2
Basic Cytogenetics and the Role of Genetics in Cancer Development
gene.41 It is present in approximately 75% of ALCL with
ALK
gene rearrangement. In the remaining approximately 25% of
cases, 2p23/ALK locus translocates with various partner genes.41
The common molecular features of all
ALK
rearrangements is
the fusion of the ALK tyrosine kinase domain to the 5' region
of partners which provide a strong promoter and most likely
an oligomerization motif allowing constitutive activation and
aberrant expression of the ALK kinase.
ALK
gene encodes for a receptor tyrosine kinase normally
expressed in fetal and mature nervous systems but not in lym-
phoid cells. As any receptor tyrosine kinase and in normal situ-
ation, ALK protein will activate signaling pathway and cell cycle
after oligomerization induced by binding with its ligand. In
ALK
rearrangements, the partner gene brings to
ALK
the abil-
ity to self-associate in a ligand-independent fashion, leading to
its constitutive activation. In addition, the gene partner brings
a strong promoter, driving illegitimate and high levels of ALK
receptor tyrosine kinase fusion gene expression in lymphoid
cells. The functional consequence is to exaggerate and dysregu-
late otherwise normal downstream signals which will promote
cell growth and inhibit apoptosis.41 Clearly, ALK activation is
a critical step in the development of ALCL of T cell origin. As
ALK
gene is not expressed in normal lymphoid cells, the immu-
nodetection of ALK protein in a lymphoid tumor represents a
highly sensitive test for identification of lymphoma with
ALK
rearrangement, correlating in nearly 100% of cases with the
presence of such abnormality.
Regardless of other clinical and biological prognostic param-
eters, the outcome for patients with ALK-positive ALCL is signifi-
cantly better than that for patients with ALK-negative ALCL with
the 5-year survival rates ranging between 79 and 88% and 28
and 40%, respectively.42 Additional information on lymphomas
is found in Chapter 24 Lymph Nodes and Flow Cytometry.
Sarcomas
Although sarcomas are relatively rare neoplasms in adult-
hood, they represent the most frequent malignant tumors in
childhood and young adults. Abundant genetic studies have
revealed that a significant number of sarcoma are associated
with specific chromosomal abnormalities (mainly chromo-
somal translocations) that can be used as practical diagnostic
markers in histological equivocal cases.13,14,43,44 A typical exam-
ple is the so-called "small round blue cell" undifferentiated
pattern shared by disparate tumor entities such as embryonal
or alveolar rhabdomyosarcoma, Ewing's sarcoma, neuroblast-
oma, and lymphoma.
Two major genetic groups distinguishable at the cytogenetic
level are observed in sarcomas. One group is characterized by a
near-diploid karyotype with a single or few chromosomal abnor-
malities, whereas the second exhibits complex karyotype with
numerous aberrations that reflect severe disturbance in genomic
stability. Sarcoma with genetic abnormalities not detectable by
conventional cytogenetics and/or FISH means—such as GIST and
its specific
c-KIT
mutation—will not be discussed in this section.
Sarcomas with Single Karyotypic Abnormalities
This group is characterized by karyotype harboring single and
tumor-specific chromosomal translocations (Table 2.2). Most
of these translocations lead to fusion genes encoding aberrant
transcription factors but a small subset creates aberrant chimeric
genes related to growth-factor signaling pathway.
Table 2.2
Translocations associated with sarcomas
Translocation
Genes
Type of fusion gene
EwING'S sarcoma
t(11;22)(q24;q12)
EWSR1-FLI1
Transcription factor
t(21;22)(q22;q12)
EWSR1-ERG
Transcription factor
t(7;22)(p22;q12)
EWSR1-ETV1
Transcription factor
t(17;22)(q21;q 12)
EWSR1-ETV4
Transcription factor
t(2;22)(q33;q12)
ewsr1-fev
Transcription factor
CLEAR-CELL SARCOMA
t(12;22)(q13;q 12)
EWSR-ATF1
Transcription factor
DESMOPLASTIC SMALL ROuND-CELL TuMOR
t(11
;22)(p 13;q 12)
EWSR-WT1
transcription factor
m y x o id chondrosarcom a
t(9;22)(q22-31;q11-12)
EWSR-NR4A3
transcription factor
m y x o id liposarcom a
t(2;16)(q13;p11)
FUS-DDIT3
transcription factor
t(12;22)(q 13;q 12)
EWSR1-DDIT3
transcription factor
alveo lar rh abd om yo sarco m a
t(2;13)(q35;q 14)
pAX3-FKHR
transcription factor
t(1 ;13)(p36;q14)
pAX7-FKHR
transcription factor
syno vial sarcoma
t(X;18)(p 11 ;q 11)
syt-ssx
transcription factor
DERMATOFIBROSARCOMA PROTuBERANS
t(17;22)(q22;q 13)
COL1A1-pDGFB
Growth factor
CONGENITAL FIBROSARCOMA
t(12;15)(p13;q25)
ETV6-NTRK3
transcription factor-
receptor
INFLAMMATORY MYOFIBROBLASTIC TuMOR
2p23 rearrangements
TMp3-ALK;
TMp4-ALK
Growth factor-receptor
alveo lar soft-part sarcoma
t(X;17) (p 11.2;q25)
aspl-tfe3
transcription factor
The Ewing's family of tumors, which includes Ewing's sar-
coma and primitive neuroectodermal tumor (ES/PNET), are
characterized by a t(11;22)(q24;q12) translocation leading to
the
EWSR1-FLI1
fusion gene and observed in nearly 90% of
cases of ES/PNET (Fig. 2.13). The remaining cases show alter-
native chromosomal translocations fusing the
EWSR1
gene
(chromosome 22q12) with partner genes other than
FLI1
and
that belong to the same ETS family of transcription factors.
EWSR1
gene is also involved in chromosomal translocations
arising in several other tumoral entities such as the intra-
abdominal desmoplastic small round-cell tumor (DSRCT),
myxoid chondrosarcoma, and clear cell sarcoma. However,
EWSR1
gene fused in each case with gene partners not encoun-
tered in the Ewing's family of tumors, giving rise to specific
fusion genes suitable for diagnostic purposes.13,43,44
Some new data indicate that soft-tissue tumors can no
longer be classified only on basis of their site of origin but also
35
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