
==== Front
Turk J BiolTurk. J. BiolTurkish Journal of Biology1300-01521303-6092The Scientific and Technological Research Council of Turkey 10.3906/biy-1810-2ArticleSystematic analysis of the frequently amplified 2p15-p16.1 locus reveals PAPOLG as a potential proto-oncogene in follicular and transformed follicular lymphoma KURŞUN Deniz https://orcid.org/0000-0002-1253-124223KÜÇÜK Can https://jason77@example.com
1 
Department of Medical Biology, Faculty of Medicine, Dokuz Eylül University
,
Ä°zmir
,
Turkey

2 
Ä°zmir Biomedicine and Genome Center (IBG)
,
Ä°zmir
,
Turkey

3 
İzmir International Biomedicine and Genome Institute (iBG-İzmir), Dokuz Eylül University
,
Ä°zmir
,
Turkey
CONFLICT OF INTEREST: 

none declared

2019 5 4 2019 43 124 132 Copyright © 2019 The Author(s)2019This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use and redistribution provided that the original author and source are credited.Transformed follicular lymphoma (tFL) originates from histological transformation of follicular lymphoma (FL), which is the most common indolent non-Hodgkin lymphoma. High-resolution genomic copy-number analysis previously identified frequent amplification of the 2p15-p16.1 locus in FL and tFL cases. The genes (i.e. BCL11A, PAPOLG, PUS10, and USP34) in this amplified locus have not been systematically investigated to date in terms of their role in FL pathogenesis or transformation to tFL. Here we investigated the relationship between amplification and expression of genes in 2p15-p16.1 as well as their expression after histological transformation. NCBI GEO SNP array and gene expression profile (GEP) data of tFL cases were analyzed to evaluate the relationship between amplification and mRNA expression. Moreover, transcript levels of these four genes in FL cases were compared with those of patient-matched tFL cases and normal B-cells. Amplification of the 2p15-p16.1 locus is associated with increased transcription of BCL11A and PAPOLG in tFL cases, of which the latter showed increased expression after histological transformation. Compared with the level in normal B-cells, PAPOLG was significantly overexpressed in FL cases, but expression levels of the other three genes did not show any significant difference. Altogether these results suggest that PAPOLG may be the most critical gene in terms of transformation to tFL.

Amplification2p15-161BCL11APAPOLGPUS10USP34proto-oncogenetFL
==== Body
1. Introduction
Follicular lymphoma (FL) is the second most common
type of lymphoma in the world (Diumenjo et al., 2016). FL occasionally undergoes histological transformation
to higher grade lymphomas such as difuse large B-cell
lymphoma (DLBCL) or Burkitt lymphoma
(Lossos and
Gascoyne, 2011). The characteristic genetic abnormality
of FL and transformed follicular lymphoma (tFL) is
the t(14;18) chromosomal translocation that leads to
constitutive overexpression of BCL2, which promotes
survival of germinal center B-cells
(Tsujimoto et al., 1985). Recurrent mutations in chromatin regulator genes such
as MLL2, EZH2, or CREBBP have been identified to drive
FL tumorigenesis
(Okosun et al., 2014). Recent studies
showed that protection against apoptosis allows
earlystage FL cells to proliferate rapidly and acquire additional
genetic, epigenetic, and metabolic abnormalities associated
with FL pathogenesis
(Küppers and Stevenson, 2018;
Link, 2018; Minoia et al., 2018). However, the full list of
molecular abnormalities related to the development of FL
has not been identified or characterized yet.

Histological transformation of FL to higher grade
malignancies such as DLBCL has been estimated to
occur in ~50% of cases during the course of the disease
(Kridel et al., 2012). These tFL cases have a very aggressive
clinical course with a median survival time of 1.7
years posttransformation
(Al-Tourah et al., 2008)
. P53 mutations (Coco et al., 1993)
and a pluripotency signature related to MYC overexpression (Gentles et al., 2009) have been identified to be associated with transformation of
FL to tFL; however, the full list of molecular aberrations
associated with tFL has not been addressed yet.

