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1 RPL5 on 1P22.1 Is Recurrently Deleted in Multiple Myeloma and Its

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1 RPL5 on 1P22.1 Is Recurrently Deleted in Multiple Myeloma and Its CORE Metadata, citation and similar papers at core.ac.uk Provided by Lirias 1 RPL5 on 1p22.1 is recurrently deleted in multiple myeloma and its expression is linked 2 to bortezomib response 3 4 Isabel JF Hofman1, Mark Van Duin2, Elke De Bruyne3, Laura Fancello1, George Mulligan4, 5 Ellen Geerdens5,6, Emanuela Garelli7, Cecilia Mancini8, Heidi Lemmens9, Michel Delforge9, 6 Peter Vandenberghe9, Iwona Wlodarska5, Anna Aspesi10, Lucienne Michaux9, Karin 7 Vanderkerken3, Pieter Sonneveld2, Kim De Keersmaecker1 8 9 1 KU Leuven - University of Leuven, Department of Oncology, LKI - Leuven Cancer Institute, 10 Leuven, Belgium 11 2 Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands 12 3 Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit 13 Brussels (VUB), Brussels, Belgium 14 4 Takeda Pharmaceuticals International Co., Cambridge, MA, USA 15 5 KU Leuven - University of Leuven, Center for Human Genetics, LKI - Leuven Cancer 16 Institute, Leuven, Belgium 17 6 VIB Center for the Biology of Disease, Leuven, Belgium 18 7 Dipartimento Scienze della Sanità Pubblica e Pediatriche, Univ.Torino, Torino, Italy 19 8 Dipartimento di Scienze Mediche, Univ.Torino, Torino, Italy 20 9 Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium 21 10 Department of Health Sciences, Universita' del Piemonte Orientale, Novara, Italy 22 23 24 25 26 27 CORRESPONDENCE 28 Kim De Keersmaecker, Campus Gasthuisberg O&N1, box 603, Herestraat 49, 3000 Leuven. 29 Tel 0032 16 373167 30 [email protected] 31 32 33 DISCLOSURE OF CONFLICTS OF INTEREST 34 GM discloses employment with Takeda Pharmaceuticals International Co. 35 36 37 WORD COUNTS: 38 Abstract (max 200): 200 39 Main text (excluding abstract, legends, disclosures, acknowledgements, contributions and 40 refs; max 4000): 3941 41 Figures: 5 42 Tables: 2 43 References (max 60): 38 44 45 1 46 ABSTRACT 47 48 Chromosomal region 1p22 is deleted in ≥20% of multiple myeloma (MM) patients, suggesting 49 the presence of an unidentified tumor suppressor. Using high-resolution genomic profiling, we 50 delimit a 58 kb minimal deleted region (MDR) on 1p22.1 encompassing two genes: ectopic 51 viral integration site 5 (EVI5) and ribosomal protein L5 (RPL5). Low mRNA expression of 52 EVI5 and RPL5 was associated with worse survival in diagnostic cases. Patients with 1p22 53 deletion had lower mRNA expression of EVI5 and RPL5, however, 1p22 deletion status is a 54 bad predictor of RPL5 expression in some cases, suggesting that other mechanisms 55 downregulate RPL5 expression. Interestingly, RPL5 but not EVI5 mRNA levels were 56 significantly lower in relapsed patients responding to bortezomib and; both in newly 57 diagnosed and relapsed patients, bortezomib treatment could overcome their bad prognosis 58 by raising their progression-free survival to equal that of patients with high RPL5 expression. 59 In conclusion, our genetic data restrict the MDR on 1p22 to EVI5 and RPL5 and although the 60 role of these genes in promoting MM progression remains to be determined, we identify RPL5 61 mRNA expression as a biomarker for initial response to bortezomib in relapsed patients and 62 subsequent survival benefit after long-term treatment in newly diagnosed and relapsed 63 patients. 64 2 65 INTRODUCTION 66 67 Multiple myeloma (MM) accounts for up to 10% of all hematologic malignancies. Patient 68 outcome has improved significantly in the last decade, partially due to the introduction of 69 novel agents, such as immunomodulatory drugs (IMiDs) as well as the proteasome inhibitors 70 (bortezomib and second generation agents carfilzomib and ixazomib). Nevertheless, not all 71 patients respond to these new drugs, and factors determining response are still poorly 72 understood.1,2 In the light of high costs and higher occurrence of severe side-effects such as 73 peripheral neuropathy associated with bortezomib treatment1,3, future efforts should be 74 directed to developing biomarkers that can identify patients that will benefit from a particular 75 drug or drug scheme. 76 MM, like other cancers, is caused by stepwise accumulation of genetic abnormalities. 77 Chromosomal translocations involving the immunoglobulin heavy (IgH) locus causing 78 overexpression of targeted oncogenes are primary events. The most prevalent of these 79 translocations are t(11;14)(q13;q32) and t(4;14)(p16;q32), each present in 15% of cases. In 80 the absence of IgH translocations, the disease is usually characterized by hyperdiploidy, 81 specifically trisomy of odd chromosomes. Secondary hits then cause progression from 82 asymptomatic monoclonal gammopathy of undetermined significance (MGUS), to smoldering 83 myeloma, and finally to symptomatic myeloma with organ damage and bone lesions. 