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Systematic Analysis of the Frequently Amplified 2P15-P16.1 Locus Reveals PAPOLG As a Potential Proto-Oncogene in Follicular and Transformed Follicular Lymphoma

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Systematic Analysis of the Frequently Amplified 2P15-P16.1 Locus Reveals PAPOLG As a Potential Proto-Oncogene in Follicular and Transformed Follicular Lymphoma Turkish Journal of Biology Turk J Biol (2019) 43: 124-132 http://journals.tubitak.gov.tr/biology/ © TÜBİTAK Research Article doi:10.3906/biy-1810-2 Systematic analysis of the frequently amplified 2p15-p16.1 locus reveals PAPOLG as a potential proto-oncogene in follicular and transformed follicular lymphoma 1,2 1,2,3, Deniz KURŞUN , Can KÜÇÜK * 1 İzmir International Biomedicine and Genome Institute (iBG-İzmir), Dokuz Eylül University, İzmir, Turkey 2 İzmir Biomedicine and Genome Center (IBG), İzmir, Turkey 3 Department of Medical Biology, Faculty of Medicine, Dokuz Eylül University, İzmir, Turkey Received: 01.10.2018 Accepted/Published Online: 07.12.2018 Final Version: 05.04.2019 Abstract: 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. Key words: Amplification, 2p15-16.1, BCL11A, PAPOLG, PUS10, USP34, proto-oncogene, tFL 1. Introduction Histological transformation of FL to higher grade Follicular lymphoma (FL) is the second most common malignancies such as DLBCL has been estimated to type of lymphoma in the world (Diumenjo et al., 2016). occur in ~50% of cases during the course of the disease FL occasionally undergoes histological transformation (Kridel et al., 2012). These tFL cases have a very aggressive to higher grade lymphomas such as diffuse large B-cell clinical course with a median survival time of 1.7 lymphoma (DLBCL) or Burkitt lymphoma (Lossos and years posttransformation (Al-Tourah et al., 2008). P53 Gascoyne, 2011). The characteristic genetic abnormality mutations (Coco et al., 1993) and a pluripotency signature of FL and transformed follicular lymphoma (tFL) is related to MYC overexpression (Gentles et al., 2009) have the t(14;18) chromosomal translocation that leads to been identified to be associated with transformation of constitutive overexpression of BCL2, which promotes FL to tFL; however, the full list of molecular aberrations survival of germinal center B-cells (Tsujimoto et al., 1985). associated with tFL has not been addressed yet. Recurrent mutations in chromatin regulator genes such Genome-wide copy number analysis of FL and tFL cases as MLL2, EZH2, or CREBBP have been identified to drive identified recurrent gain/amplification of the 2p15-p16.1 FL tumorigenesis (Okosun et al., 2014). Recent studies locus that includes BCL11A, PAPOLG, PUS10, REL, and showed that protection against apoptosis allows early- USP34, which are candidate proto-oncogenes (Eide et al., stage FL cells to proliferate rapidly and acquire additional 2010; Bouska et al., 2014). A recent report (Hu et al., 2017) genetic, epigenetic, and metabolic abnormalities associated showed a weak correlation between REL amplification with FL pathogenesis (Küppers and Stevenson, 2018; and its mRNA expression. The same study also showed Link, 2018; Minoia et al., 2018). However, the full list of that ectopic expression of REL marginally promoted cell molecular abnormalities related to the development of FL growth in an FL cell line in limiting serum concentrations. has not been identified or characterized yet. Altogether these observations suggest that other gene(s) * Correspondence: [email protected] 124 This work is licensed under a Creative Commons Attribution 4.0 International License. KURŞUN and KÜÇÜK / Turk J Biol located in the amplified 2p15-p16.1 locus may act as matched diagnostic pretransformation FL biopsy samples proto-oncogene(s) contributing to the development of were available were also described previously (Lossos et follicular or transformed follicular lymphoma. To the best al., 2002). The ethics committee approval information of our knowledge, no study has systematically investigated for the patient samples used in this study was provided the role of genes other than REL in the 2p15-p16.1 locus in previous studies of the publicly available data. The on the development of FL or tFL. available ethical committee numbers are as follows: the Some studies functionally characterized BCL11A as a regional committee of Oslo, Norway, for research ethics proto-oncogene in different cancer types. Overexpression (protocol no. S-05 209) and the Institutional Review Board of BCL11A has been shown to promote acute leukemia (IRB) of