Genome-wide copy number analysis of FL and tFL cases
identified recurrent gain/amplification of the 2p15-p16.1
locus that includes BCL11A, PAPOLG, PUS10, REL, and
USP34, which are candidate proto-oncogenes
(Eide et al.,
2010; Bouska et al., 2014)
. A recent report (Hu et al., 2017)
showed a weak correlation between REL amplification
and its mRNA expression. The same study also showed
that ectopic expression of REL marginally promoted cell
growth in an FL cell line in limiting serum concentrations.
Altogether these observations suggest that other gene(s)
located in the amplified 2p15-p16.1 locus may act as
proto-oncogene(s) contributing to the development of
follicular or transformed follicular lymphoma. To the best
of our knowledge, no study has systematically investigated
the role of genes other than REL in the 2p15-p16.1 locus
on the development of FL or tFL.

Some studies functionally characterized BCL11A as a
proto-oncogene in different cancer types. Overexpression
of BCL11A has been shown to promote acute leukemia
using ex vivo and in vivo experimental models
(Yin et
al., 2009). In addition, BCL11A has been shown to be an
oncogene for triple-negative breast cancer with critical
roles in the epithelial stem and progenitor cells (Khaled
et al., 2015). Knock-down of BCL11A led to apoptosis
of a B-cell lymphoma cell line in the presence of a
chemotherapeutic agent (He et al., 2014).

PAPOLG (neo-PAP) was shown to be involved in
the posttranscriptional modification of the 3' ends of
transcripts through the addition of adenine nucleotides
(Kyriakopoulou et al., 2001), which is critical in terms
of mRNA stability and initiation of translation
(Yang et al., 2014)
. PAPOLG was reported to be overexpressed in
some cancer cell types such as breast, colon, ovary, and
pancreas (Topalian et al., 2001)
, suggesting that it may be a proto-oncogene. It is noteworthy that a mutated version of PAPOLG was described as a tumor-associated antigen that
can be recognized by CD4+ T cells in melanoma patients
(Topalian et al., 2002).

USP34 plays a critical role in DNA repair in response
to double-strand breaks, and it may be involved in the
maintenance of genome stability
(Sy et al., 2013). USP34
has been shown to promote Wnt/β-catenin signaling,
which has an important role in several human cancers
(Lui et al., 2011)
. PUS10 (DOBI), a novel pseudouridine synthase
(McCleverty et al., 2007)
, was reported to modify uridine 55 in the TΨC arm of tRNAs (Kamalampeta et al.,
2013). Pseudouridine synthases act as RNA chaperones; they facilitate correct folding and assembly of tRNAs
(McCleverty et al., 2007).

In the present study, we evaluated the relationship
between gene copy number and mRNA expression of
BCL11A, PAPOLG, PUS10, and USP34 genes located in
the frequently amplified 2p15-p16.1 locus in tFL patient
samples, and evaluated whether expression of these genes
increases after histological transformation of FL to tFL.

2. Materials and methods
2.1. Patient samples
The characteristics of the 42 tFL cases used to evaluate
the relationship between amplification and mRNA
expression of genes located in 2p15-p16.1 were defined
previously (Bouska et al., 2014; Hu et al., 2017)
. Similarly, the characteristics of the 12 tFL cases whose patientmatched diagnostic pretransformation FL biopsy samples
were available were also described previously
(Lossos et
al., 2002). The ethics committee approval information
for the patient samples used in this study was provided
in previous studies of the publicly available data. The
available ethical committee numbers are as follows: the
regional committee of Oslo, Norway, for research ethics
(protocol no. S-05 209) and the Institutional Review Board
(IRB) of University of Nebraska Medical Center (no:
IRB# 513-08-EP). The descriptions for DNA and/or RNA
isolation and all subsequent experimental procedures of
SNP array or DNA microarray experiments are available
in the NCBI Gene Expression Omnibus (GEO) database
(accession numbers: GSE67385, GSE81183, GSE3458, and
GSE55267). The characteristics of the tFL cases used in
this study to evaluate the relationship between gene copy
number and expression are shown in Table S1.

2.2. Selection of genes in the 2p15-p16.1 locus for copy
number and expression analyses
The genes evaluated in the present study, which are located
in the frequently amplified 2p15-p16.1 locus, were chosen
based on a previous study that comprehensively analyzed
copy number alterations in FL and tFL cases
(Bouska et
al., 2014). The amplified 2p15-p16.1 locus corresponded
to recurrent copy number aberration (rCNA) ID: 693,
which is a minimal region of abnormality that includes
REL, BCL11A, PAPOLG, PUS10, and USP34 genes. As the
role of REL in FL/tFL pathobiology was characterized in a
recent report (Hu et al., 2017), the other four genes were
evaluated in the current study.

