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Chapter 6 CSE1L, DIDO1 and RBM39 in Colorectal VU Research Portal Chromosome 20q genes in the pathogenesis of colorectal cancer Sillars-Hardebol, A.H. 2012 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Sillars-Hardebol, A. H. (2012). Chromosome 20q genes in the pathogenesis of colorectal cancer. 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Sep. 2021 CHAPTER 6 CSE1L, DIDO1 and RBM39 in colorectal adenoma to carcinoma progression Submitted for publication Anke H Sillars-Hardebol Beatriz Carvalho Jeroen A M Beliën Meike de Wit Pien M Delis-van Diemen Marianne Tijssen Mark A van de Wiel Fredrik Pontén Remond J A Fijneman Gerrit A Meijer Chapter 6 Abstract Background: Gain of chromosome 20q is an important factor in the progression from colorectal adenomas to carcinomas. Genes that drive 20q gain are expected to show cor- relation of mRNA and protein expression levels with 20q DNA copy number status while functionally influencing cancer processes. CSE1L, DIDO1 and RBM39 are located on the 20q amplicon and affect processes such as cell viability and anchorage-independent growth in colorectal cancer. This study aimed to investigate whether CSE1L, DIDO1 and RBM39 may drive 20q amplification. Methods: Protein expression levels were examined by immunohistochemical evaluation of tissue microarrays containing a series of colorectal adenoma and carcinoma samples, which were characterized by genome-wide (microarray-based) DNA and mRNA profil- ing. Results: CSE1L, DIDO1 and RBM39 mRNA expression levels correlated with chromo- some 20q DNA copy number status. CSE1L protein expression was not associated with 20q gain, although its expression was increased in carcinomas compared to adenomas. DIDO1 and RBM39 protein expression was quite strong in the majority of tumors irre- spective of 20q DNA copy number status. Conclusion: The lack of correlation between protein expression levels and 20q DNA copy number status implies that CSE1L, DIDO1 and RBM39 are merely passengers rather than drivers of chromosome 20q gain in colorectal adenoma-to-carcinoma progression. 96 CSE1L, DIDO1 and RBM39 in colon tumour progression Introduction Colorectal cancer (CRC) is the second cause of cancer related deaths in the western world [1]. Worldwide CRC accounts for 600,000 deaths annually. CRC development from normal colon epithelium is initiated by disruption of the WNT signalling pathway which gives rise to benign precursor lesions, i.e. adenomas. Colorectal adenomas can progress into CRC, which is estimated to take place in about 5% of cases [2]. CRC carcinogenesis is driven by multiple genetic alterations, which accumulate in a developing tumor upon introduction of genomic instability. Microsatellite instability (MSI) is caused by failure of the DNA mismatch repair system and leads to accumulation of DNA mutations in approximately 15% of CRCs. Chromosomal instability (CIN) is observed in the majority of CRCs (about 85%) and is characterized by gains and losses of chromosomal regions. These gross aberrations lead to deletion or amplification of tumor suppressor genes, oncogenes, and/or noncoding RNAs such as miRNAs, resulting in aberrant expression of genes that affect cancer-related biological processes [3, 4]. Gain of chromosomal region 20q is frequent in CRC; it is present in more than 60% of carcinomas [5, 6]. Several functional consequence of chromosome 20q gain have been reported; 20q gain has been associated with colorectal adenoma-to-carcinoma progres- sion [6] and it correlates with poor prognosis in CRC patients [7]. Usually, large fragments of the 20q arm are amplified as a whole, suggesting a role of multiple 20q genes on CRC progression. Recently, we confirmed by functional analyses that multiple genes on chromosome 20q contribute to cancer processes [8]. AURKA and TPX2 were identified as genes that promote 20q gain-driven colorectal adenoma-to-carcinoma progression. However, other genes located on 20q also contributed to cancer-related processes, in- cluding CSE1L, DIDO1 and RBM39. CSE1L and RBM39 affect cell viability while CSE1L and DIDO1 contribute to anchorage-independent growth (Supplementary Figure 1) [8]. Therefore, these genes may be drivers of 20q gain associated tumor progression. Chromosomal regions that frequently show increased copy numbers in tumors are be- 6 Chapter lieved to drive carcinogenesis by affecting mRNA and protein expression levels of rel- evant ‘driver’ genes. Therefore, genes whose mRNA and protein expression is influenced by its DNA copy number status are candidate genes that may drive the gain of the am- plicon. From previous studies it is known that increased mRNA expression of genes lo- cated on amplified