University of Nebraska Medical Center (no: using ex vivo and in vivo experimental models (Yin et IRB# 513-08-EP). The descriptions for DNA and/or RNA al., 2009). In addition, BCL11A has been shown to be an isolation and all subsequent experimental procedures of oncogene for triple-negative breast cancer with critical SNP array or DNA microarray experiments are available roles in the epithelial stem and progenitor cells (Khaled in the NCBI Gene Expression Omnibus (GEO) database et al., 2015). Knock-down of BCL11A led to apoptosis (accession numbers: GSE67385, GSE81183, GSE3458, and of a B-cell lymphoma cell line in the presence of a GSE55267). The characteristics of the tFL cases used in chemotherapeutic agent (He et al., 2014). this study to evaluate the relationship between gene copy PAPOLG (neo-PAP) was shown to be involved in number and expression are shown in Table S1. the posttranscriptional modification of the 3’ ends of 2.2. Selection of genes in the 2p15-p16.1 locus for copy transcripts through the addition of adenine nucleotides number and expression analyses (Kyriakopoulou et al., 2001), which is critical in terms The genes evaluated in the present study, which are located of mRNA stability and initiation of translation (Yang et in the frequently amplified 2p15-p16.1 locus, were chosen al., 2014). PAPOLG was reported to be overexpressed in based on a previous study that comprehensively analyzed some cancer cell types such as breast, colon, ovary, and copy number alterations in FL and tFL cases (Bouska et pancreas (Topalian et al., 2001), suggesting that it may be a al., 2014). The amplified 2p15-p16.1 locus corresponded proto-oncogene. It is noteworthy that a mutated version of to recurrent copy number aberration (rCNA) ID: 693, PAPOLG was described as a tumor-associated antigen that which is a minimal region of abnormality that includes can be recognized by CD4+ T cells in melanoma patients REL, BCL11A, PAPOLG, PUS10, and USP34 genes. As the (Topalian et al., 2002). role of REL in FL/tFL pathobiology was characterized in a USP34 plays a critical role in DNA repair in response recent report (Hu et al., 2017), the other four genes were to double-strand breaks, and it may be involved in the evaluated in the current study. maintenance of genome stability (Sy et al., 2013). USP34 has been shown to promote Wnt/β-catenin signaling, 2.3. Selection of DNA microarray probe sets for gene ex- which has an important role in several human cancers pression analysis (Lui et al., 2011). PUS10 (DOBI), a novel pseudouridine The sensitivity and specificity values of HG U133 Plus 2.0 synthase (McCleverty et al., 2007), was reported to modify DNA microarray probe sets available for the analyzed genes uridine 55 in the TΨC arm of tRNAs (Kamalampeta et al., were determined using the GeneAnnot database (Chalifa- 2013). Pseudouridine synthases act as RNA chaperones; Caspi et al., 2003). If more than one probe set is available they facilitate correct folding and assembly of tRNAs for a gene, then the one with the highest sensitivity and (McCleverty et al., 2007). specificity value was chosen for subsequent analyses. If In the present study, we evaluated the relationship more than one probe set for a gene (e.g., PAPOLG and between gene copy number and mRNA expression of USP34) has specificity and sensitivity values equal to BCL11A, PAPOLG, PUS10, and USP34 genes located in one, then both probe sets were evaluated in transcript the frequently amplified 2p15-p16.1 locus in tFL patient expression analyses. samples, and evaluated whether expression of these genes 2.4. Gene copy number and transcript expression analysis increases after histological transformation of FL to tFL. Normalized SNP array (Affymetrix Mapping 250 K Nsp SNP Array) probe values of the BCL11A, PAPOLG, PUS10, 2. Materials and methods and USP34 genes were obtained from the NCBI GEO 2.1. Patient samples database (accession number: GSE67385). These probe The characteristics of the 42 tFL cases used to evaluate values were determined using the Genotyping Console the relationship between amplification and mRNA software (Affymetrix Inc., Santa Clara, CA, USA). Gene expression of genes located in 2p15-p16.1 were defined copy numbers were estimated by calculating the average previously (Bouska et al., 2014; Hu et al., 2017). Similarly, value of all corresponding SNP array probes for each the characteristics of the 12 tFL cases whose patient- gene in 42 tFL samples with available DNA microarray 125 KURŞUN and KÜÇÜK / Turk J Biol data (Figures 1A–1D).
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