PART ONE
General Cytology
Fig. 2.13 Karyotype of an Ewing's tumor
with
the characteristic t(11;22)(q24;q12) chromosomal
translocation (arrows) leading to the
EWS-FLU
fusion gene. Secondary recurrent chromosomal
abnormalities such as monosomies 6 and 15 and
trisomies 2 and 14 are also observed.
according to their genetic aberrations.43,45 Congenital fibrosar-
coma and mesoblastic nephroma were thought to be unrelated
tumors until cytogenetic analysis revealed a common aberra-
tion, hence the t(12;15)(p13;q25) translocation with subja-
cent
ETV6-NTRK3
fusion gene, indicating that they are simply
the same tumoral entity that develops in different locations.
Another similar example is illustrated by the t(X;17)(p11.2;q25)
translocation shared by the alveolar soft-part sarcoma (ASPS)
and a cytogenetic subset of childhood papillary renal cell car-
cinoma (PRCC).46 Although this translocation is cytogeneti-
cally unbalanced in ASPS and balanced in PRCC, it gives rise
at the molecular level to the same
ASPL-TFE3
fusion transcript
in both tumoral types. Therefore, some fusion genes can exert
their oncogenic properties in more than one target cell type and
seems not to play any role in cell differentiation. On the other
hand, in vitro experiments showed that fusion proteins such as
EWS-FLI1 contribute to the phenotypic features of ES/PNET by
subverting the differentiation program of its neural crest precur-
sor cell to a less differentiated and more proliferative state. In
synovial sarcoma, the
SYT
gene on chromosome 18q11 can fuse
with various members of the SSX cluster located on chromo-
some Xp11 (Fig. 2.14). The
SSX2
translocation partner is more
likely observed in monophasic synovial sarcoma, whereas
SSX1
is much often associated with the biphasic forms, indicating
that this latter gene partner may drive epithelial differentiation
in synovial sarcoma. Finally, some data support the hypothesis
that the gene fusion occurs in an already established lineage that
imposes constraints such that the target cell selects the fusion
gene. In contrast, other observations suggest that this fusion will
modulate the phenotypic features of the undifferentiated pre-
cursor harboring this fusion gene.45
Sarcoma-associated chromosomal translocations and/or their
respective fusion genes may have some prognostic impacts.14,43 In
Ewing's sarcoma, several molecular variants are observed in the
EWS-FLI1
fusion gene due to various breakpoint junctions. The
most common, designated type 1 (linking exon 7 of
EWS
with
exon 6 of
FLI1
) is associated with a better prognosis than other
variants. The
SYT-SSX
fusion type in synovial sarcoma appears to
be a significant prognostic factor since patients with the
SYT-SSX2
variant have an improved overall survival when compared with
SYT-SSX1
positive patients, independent of the histological type.
Patients with metastatic alveolar rhabdomyosarcoma having the
PAX7-FKHR
fusion gene show a substantially better prognosis
than those with the
PAX3-FKHR
translocation. These variations
in behavior could be due to subtle differences in the biochemical
activities of the variant fusion proteins, with a better prognosis
associated with variants having a less transcriptional activity.
The close association between specific translocations and
distinct sarcoma types indicates that they are early events in
tumorigenesis but their exact role in tumor development remains
often difficult to assess. In the small subset of translocations
with aberrant chimeric genes related to growth-factor signaling
pathways (see Table 2.2), the pathogenesis arises through cell
cycle activation although this is probably not sufficient per se to
induce full transformation. The great majority of chromosomal
translocations in sarcoma involve transcription factors without
obvious putative oncogenic properties at first sight. Transcription
factors are proteins that directly interact with the DNA strand of
their target genes, and regulate the expression of these genes by
binding their promotor regions upstream of RNA transcription
sites. A translocation will lead to aberrant gene fusion composed
of the DNA (or RNA)-binding domain of a transcription factor
fused with the transactivation domain of another transcription
factor. The functional consequence is that the transcriptional
activity of the latter will be deviated toward downstream genes
targeted by the DNA-binding domain provided by the transcrip-
tion factor partner. Moreover, most of these chimeric proteins
show enhanced transcriptional activity compared with their
constitutive normal protein, providing eventually a gain of func-
tion mechanism. It is thus believed that these phenomena lead
to dysregulation of gene expression, accounting for the tumoral
properties of fusion genes in sarcoma.
This general opinion can be illustrated by the t(2;13)(q35;q14)
and t(1;13)(p36;q14) translocations arising in alveolar rhab-
domyosarcoma and corresponding to the
PAX3/FKHR
and
PAX7/FKHR
fusion genes, respectively.43,47 Both translocations
36
previous page 42 ComprehensiveCytopathology 1104p 2008 read online next page 44 ComprehensiveCytopathology 1104p 2008 read online Home Toggle text on/off