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Identification of Copy Number Abnormalities and Inactivating Published OnlineFirst April 7, 2009; DOI: 10.1158/0008-5472.CAN-08-3701 Published Online First on April 7, 2009 as 10.1158/0008-5472.CAN-08-3701 Research Article Identification of Copy Number Abnormalities and Inactivating Mutations in Two Negative Regulators of Nuclear Factor-KB Signaling Pathways in Waldenstro¨m’s Macroglobulinemia Esteban Braggio,1 Jonathan J. Keats,1 Xavier Leleu,2 Scott Van Wier,1 Victor H. Jimenez-Zepeda,1 Riccardo Valdez,1 Roelandt F.J. Schop,1 Tammy Price-Troska,3 Kimberly Henderson,3 Antonio Sacco,2 Feda Azab,2 Philip Greipp,3 Morie Gertz,3 Suzanne Hayman,3 S. Vincent Rajkumar,3 John Carpten,4 Marta Chesi,1 Michael Barrett,4 A. Keith Stewart,1 Ahmet Dogan,3 P. Leif Bergsagel,1 Irene M. Ghobrial,2 and Rafael Fonseca1 1Mayo Clinic, Scottsdale, Arizona; 2Dana-Farber Cancer Institute, Boston, Massachusetts; 3Mayo Clinic, Rochester, Minnesota; and 4Translational Genomics, Phoenix, Arizona Abstract still unknown. Although believed to be predominantly sporadic, Waldenstro¨m’s macroglobulinemia (WM) is a distinct clinico- familial cases suggest a possible predisposing genetic defect (2, 3). biological entity defined as a B-cell neoplasm characterized by The genetic basis of the disease remains poorly defined. Few a lymphoplasmacytic infiltrate in bone marrow (BM) and IgM recurrent chromosomal abnormalities have been reported in WM, paraprotein production. Cytogenetic analyses were historical- reflecting the difficulty in obtaining tumor metaphases for ly limited by difficulty in obtaining tumor metaphases, and the karyotype studies. Deletion of 6q is the most common abnormality, genetic basis of the disease remains poorly defined. Here, we identified in approximately half of the patients when analyzed by performed a comprehensive analysis in 42 WM patients by fluorescence in situ hybridization (FISH; ref. 4). To a lesser extent, using a high-resolution, array-based comparative genomic trisomy of chromosome 4(5) and 13q14and 17p13 deletions have hybridization approach to unravel the genetic mechanisms been described. Deletions on 13q14and 17p13 are mainly associated associated with WM pathogenesis. Overall, 83% of cases have with advance disease (6). On the other hand, no high-resolution chromosomal abnormalities, with a median of three abnor- whole-genome approaches have been used in the study of WM. n n malities per patient. Gain of 6p was the second most common Nuclear factor- B (NF- B) comprises a family of transcription abnormality (17%), and its presence was always concomitant factors that regulate the transcription of hundreds of genes with 6q loss. A minimal deleted region, including MIRN15A involved in inflammation, innate immunity, cell growth, and n and MIRN16-1, was delineated on 13q14 in 10% of patients. Of apoptosis (7). NF- B transcription factors are homodimeric and interest, we reported biallelic deletions and/or inactivating heterodimeric complexes formed by five members of the Rel n n mutations with uniparental disomy in tumor necrosis factor family: NF- B1 (p50), NF- B2 (p52), RELA (p65), RELB, and c-REL. n (TNF) receptor–associated factor 3 and TNFa-induced protein Two signaling pathways are involved in the regulation of NF- B 3, two negative regulators of the nuclear factor-KB (NF-KB) complexes (canonical and noncanonical), which are respectively signaling pathway. Furthermore, we confirmed the association responsible for the activation of p50 and p52 from their inactive between TRAF3 inactivation and increased transcriptional precursors p105 and p100 (8, 9). The activation of these pathways activity of NF-KB target genes. Mutational activation of the NF- results in the translocation of p50/RELA and p52/RELB complexes KB pathway, which is normally activated by ligand receptor into the nucleus and the subsequent transcriptional activation of interactions within the BM microenvironment, highlights its target genes. Constitutive activation of the NF-nB pathways, either biological importance, and suggests a therapeutic role for by inactivating mutations of negative regulators or up-regulation of inhibitors of NF-KB pathway activation in the treatment of positive regulators, has been linked to several tumor types (10, 11), WM. [Cancer Res 2009;69(8):3579–88] but the molecular basis has remained largely unknown. Recently, we identified abnormalities affecting 11 regulator genes of the NF- n Introduction B pathways in at least 17% of multiple myeloma (MM) patients and 41.3% of human myeloma cell lines (HMCL), resulting in Waldenstro¨m’s macroglobulinemia (WM) is an incurable low- the activation of NF-nB (12). Tumor necrosis factor (TNF) grade B-cell lymphoproliferative disorder characterized by bone receptor–associated factor 3 (TRAF3), a negative regulator of the marrow (BM) infiltration of a clonal population of small B noncanonical NF-nB pathway, was the most commonly affected lymphocytes, plasmacytoid lymphocytes, and plasma cells that gene, with inactivating abnormalities