The Principles of Clinical Cytogenetics - Extra Materials - Springer

Cytogenetics of Solid Tumors 429
domyosarcomas are characterized by reciprocal chromosome translocations involving the FKHR
(Forkhead transcription factor) gene on chromosome 13, whereas embryonal rhabdomyosarcomas
lack such translocations. Most alveolar rhabdomyosarcomas have fusion of the FKHR gene with the
PAX3 gene on chromosome 2 (40–42), but a smaller number contain fusions of FKHR with the PAX7
gene on chromosome 1 (43). Notably, the PAX7-FKHR fusion is often highly amplified—in the form
of double minute chromosomes—whereas the more common PAX3-FKHR fusions are not. This difference
appears to reflect the lower intrinsic expression of PAX7-FKHR, relative to that of PAX3-
FKHR, with genomic amplification therefore required to provide a comparable level of oncogene
transcript (44). The normal FKHR, PAX3, and PAX7 genes encode transcription factors, and the
PAX3-FKHR and PAX7-FKHR fusion oncogenes encode activated forms of those transcription factors
(45,46). Embryonal rhabdomyosarcomas typically lack FKHR translocations and have a distinctive
cytogenetic profile including extra copies of chromosomes 2, 8, and 20. Deletions of chromosome
11p have been studied extensively in embryonal rhabdomyosarcoma, and for some time, they were
viewed as the cardinal cytogenetic aberrations in these tumors. However, the 11p deletions are infrequent
compared to the chromosomal polysomies.
Synovial Sarcoma
Synovial sarcomas can be either biphasic (in which the tumor contains both spindle cell and epithelioid
elements) or monophasic (in which the tumor is predominantly spindle cell), and both of these
subtypes feature a reciprocal translocation involving the X chromosome and chromosome 18,
t(X;18)(p11.2;q11.2) (47,48). The (X;18) translocation is found in more than 90% of synovial sarcomas,
but not in histologic mimics such as hemangiopericytoma, mesothelioma, leiomyosarcoma, or
malignant peripheral nerve sheath tumor. The molecular underpinnings of the (X;18) translocation are
complex in that the oncogene on chromosome 18 (SYT or SS18) can be fused with either of two nearly
identical genes (SSX1 or SSX2) on the X chromosome (49). SSX1 and SSX2 are neighboring genes, and
given their close proximity, it is impossible to distinguish SYT-SSX1 and SYT-SSX2 translocations using
conventional chromosomal banding methods. However, the alternate SSX fusions can be demonstrated
by FISH (see Chapter 17, Fig. 13) or RT-PCR (50,51). Notably, synovial sarcomas with the SYT-SSX1
fusion are invariably biphasic, whereas those with SYT-SSX2 can be either biphasic or monophasic and
have better metastasis-free survival compared to those with SYT-SSX1 fusions (52).
Adipose Tumors
Adipose tumors present a paradigm in solid-tumor cytogenetics, in that virtually all histological
subtypes, whether benign or malignant, contain distinctive chromosomal aberrations (see Table 1).
Useful diagnostic markers include 12q rearrangement in lipoma, ring chromosomes in well-differentiated
and dedifferentiated liposarcoma, t(12;16) translocations in mxyoid/round cell liposarcoma,
and cytogenetic complexity in pleomorphic liposarcomas.
Benign lipomas can be grouped into three general cytogenetic categories: (1) those with rearrangements
of the mid-portion of the long arm of chromosome 12 (band 12q15); (2) those with clonal aberrations
not involving 12q15; and (3) those with normal karyotypes (53–55). The chromosome 12q15
rearrangements target the HMGIC (high-mobility group IC) transcriptional regulatory gene (56), with
formation of an HMGIC fusion oncogene, usually resulting from an inversion or translocation with various
partner chromosomes. Other nonrandom aberrations include rearrangement of the short arm of chromosome
6 and deletion of the long arm of chromosome 13, which are each seen in fewer than 10% of
lipomas (54). Lipomas with deletions of the long arm of chromosome 16, often accompanied by deletions
of the long arm of chromosome 13, generally have spindle cell or pleomorphic histology (55,57).
Characteristic cytogenetic aberrations are found in several other benign adipose tumors. Lipoblastomas
are pediatric adipose tumors containing variable numbers of primitive cells (lipoblasts), and these tumors
generally contain translocations involving the long arm of chromosome 8 at bands 8q11-q12, which result