2.3. Selection of DNA microarray probe sets for gene
expression analysis
The sensitivity and specificity values of HG U133 Plus 2.0
DNA microarray probe sets available for the analyzed genes
were determined using the GeneAnnot database (
ChalifaCaspi et al., 2003
). If more than one probe set is available
for a gene, then the one with the highest sensitivity and
specificity value was chosen for subsequent analyses. If
more than one probe set for a gene (e.g., PAPOLG and
USP34) has specificity and sensitivity values equal to
one, then both probe sets were evaluated in transcript
expression analyses.

2.4. Gene copy number and transcript expression analysis
Normalized SNP array (Afymetrix Mapping 250 K Nsp
SNP Array) probe values of the BCL11A, PAPOLG, PUS10,
and USP34 genes were obtained from the NCBI GEO
database (accession number: GSE67385). These probe
values were determined using the Genotyping Console
software (Afymetrix Inc., Santa Clara, CA, USA). Gene
copy numbers were estimated by calculating the average
value of all corresponding SNP array probes for each
gene in 42 tFL samples with available DNA microarray
data (Figures 1A-1D). These 42 tFL cases were then
divided into two 10-sample groups based on the highest
or lowest SNP array probe values for each gene evaluated
(i.e. BCL11A, PAPOLG, PUS10, or USP34). After that, the
NCBI GEO2R gene expression analysis tool
(Barrett et al.,
2013)
was applied to log2-normalized, median centered
Afymetrix Human Genome U133 Plus 2.0 data available
as a part of the GSE81183 data set to address whether
mRNA expression of each of these four genes differed in
tFL cases with low or high gene copy numbers (Figure 2A).
The SNP array probe sets evaluated for these genes were
as follows: BCL11A: SNP_A-1794265, SNP_A-1813498,
SNP_A-2071773, SNP_A-2256538, and SNP_A-4193303;
PAPOLG: SNP_A-1892864, SNP_A-2054939,
and SNP_A-2094019; PUS10: SNP_A-1808220,
SNP_A-2198855, and SNP_A-4208127; USP34:
SNP_A-1788538, SNP_A-1845416, SNP_A-1943045,
SNP_A- 1956271, and SNP_A-1963530.

Figure 1 Copy number estimates of four genes located in the 2p15-p16.1 locus in transformed follicular lymphoma cases. Gene copy numbers were estimated by calculating the average SNP array (Affymetrix mapping 250K Nsp SNP array) probe values for BCL11A
(A), PAPOLG (B), PUS10 (C), and USP34 (D) for each of 42 tFL cases for which corresponding DNA microarray data are also available. Means ± SD for values of SNP array probes are shown for each gene. SNP probes used to estimate the copy number of each gene are described in the Materials and methods section. SD: Standard deviation.

Figure 2 Schematic depiction of the strategies used for mRNA expression analyses of amplified genes in follicular or transformed follicular lymphoma cases. A) Transformed follicular lymphoma cases were divided into two groups based on the high or low copy
number of BCL11A, PAPOLG, PUS10, and USP34, which is determined using the values of normalized SNP array data. mRNA expression values were then analyzed with the GEO2R bioinformatics tool using the available DNA microarray probe sets (GEO accession number:
GSE81184); B) Transcript expression of four amplified genes was evaluated with the GEO2R tool by comparing the expression levels in FL cases vs. normal B cell subsets (GEO accession number: GSE55267); C) Transcript expression levels of the four amplified genes in 12 tFL cases (i.e. DLBCL) were compared one by one with those of pretransformation levels for each tFL case by using the GEO2R tool (GEO accession number: GSE3458).

2.5. Evaluation of transcript levels of the amplified genes
in FL cases and normal B cell subsets
The transcript expression level of the genes located in the
2p15-p16.1 amplicon was determined in FL cases (n = 63)
and normal B-cell subsets (n = 6) by applying the GEO2R
bioinformatics tool to the normalized GEP data set
available as a part of the NCBI GEO database (accession
number: GSE55267) by comparing the expression levels
in FL cases to those in normal B cell subsets (Figure 2B).
Similarly, transcript expression levels of these genes in FL
cases were compared using GEO2R by dividing the FL
cases into low- and high-grade groups (i.e. stage 1–2 vs.
stage 3–3a) using the metadata available in GSE55267.

