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signatures for diagnosis, prognosis, and prediction of treatment response for a vari-
ety of human cancers. In the remaining part of this section, we will review in more
detail the current state of development for miRNAs as tissue-based cancer biomark-
ers using CLL and prostate cancer as examples of common hematopoietic and solid
malignancies, respectively. CLL is one of the most extensively studied malignancies
regarding miRNA expression profiling and biomarker potential, whereas prostate
cancer is less well characterized. Hence, existing studies for these diseases exem-
plify different investigatory stages of miRNA biomarker development for cancer.
13.3.3
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is characterized by accumulation of small,
mature B cells and is the most common type of leukemia in Western countries [
136
] .
CLL has a highly variable clinical course. Some patients present with indolent dis-
ease that requires no or little treatment, while others have an aggressive form asso-
ciated with rapid disease progression and death. In a pioneering study from 2002,
Calin et al
.
showed that miR-15a and miR-16-1 are located at 13q14, a commonly
deleted chromosomal region in CLL, and that expression of these miRNAs was
downregulated in more than half of all CLLs [
4
] . This was the fi rst strong evidence
for an association between miRNAs and human cancer. The same group of authors
later showed that miR-15a and miR-16 exert tumor suppressor functions in CLL by
direct targeting of the anti-apoptotic protein BCL2 (B-cell CLL/lymphoma 2) [
6
] ,
suggesting that these miRNAs could have therapeutic potential in CLL. A separate
(Chap. 14) in this topic addresses the utility of miRNAs as cancer therapeutics.
CLL was the first human malignancy to be analyzed by genome-wide miRNA
expression profiling using microarrays [
106
]. The initial study included 41 CLL sam-
ples from 38 patients plus 6 normal samples. The authors identified a miRNA signa-
ture that could distinguish CLL from normal CD5+ B cells as well as three distinct
miRNA signatures associated with known prognostic factors for CLL, i.e., presence
or absence of zeta-chain-associated protein kinase 70-kD (ZAP70) expression, immu-
noglobulin heavy chain variable (IgH
V
) region mutations, and 13q14 deletion, respec-
tively [
106
]. This early study clearly showed the potential of miRNAs for molecular
classification of cancer into clinically and biologically relevant subgroups.
Consistent with this, CLL was the first malignancy for which a miRNA-based
prognostic signature was reported. Using miRNA expression profiles from 94 CLL
samples, Calin et al
.
[
32
] revealed an expression signature composed of 13 miR-
NAs that was significantly associated with known prognostic factors for CLL
(ZAP70 expression and IgH
V
region mutation status) and with disease progression.
It is of note that miR-15a, miR-16-1, miR-29a, miR-29b, miR-29c, and miR-223
were among the 13 miRNAs in this signature. Furthermore, from the original
profiling data set, nine miRNAs (including miR-29c and miR-181a) were found to
be able to predict time to disease progression for patients diagnosed with CLL,
although an independent patient sample set was not used to confirm the results
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