identified in f12% of secrete monoclonal IgM antibody (1). The etiology of the disease is patients (12). Additional inactivating abnormalities were identified in other negative NF-nB regulators (CYLD, cIAP1, cIAP2, and Note: Supplementary data for this article are available at Cancer Research Online TRAF2), as well as gain-of-function mutations in positive regulators (http://cancerres.aacrjournals.org/). (MAP3K14/NIK, NF-jB1, NF-jB2, CD40, LTBR, and TNFRSF13B/ Requests for reprints: Rafael Fonseca, Mayo Clinic Cancer Center, 13400 East Shea Boulevard, Collaborative Research Building, 3-006 Scottsdale, AZ 85259-5494. TACI) of NF-nB signaling, albeit less frequently (12, 13). Based on Phone: 480-301-4280/480-301-8335; Fax: 480-301-8387/480-301-8572; E-mail: these observations and previous studies in other B-cell neoplasias [email protected]. I2009 American Association for Cancer Research. (14–16), we hypothesized that abnormalities in genes that regulate doi:10.1158/0008-5472.CAN-08-3701 the NF-nB pathways might also be present in WM. www.aacrjournals.org 3579 Cancer Res 2009; 69: (8). April 15, 2009 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst April 7, 2009; DOI: 10.1158/0008-5472.CAN-08-3701 Cancer Research Table 1. Delineation of MDRs and MARs based on recurrent abnormalities identified in >5% of patients Cytoband Chromsome position (bp) Loss (%) Gain (%) Size (Mb) Expressed CIG 3q13.3-q28 chr3: 121238508-199379625 9.5 78.1 4q13.1-q35.2 chr4: 65598026-191173837 11.9 125.6 6p12.2-p25 chr6: 1-39874314 16.6 39.8 6q16.1 chr6: 93266833-97766491 33.3 4.5 MANEA 6q21-q22.1 chr6: 105811723-107183767 38.1 1.4 PRDM1, AIM1 6q23 chr6: 138093510-141518652 38.1 3.4 TNFAIP3 6q25.2-q25.3 chr6: 155012960-159967461 33.3 4.9 No CIG 7q22.1-q22.2 chr7: 99534923-103321939 7.1 3.8 STAG3, CUTL1 8p chr8: 1-43647063 7.1 43.6 8q chr8: 76726872-136133311 9.5 59.4 11q22-q23.3 chr11: 102986825-117384510 7.1 14.4 ATM, DDX10, POU2AF1, SDHD, KIAA0999 11q23.2-q24chr11: 121042811-128566270 7.1 7.5 FLI1 13q14 chr13: 49414571-50454033 9.5 1.0 MIRN15a, MIRN16-1* 17p11.2-p13.3 chr17: 1-17570789 7.1 17.5 NXN, SKIP, KIAA0664, ITGAE, MINK1, ZNF232, USP6, CENTB1, TNK1, TP53, PER1, PIK3R5, DNAH9, MAP2K4, NCOR1, COPS3 18 chr18: 16793910-58926021 16.6 42.1 Xq27.1-q28 chrX: 149024400-154582473 9.5 5.6 BGN, IRAK1, FLNA, F8, MTCP1, BRCC3 NOTE: In regions smaller than 20 Mb were listed the cancer implicated genes expressed in at least 50% of WM patients. Cancer implicated genes include tumor suppressor genes and/or genes with inactivated mutations already described. Abbreviation: CIG, cancer implicated genes. *No CIG were found in 13q14, but microRNAs with proposed cancer implicated function were identified. The aim of this study was to perform a comprehensive, high- the manufacturer’s protocols with some modifications. Briefly, 1.2 Agof resolution, array-based comparative genomic hybridization (aCGH) tumor and reference DNAs were separately digested with bovine DNaseI analysis to identify genomic abnormalities present in WM, (Ambion) for 12 min at room temperature. The normal human reference especially focusing on the status of NF-nB pathway key regulators. DNA is composed of a mixture of DNA derived from multiple female donors (Promega). In patients with low DNA yields, a linear whole-genome We identified biallelic deletions and loss of heterozygosity with n amplification procedure was incorporated before the DNA digestion step inactivating mutations in two negative regulators of the NF- B (GenomiPhi DNA amplification kit; GE Healthcare). Next, random primers signaling pathways, TRAF3 and TNFa-induced protein 3 (TNFAIP3/ and exo-Klenow fragment were used to differentially label tumor (Cy5) and A20), highlighting the role of these pathways in WM pathogenesis. reference (Cy3) genomic DNA samples (Agilent Technologies). Labeled genomic reactions were cleaned up with Microcon YM-30 columns j Materials and Methods (Millipore) and hybridized at 65 C for 40 h. Microarrays were scanned in a DNA Microarray Scanner (Agilent Technologies). Feature extraction Patients. Fifty-seven WM patients were included in this study. Clinical was performed with Feature Extraction Software, version 9.5 (Agilent and laboratory features of the patients are shown in Supplementary Technologies). Data were analyzed using the CGH Analytics 3.5.1 software Table S1. BM samples and lymph node biopsies were collected after (Agilent Technologies). informed consent was obtained in accordance with the Declaration of The abnormalities were identified using a two-probe filter and aberration Helsinki. The Mayo Clinic Institutional Review and Dana-Farber Cancer detection modules 1 and 2 algorithms (17) with thresholds of 7.5 and Institute review boards approved the study. For FISH experiments from BM 5.5, respectively. Based on the study done in 50 healthy Caucasian males by samples, cytospin slides were prepared from ACK lysis buffer–treated BM de Smith and colleagues (18), we identified and eliminated copy number aspirates to remove red blood cells.
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