2.6. Comparison of mRNA expression levels of genes in
the 2p15-p16.1 locus in tFL cases before and after
histological transformation
Previously reported gene expression profiles of 12 tFL
cases, which were derived from the Lymphochip cDNA
microarray platform, were obtained from the NCBI GEO
database (accession number: GSE3458). The Lymphochip
microarray platform consists of 37,632 hotspots that
represent 32,876 unique cDNA clones. In this microarray
platform, the posttransformation (i.e. tFL) and the
diagnostic FL samples that were obtained from the same
patients were labeled with Cy5 or Cy3 uflorescent dye,
respectively. For each transcript, the Cy5 to Cy3 ratio
was used to calculate the fold-change in expression after
histological transformation of FL cases (Figure 2C).
Relative transcript expression values from BCL11A cDNA
clones (clone IDs: 7940 and 18549), PAPOLG (clone IDs:
845 and 6572), PUS10 (clone IDs: 32285 and 12710), and
USP34 (clone IDs: 21935) were determined using the
NCBI GEO2R gene expression analysis tool
(Barrett et al.,
2013) in these tFL cases.

2.7. Statistical analysis
A two-sample Student's t-test was applied to evaluate the
statistical significance for the difference observed in mRNA
expression of the evaluated genes between tFL cases with
amplification and tFL cases without amplification using
Microsoft Excel 2016. Any difference with P < 0.05 was
considered statistically significant.

3. Results
3.1. BCL11A and PAPOLG are significantly
overexpressed in tFL cases with amplification
Forty-two tFL cases (Bouska et al., 2014; Hu et al., 2017)
were divided into two subgroups based on the average
probe intensity values of each of BCL11A, PAPOLG,
PUS10, and USP34 to compare expression levels in cases
with or without amplification of these genes. Analysis of
mRNA expression values using the GEO2R tool showed
significantly increased BCL11A mRNA expression in tFL
cases with a high copy number compared to cases with
a low copy number of the corresponding gene (Figure 3A). Interestingly, PAPOLG showed significantly higher
mRNA levels in tFL cases with amplification of PAPOLG
(Figure 3B). Transcript expression of PUS10 or USP34 did
not show overexpression in the cases with amplification
compared to the cases with normal gene copy numbers
(Figures 3C and 3D).

Figure 3 Amplification of BCL11A or PAPOLG is associated with increased transcript expression levels in transformed follicular lymphoma cases. mRNA expression levels of tFL cases with BCL11A (A), PAPOLG (B), PUS10 (C), and USP34 (D) amplifications were
compared to those with no amplification of the corresponding gene using probe set values (NCBI GEO dataset: GSE81183) individually and displayed using box-and-whisker plots (t-test, *: P < 0.01). n.s: nonsignificant.

3.2. PAPOLG and PUS10 mRNA expression increases
after histological transformation to tFL
To address whether expression of genes located in 2p15-p16.1
increases in FL samples after histological transformation to
aggressive B-cell lymphoma (e.g., DLBCL), we evaluated
whether mRNA expression of genes in 2p15-p16.1 (i.e.
BCL11A, PAPOLG, PUS10, and USP34) increased in 12
FL cases after histological transformation to tFL using the
NCBI GEO2R bioinformatics tool (Figure 4). We did not
observe upregulation of BCL11A mRNA expression in most
of the tFL cases analyzed using two different BCL11A cDNA
clones (Figure 4A). PAPOLG and PUS10 mRNA expression
increased in 75% of FL cases (9 of 12 cases) (Figures 4B and 4C). Most cases did not show upregulation of USP34
expression after histological transformation to tFL (Figure 4D).

Figure 4 Transcript expression levels of PAPOLG or PUS10 increase in transformed follicular lymphoma tumors compared with those of patient-matched pretransformation tumors. The change in BCL11A (A), PAPOLG (B), PUS10 (C), and USP34 (D) mRNA expression
in 12 tFL cases compared to that of pretransformation levels was shown using cDNA microarray clones available in the Lymphochip platform. Clone IDs for each gene are shown near each plot (NCBI GEO accession number: GSE3458).

3.3. PAPOLG is overexpressed in follicular lymphoma
cases compared to normal B cells
Next, transcript expression levels of the four amplified
genes were evaluated in FL cases (n = 63) and normal
B-cell subsets (n = 6) to observe whether their expression
is upregulated in FL cases. Of all four evaluated genes,
only PAPOLG showed significant upregulation of mRNA
expression in FL cases, whereas no significant change was
observed for the transcript levels of BCL11A, PUS10, and
UPS34 genes (Figures 5A–5D).

