Page 1557 - Hematology_ Basic Principles and Practice ( PDFDrive )

1384 Part VII Hematologic Malignancies

t(4;14). The reasons for this strong association are so far unknown. this region is associated with a poor outcome; however, further studies
Both FGFR3 and MMSET are potential therapeutic targets, and are required in order to ascertain the clear prognostic impact of 1q
several tyrosine kinase inhibitors are currently being tested in order gains. A number of important genes in addition to CKSB are located
to inhibit FGFR3 function. in this region, including the interleukin 6 (IL-6) receptor. 3
The t(14;16)(q32;q23) involves the c-MAF gene located at the
16q23 breakpoint. c-Maf is a basic zipper transcription factor that
positively regulates cyclin D2 and ITGB7 (Table 86.2). Although this GENOMICS
translocation is reported in only 5% of patients with MM, it is
observed in 25% of MM cell lines, suggesting its role in cell prolifera- Expression Profiling
tion as well as its association with aggressive behavior of the disease.
+
t(14;16) is considered to be associated with poor prognosis. The other Several investigators have performed expression profiling of CD138
translocation partner of 14q32 is 20q11, observed in less than 5% myeloma cells using high-density microarrays in order to better
patients. It dysregulates MAFB expression, another basic transcrip- understand the pathobiology of myeloma, develop prognostic models,
tion factor belonging to the MAF family, and it has as yet unclear identify new targets for drug development, and develop personalized
molecular consequences. It is also considered to be associated with a medicine approaches. These studies have identified sequential genetic
poor outcome; however, studies have been very small because of its changes from normal plasma cells to plasma cells from patients with
infrequent occurrence. MGUS and MM, and they have provided clues to the molecular basis
Although c-Myc is increasingly being considered to play a role in for malignant transformation and potential therapeutic targets.
myeloma pathobiology, t(8;14) translocations involving c-Myc are Expression profiling in combination with cytogenetic changes has
rare, unlike Burkitt lymphoma, where it is considered a classic feature. been used to classify myeloma in order both to identify phenotypic
Almost 20% of patients with 14q32 translocation have other partners and molecular subgroups as well as to develop a prognostic scoring
with unclear clinical or molecular significance. system. The molecular classification compared profiles from MM
cells with those from MGUS representing an initial indolent form of
the disease and MM cell lines representing cells with a more aggres-
Deletion 17p sive phenotype. A later, more detailed classification identified differ-
ent subgroups, based mainly on cyclin D gene expression and on the
Loss of the short arm of chromosome 17 [del(17p)] has been described different 14q32 translocations. This molecular classification, refined
in about 10% of patients with early-stage MM. The deletion involves in 2006, identified seven subclasses of myeloma. In this model, the
the major part of the short arm of chromosome 17 with consequent first class was defined by the translocation t(4;14) and was identified
loss of a number of genes, including p53 (Table 86.2). However, p53 by overexpression of the MMSET and/or FGFR3 genes. The second
abnormalities represent an important late event, mostly acquired class was related to the translocation t(14;16) or t(14;20) and was
during evolution and associated with progression to an aggressive defined by upregulation of one of the MAF genes. Cases with
form of the disease. A study of p53 gene mutations in 52 patients CCND1 or CCND3 upregulation [owing to the translocations
with myeloma showed that 7 of 52 patients had p53 abnormalities, t(11;14) or t(6;14)] clustered in two different classes, CD1 (class 3)
all with an advanced, clinically aggressive acute/leukemic stage of and CD2 (class 4). The CD2 group was characterized by CD20
MM. Patients presenting with del(17p) have a poor prognosis, despite expression. The fifth group was characterized by hyperdiploidy. The
the use of novel agent combinations or HDT and transplant. Muta- last two groups were characterized by a low incidence of bone disease,
tions of the TP53 gene are uncommon events in myeloma, especially according to low Dickkopf-related protein 1 (DKK1) expression,
at diagnosis. 3 whereas the last group was characterized by increased expression of
genes involved in proliferation. This molecular classification has been
further modified by the Dutch-Belgian Hemato-Oncology Group
Deletion 13q14 (HOVON) group. This analysis did not confirm the “low bone
disease” group, but three other subgroups were identified: one group
Deletion of chromosome 13 or part of its long arm is detected in characterized by overexpression of cancer testis antigen genes, another
approximately 15% to 20% of the patients by conventional cytoge- group defined by overexpression of positive regulators of the nuclear
netics and by interphase FISH in 50% of the patients. Interestingly, factor-κB (NFκB) pathway, and a third subgroup enriched for
5
del(13q) is also detected in 50% of patients with MGUS by FISH, “myeloid” genes (unclear significance). Various prognostic signatures
predominantly in a small subpopulation of cells, indicating that it is have also been developed using these expression profile data to
a secondary genetic event occurring after initial clonal expansion. identify high-risk disease. RNA sequencing is now replacing
Although the retinoblastoma gene is present in the deleted region, microarray-based expression profiling, providing additional genomic
the exact molecular consequence of del(13q) has not yet been ascer- correlates including transcriptome modifiers and splicing.
tained. A number of studies, especially with conventional agents as
well as HDT, have identified del (13q) to be a poor prognostic feature
in myeloma; however, recent studies have identified that there is an Copy Number Alteration
association between del (13q) and t(4;14), and in absence of t(4;14),
del(13q) by itself is not associated with a poor prognosis, especially DNA-based high-throughput techniques such as array comparative
3
with the use of novel agents. However, del(13q) detected by conven- genomic hybridization (CGH) and high-density single-nucleotide
tional cytogenetics is still considered a poor prognostic feature. polymorphism (SNP) arrays have identified recurrent copy number
Interestingly, del(13q) is also common in chronic lymphocytic leu- alterations (CNAs). These studies have identified significant molecu-
6
kemia but does not confer an adverse prognosis. lar heterogeneity (Fig. 86.2). CNAs have been observed in 98% of
192 newly diagnosed patients with MM. Two distinct groups were
observed. One group of patients showed a hyperdiploid phenotype
Abnormalities of the 1q Region with gains of chromosomes 3, 5, 7, 9, 11, 15, 18, 19, and 21 and/
or loss of chromosomes 13, 22, and X (in female cases). The second
Recent studies have reported the biologic role and prognostic implica- group is characterized by gain or loss of subchromosomal region.
tions of a gain of 1q. In fact, this is one of the most frequently These include deletion of 1p, 6q, 8p, 12p, 14q, 16p, 16q, and 20p
reported cytogenetic abnormalities in MM, being described in about as well as amplification of 1q and 6p. The genomic heterogeneity
one-third of the patients. This abnormality has also been reported in observed within the hyperdiploid group is driven by the presence of
a number of other hematologic and solid tumors. A gain of the 1q21 either gain of copies of chromosome 1q and/or chromosome 11,
chromosomal region or overexpression of the CKS1B gene located in chromosome 13 loss, or chromosome 5 gain. Subclasses of