84 Secondary events consist of mutations, chromosomal translocations and/or copy number 85 changes. The mutational spectrum of MM has recently been characterized using genome 86 wide next generation sequencing, which has revealed a heterogeneous mutational landscape 87 with few recurrently affected genes. Only three genes have been found to be mutated in more 88 than 10% of patients: KRAS (22% of cases), NRAS (20%) and FAM46C (12%).4-7 With regard 89 to chromosomal abnormalities, secondary hits consist of t(8;14)(q24;q32) causing MYC 90 activation, as well as copy number changes, with the most common ones being gains on 1q, 91 3p, 6p, 9p, 11q, 19p, 19q and 21q along with deletions of 1p, 4q, 16q and 22q. For some of 92 these regions, candidate oncogenes and tumor suppressors contributing to disease 93 progression have been identified.3, 8-10 3 94 Among the deleted regions, 1p is one of the most prevalent with up to 30% of myeloma 95 patients carrying the deletion. Four distinct minimally deleted regions (MDRs) have been 96 identified on 1p (1p12, 1p21.3p22.1, 1p31.1 and 1p32.3), of which 1p21.3p22.1 is the most 97 common one (15-22% of patients).11-13 This region is associated with higher incidence of 98 t(4;14)(p16;q32) and deletion of 17p and 13q14, and is a negative prognostic factor for 99 progression-free survival (PFS) and overall survival (OS) in newly diagnosed patients.13 Low 100 expression of several genes on 1p22 is part of a high risk MM gene signature.14 So far, 101 however, no tumor suppressor has been identified on this cytoband. Previously, an MDR of 102 1p21.3p22.1 encompassing 35 genes was defined and MTF2 and TMED5 were proposed as 103 candidate tumor suppressors in this region, as they show differential expression between 104 deleted and non-deleted cases. However, no mutations were found in these genes, low MTF2 105 expression does not affect PFS or OS, and the association between low TMED5 expression 106 and shorter survival is only borderline significant.11,12 107 To uncover potentially clinically relevant tumor suppressors on 1p22, we performed an in- 108 depth genetic analysis of 1p22 in MM. We delineate an MDR encompassing only 2 genes 109 (EVI5 and RPL5) and show for each of these genes that low expression is associated with 110 lower survival in newly diagnosed but not in relapse patients. RPL5 expression is significantly 111 lower in relapse patients with initial response to bortezomib and both newly diagnosed and 112 relapse patients with low RPL5 expression have better PFS when bortezomib is included in 113 their treatment scheme. We thus identify RPL5 expression levels as a novel clinical biomarker 114 for response to bortezomib. 115 116 MATERIALS AND METHODS 117 118 Patient samples 119 We studied 35 advanced diagnostic MM bone marrow samples available at UZ Leuven with at 120 least 70% plasma cells (Supplementary Table 1). All cases were routinely characterized by 121 FISH, as described previously.15 This study was approved by the ethical committee of the UZ 122 Leuven. Copy number, mutation and gene expression data of the Multiple Myeloma Research 123 Consortium (MMRC) (https://www.broadinstitute.org/mmgp/home) were also used. For 4 124 survival analyses, we analyzed data from the phase III HOVON-65/ GMMG-HD4 and APEX 125 trials.16-18 In the phase III HOVON-65/ GMMG-HD4 trial, newly diagnosed MM patients were 126 treated with an experimental PAD protocol (bortezomib, doxorubicin, dexamethasone with 127 bortezomib maintenance) or a conventional VAD protocol (vincristine, doxorubicin, 128 dexamethasone with thalidomide maintenance). In the APEX trial, bortezomib versus high- 129 dose dexamethasone monotherapy was tested in relapsed patients. All study participants 130 provided informed consent to use their data for research purposes and all studies were 131 conducted according to the Declaration of Helsinki. 132 133 High resolution copy number arrays 134 UZ Leuven cases were analyzed on Cytoscan HD arrays (Affymetrix). Data were processed 135 using Chromosome Analysis Suite (ChAS) software (Affymetrix) with hg19 as reference. In 136 order to call a deletion, we required at least 20 consecutive markers with a weighted log2 ratio 137 of -0.15 or less. Raw data is available at NCBI as GEO accession GSE73976. 138 139 Analysis of gene expression levels in patients 140 The 245 MMRC cases with copy number and expression data available on 141 (https://www.broadinstitute.org/mmgp/home) were analyzed. Patients with a log2 copy 142 number ratio >-0.1 for 1p22.1 were considered non-deleted; ratios <-0.6 were considered 143 deleted. Patients with values between -0.1 and -0.6 were excluded. 144 145 Bortezomib response analysis 146 Gene expression array data from the APEX trial were used (GSE9782). Only the bortezomib 147 arm of the trial was used in this analysis. Patients with complete remission, partial response 148 or minimal response were assigned to the group of responders. Patients with no change or 149 progressive disease were considered non-responders. Probe sets with differential signal 150 between responders and non-responders were calculated using limma (Bioconductor).19 The 151 entire list of probe sets was ranked according to log2 fold changes and used as input for 152 Gene Set Enrichment Analysis (GSEA) against the MSigDB C2 KEGG and C1 positional 153 gene sets.20,21 Only GSEA results with a FDR q-value <0.2 were considered.
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