Figure 5 Transcript expression levels of PAPOLG are significantly higher in follicular lymphoma cases compared to the levels in normal B cells. Expression levels of BCL11A (A), PAPOLG (B), PUS10 (C), and USP34 (D) genes were evaluated in FL cases (n = 63) and normal B cell subsets (n = 6) using the GEP data available (GEO accession number: GSE55267). The expression levels of each gene are shown
with box-and-whisker plots (t-test, *: P < 0.05, **: P < 0.01).

3.4. Comparison of the expression of amplified genes in
low- and high-grade follicular lymphoma cases
To address whether any of the amplified genes show higher
expression in high-stage FL cases, transcript expression of
genes in the 2p15-16.1 locus were determined in 41 high
(i.e. stage 3–3a) and 18 low (i.e. stage 1–2) stage FL cases
using the GEO2R bioinformatics tool by reanalyzing the
GEP data available in GSE55267. No significant difference
in gene expression was observed for any of the four
evaluated genes in these FL tumor samples (Figures 6A–6D).

Figure 6 The relationship between expression of amplified genes in low- and high-grade follicular lymphoma cases. Transcript expression levels of BCL11A (A), PAPOLG (B), PUS10 (C), and USP34 (D) in low grade (stage 1–2) and high grade (stage 3–3a) FL
cases are shown with box-and-whisker plots.

4. Discussion
Recurrent genomic gains/amplifications may lead to
the activation of proto-oncogenes through elevated
transcript expression. In most cases, elevated transcript
levels lead to increased protein expression of these
protooncogenes
(Bhargava et al., 2005; Borah et al., 2015)
. This
amplification-related elevated expression has been shown
to promote tumorigenesis in breast cancer cells through
constitutive activation of the Akt signaling pathway
(She
et al., 2008)
or chemotherapy resistance in solid tumors
such as lung cancer (Engelman et al., 2007) and breast
cancer
(Li et al., 2010)
. Interestingly, amplification of
oncogenes such as n-MYC in neuroblastoma
(Brodeur et
al., 1984)
or HER2/NEU amplification in breast carcinoma
(Press et al., 1997) was shown to predict poor prognosis
in cancer patients. Recurrent gains/amplifications have
also been commonly observed in lymphoid malignancies.
For instance, amplification of BMI-1, a proto-oncogene
involved in regulation of proliferation and senescence
(Jacobs et al., 1999), was reported to be associated with
high BMI-1 expression in mantle cell lymphoma cases
(Bea
et al., 2001)
. Similarly, another study reported upregulation
of the FOXP1 proto-oncogene due to trisomy 3 or focal
amplifications in activated B-cell (ABC)-type DLBCL
(Lenz
et al., 2008)
. In particular, recurrent gain/amplification
of the 2p15-p16.1 locus, where REL, BCL11A, PAPOLG,
PUS10, and USP34 genes reside, is a common observation
in different lymphoma types including classical Hodgkin
lymphoma
(Martin-Subero et al., 2002)
and transformed
follicular lymphoma
(Bouska et al., 2014)
.



Our results suggest PAPOLG as a proto-oncogene
candidate potentially critical in FL tumorigenesis or
histological transformation of FL to tFL due to the following
observations. First, gain/amplification of PAPOLG leads to
its increased transcript expression in amplified tFL cases.
Second, PAPOLG expression increases in most FL cases
after transformation to tFL. Third, it is overexpressed
in FL cases compared to normal B cell subsets. These
observations together with the previous studies that
reported overexpression of PAPOLG (neo-PAP) in
many cancer types
(Topalian et al., 2001)
suggest that its
overexpression may have critical consequences during
the development of FL or tFL through elevated transcript
polyadenylation that may result in a more aggressive tumor
phenotype as observed for PAP, another poly A polymerase
gene, overexpressed in breast cancer
(Scorilas et al., 2000)
.

In conclusion, systematic analyses of expression of
genes located in the recurrently amplified 2p15-p16 locus
revealed PAPOLG as the most likely candidate
protooncogene in development of FL and transformation of
FL to tFL. These analyses provide the basis for functional
assays in the future that will be needed to elucidate the role
of PAPOLG in these malignancies.

Acknowledgment
We thank the Young Scientists Award Program of the
Turkish Academy of Sciences (TÜBA GEBİP 2017) (C.K.)
for supporting this study.
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