dermatofibrosarcoma protuberans have balanced (17;22) translocations,
which result in a single copy of the COL1A1-PDGFB fusion gene. The COL1A1-PDGFB oncogene
results in overexpression of PDGFB, which is a growth factor that activates platelet-derived growth
factor-β receptor (PDGFRB) and platelet derived growth factor receptor alpha (PDGFRA). This cytogenetic
observation suggested the possibility that patients with inoperable DFSP might benefit from
treatment with PDGFR inhibitors (e.g., imatinib mesylate) (see Chapter 15), and this hypothesis has
been confirmed by impressive clinical responses in several patients (82,83).
Desmoid Tumors
Desmoid tumors, which are also known as deep fibromatoses, contain various cytogenetic or
molecular aberrations, including APC (adenomatous polyposis coli) and β-catenin mutations (84,85),
and trisomies for chromosomes 8 or 20 (86). Cytogenetic deletions of the long arm of chromosome 5
are seen in occasional desmoids, resulting in loss of the APC tumor suppressor gene (87,88). However,
the most common mutations, particularly in nonfamilial desmoid tumors, are those that activate
β-catenin, and they are found in approximately 50% of cases (84,85). These mutations result in stabilization,
and resultant overexpression of the β-catenin protein. It is likely that the cytogenetic aberrations
in desmoid tumors, particularly trisomies 8 and 20, are mechanisms of progression, and are
acquired subsequent to the APC or β-catenin mutations.
Infantile Fibrosarcoma
Infantile fibrosaromas are congenital tumors comprised of fibroblastlike cells and that often show high
mitotic activity. These tumors are distinguished by trisomies of chromosomes 8, 11, 17, and 20 (89).
This same group of trisomies is found in the histologically similar pediatric renal tumor, mesoblastic