regions is rare [6, 9]. The aim of the present study was to investigate whether CSE1L, DIDO1 and RBM39 are drivers or merely passengers of 20q gain-driven colorectal adenoma-to-carcinoma progression, by investigation of mRNA and protein expression levels of these genes in colorectal adenomas and carcinomas in relation to chromosome 20q DNA copy number status. Materials and methods Determination of microsatellite instability status MSI status of colorectal tumors was determined using the MSI Analysis System (Promega Corporation, Madison, USA) according to manufacturer’s instructions. This system de- termines the length of five nearly monomorphic mononucleotide repeat markers (BAT- 25, BAT-26, NR-21, NR-24 and MONO-27) and two highly polymorphic pentanucleotide 97 Chapter 6 repeat markers (Penta C and Penta D). PCR products were separated by capillary elec- trophoresis using an ABI 3130 DNA sequencer (Applied Biosystems, Foster City, CA, USA) and analyzed using GeneScan 3100 (Applied Biosystems). An internal lane size standard was added to the PCR samples for accurate sizing of alleles and to adjust for run-to-run variations. When all markers were stable, the tumor was considered microsatellite sta- ble. Tumors with two or more instable markers were regarded to be MSI-High and tumor samples with one instable marker as MSI-Low. For further analysis MSI-Low tumors were classified as MSS. Determination of chromosome 20q DNA copy number status Chromosome 20q DNA copy number status of MSS colorectal tumors could be deter- mined for 120 tumors using two strategies. For tumors of which array CGH (comparative genomic hybridization) data was available (n = 48), the aCGH R package CGHcall was used to define copy number gain and loss by converting 2 log ratios into ordinal data, i.e. ‘+1’ for gain, ‘-1’ for loss, and ‘0’ if no DNA copy number alteration was present [10]. Gain of 20q was defined when at least 14 consecutive probes on chromosome arm 20q showed gain. MLPA (multiplex ligation-dependent probe amplification) was used to determine 20q DNA copy number status of tumors for which no array CGH data was available (n = 72). MLPA was performed as previously described [11-13]. The MLPA probe mixture con- tained 16 probes targeting genes on chromosome 20 and 23 probes targeting genes on chromosomes 8 and 13. A pool of DNA isolated from formalin-fixed paraffin-embedded normal colon mucosa from 20 individuals without CRC was used as reference DNA. For each sample, tumor to normal DNA copy number ratios were calculated per probe by dividing the median peak heights in the tumor tissue by the median peak heights in the reference DNA. In order to perform ratio normalization, the median of the tumor to reference DNA copy number ratios of the control genes in the probe mixture were set to 1.0. Tumors were classified as having chromosome 20q gain when at least 50% of all probes on chromosome 20q showed a ratio of 1.3 or greater. Statistical analysis of array CGH and mRNA expression array data Data on DNA copy number ratio of the actual gene locus and mRNA expression in colorec- tal adenomas and carcinomas have been previously obtained by array CGH (compara- tive genomic hybridization) and mRNA expression microarrays, respectively [6]. Copy number ratios of the actual gene loci were determined by taking the tumor to normal DNA copy number ratio of the BAC (bacterial artificial chromosome) clone that covers the gene locus (e.g RP1-155G6 for CSE1L, RP4-563E14 for DIDO1 and RP11-353C18 for RBM39). The smoothened, but not called, ratio was used as a continuous variable. Dif- ferences in DNA copy number ratio and mRNA expression levels between adenomas and carcinomas and differences between tumors with and without 20q gain were assessed by the Mann-Whitney test. Correlation of array CGH and mRNA expression data was evaluated by Pearson correlation. For statistical analysis of protein expression, tumors were classified into two groups based on the maximum staining score; weak and mod- erate staining versus strong staining. The Chi-Square test was used to compare protein expression between adenomas and carcinomas and tumors with and without 20q gain. All statistical analyses were performed in SPSS (version 15.0 for Windows, SPSS, Chicago, 98 CSE1L, DIDO1 and RBM39 in colon tumour progression Illinois, USA). Immunohistochemical analyses on tissue microarrays Immunohistochemical stainings of CSE1L, DIDO1 and RBM39 were performed on two tissue microarrays containing per tumor up to 3 cores (0.6 mm) from 82 colorectal ad- enomas and 82 carcinomas that were collected retrospectively from 2001 to 2008 at the VU University medical center, Amsterdam, The Netherlands.
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