Alberto Risueño Pérez - Gredos - Universidad de Salamanca

Annals of Oncology original article
Table 4. Characteristics of the CLL series (IgVH mutational status,
number of aberrations, FISH subgroup and frequency of recurrent
alterations detected by aCGH) according to the status of disease
(at diagnosis versus progression)
Characteristics Status of disease
At diagnosis (%) Progression (%)
IgVH mutational status
Mutated 63.6 46.7
Unmutated
Number of aberrations
36.4 53.3
£5 64 52.9
>5
FISH subgroup
36 47.1
Normal FISH 38 a
11.8
13q deletion 40 29.4
Trisomy 12 8 41.2 a
17p deletion 6 17.6
11q deletion 6 11.8
t(14q32) 16 5.9
Recurrent alteration by aCGH
Gains
1q21.3–q22 24 17.6
1q31.2 8 29.4
6p21.31–p21.1 18 23.5
10q22.3 6 11.8
11q13.1 24 17.6
11q13.3 20 23.5
12 6 41.2 a
16q23.2–q24.2 22 17.6
17q25.3 20 17.6
18q21.2 6 17.6
20q13.12
Losses
20 17.6
5q13.3–q14.1 8 0
5q31.1 8 0
7q22 4 11.8
11q13.3 16 17.6
11q22.3–q23.1 8 11.8
13q14.2–q14.3 24 11.8
17p13.2–p13.1 10 11.8
18q21.2 8 5.9
a Statistically significant associations (P < 0.05).
aCGH, array comparative genomic hybridization; CLL, chronic
lymphocytic leukemia.
involvement of this region, delineating the commonly gained
region at 20q between 42 188 467–44 495 323 bp (2.31 Mb)
(Figure 1).
gene expression profile confirmed the dosage
effect of aCGH changes
In order to assess the relevance of the genomic imbalances in
gene expression, a gene expression profile study was carried
out. For this purpose, we grouped the cases by aCGH findings.
The group of patients displaying trisomy 12 showed
deregulation of 89 genes when compared with the rest of
patients. A total of 76 of the 89 genes were overexpressed in
relation to the other patients and 56% of them were located on
chromosome 12.
It should be noted that overexpression of the 52 genes
located in 20q13.12 (Figure 1), the 20q region gained by aCGH,
was also observed (P = 0.01). Among these genes, we found
well-known protein-coding cancer-related genes (supplemental
Table S1, available at Annals of Oncology online) such as PI3
(elafin), SLPI (secretory leukocyte peptidase inhibitor) and
WFDC2 [whey acidic protein (WAP) four-disulfide core
domain 2], members of the WAP family; PIGT
(phosphatidylinosotol glycan anchor biosynthesis, class T),
a component of the glycosylphosphatidylinositol (GPI) glycan
transamidase complex; HNF4A (hepatocyte nuclear factor 4,
alpha) and YWHAB (tyrosine 3-monooxygenase/tryptophan
5-monooxygenase activation protein, beta polypeptide),
members of the SMAD and Ras signal transduction pathways,
respectively. In addition, ADA (adenosine deaminase),
a regulator of B-cell proliferation, overexpression was also
present in CLL cases with gains on 20q.
Moreover, in patients with the 17p13 deletion, a significant
proportion (83%) of the differentially underexpressed genes
clustered in this region (P < 0.05). Among the downregulated
genes were GPS2 (G protein pathway suppressor 2)/AMF1, SGSM2
(small G protein signaling modulator 2), DRG2 (developmentally
regulated GTP-binding protein 2), SAT2 (spermidine/spermine
N1-acetyltransferase family member 2) and C17orf49
(chromosome 17 open reading frame 49). This gene dosage effect
was also observed in CLL patients showing 11q-. Thus, all the genes
located in the minimal region of deletion observed with aCGH on
11q22.3–q23.2 (108518932–112964950 bp) were downregulated
when compared with the rest of patients (P < 0.01).
discussion
The presence of cytogenetic abnormalities is a hallmark of CLL.
Indeed, these abnormalities have been associated with the
prognosis or progression of the disease and for this reason the
genetic changes have been extensively studied in CLL [30, 31].
The present study integrates genomic and gene expression
profile analyses in a cohort of 67 CLL patients. Overall, the
results enable us to detect hitherto undescribed recurrent
alterations in CLL, such as gains on chromosome 20 and
confirm the dosage effect, not only for the common cytogenetic
abnormalities but also for this new genetic abnormality.
The present study found genomic copy number changes
in 75% of the CLL patients. Our findings are similar to those
previously reported in this disease [19, 22, 23, 32]. Detection
rates of genomic alterations involving loci known to be
associated with CLL occurred at expected frequencies [33] and
overall, correlation between FISH and aCGH was observed
except in the 13q- subgroup. Both FISH and aCGH revealed
that 13q- was an heterogeneous group in size of the deletion
and percentage of cells displaying the abnormality.
Interestingly, when aCGH failed to demonstrate the presence of
13q deletion, FISH data revealed that most of these cases had