Cytogenetic and Genome Research

Isik S.a· Gunden G.a· Gunduz E.b· Akay O.M.c· Aslan A.d· Ozen H.e· Cilingir O.a· Erzurumluoglu Gokalp E.a· Kocagil S.a· Artan S.a· Gulbas Z.f· Durak Aras B.a,g

Author affiliations

aDepartment of Medical Genetics, Faculty of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey
bDepartment of Hematology, Faculty of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey
cDepartment of Hematology, Faculty of Medicine, University of Koc, Istanbul, Turkey
dDepartment of Hematology, Private Umit Hospital, Eskisehir, Turkey
eDepartment of Biostatistics, Faculty of Medicine, University of Eskisehir Osmangazi, Eskisehir, Turkey
fDepartment of Hematology, Anadolu Medical Center, İzmit, Turkey
gTranslational Medicine Research and Clinical Center, University of Eskisehir Osmangazi, Eskisehir, Turkey

Log in to MyKarger to check if you already have access to this content.

Buy FullText & PDF Unlimited re-access via MyKarger Unrestricted printing, no saving restrictions for personal use read more

CHF 38.00 *
EUR 35.00 *
USD 39.00 *

Select

KAB

Buy a Karger Article Bundle (KAB) and profit from a discount!

If you would like to redeem your KAB credit, please log in.

Save over 20% compared to the individual article price.

Learn more

Rent/Cloud Rent for 48h to view Buy Cloud Access for unlimited viewing via different devices Synchronizing in the ReadCube Cloud Printing and saving restrictions apply Rental: USD 8.50
Cloud: USD 20.00

Select

Subscribe Access to all articles of the subscribed year(s) guaranteed for 5 years Unlimited re-access via Subscriber Login or MyKarger Unrestricted printing, no saving restrictions for personal use read more

Subcription rates

Select

* The final prices may differ from the prices shown due to specifics of VAT rules.

Article / Publication Details

First-Page Preview

Received: August 11, 2021
Accepted: October 15, 2021
Published online: December 15, 2021

Number of Print Pages: 9
Number of Figures: 2
Number of Tables: 6

ISSN: 1424-8581 (Print)
eISSN: 1424-859X (Online)

For additional information: https://www.karger.com/CGR

Abstract

Deletion 13q [del(13q)] is a favorable prognostic marker if it is detected as a sole abnormality in chronic lymphocytic leukemia (CLL). However the clinical courses of cases with isolated del(13q) are quite heterogeneous. In our study, we investigated copy number variations (CNVs), loss of heterozygosity (LOH), and the size of del(13q) in 30 CLL patients with isolated del(13q). We used CGH+SNP microarrays in order to understand the cause of this clinical heterogeneity. We detected del(13q) in 28/30 CLL cases. The size of the deletion varied from 0.34 to 28.81 Mb, and there was no clinical effect of the deletion size. We found new prognostic markers, especially the gain of 16p13.3. These markers have statistically significant associations with short time to first treatment and advanced disease stage. Detecting both CNVs and LOH at the same time is an advantageous feature of aCGH+SNP. However, it is very challenging for the array analysis to detect mosaic anomalies. Therefore, it is very important to confirm the results by FISH. In our study, we detected approximately 9% mosaic del(13q) by microarray. In addition, the gain of 16p13.3 may affect the disease prognosis in CLL. However, additional studies with more patients are needed to confirm these results.

© 2021 S. Karger AG, Basel

References Arnaout H, Allah FG, Khorshid O, Elsaadany Z, Fouad N, Amer M. TSC gene expression in the newly diagnosed Egyptian acute leukemia patients. Comp Clin Pathol. 2018;27:1199–204. Arruga F, Gizdic B, Serra S, Vaisitti T, Ciardullo C, Coscia M, et al. Functional impact of NOTCH1 mutations in chronic lymphocytic leukemia. Leukemia. 2014;28:1060–70. Autore F, Strati P, Laurenti L, Ferrajoli A. Morphological, immunophenotypic, and genetic features of chronic lymphocytic leukemia with trisomy 12: a comprehensive review. Haematologica. 2018;103:931–8. Bosch F, Dalla-Favera R. Chronic lymphocytic leukaemia: from genetics to treatment. Nat Rev Clin Oncol. 2019;16:684–701. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996;87:4990–7. Cosson A, Chapiro E, Belhouachi N, Cung HA, Keren B, Damm F, et al. 14q deletions are associated with trisomy 12, NOTCH1 mutations and unmutated IGHV genes in chronic lymphocytic leukemia and small lymphocytic lymphoma. Genes Chromosomes Cancer. 2014;53:657–66. Dal Bo M, Rossi FM, Rossi D, Deambrogi C, Bertoni F, Del Giudice I, et al. 13q14 deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemia. Genes Chromosomes Cancer. 2011;50:633–43. Dighiero G, Hamblin TJ. Chronic lymphocytic leukaemia. Lancet. 2008;371:1017–29. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910–6. Durak B, Akay OM, Aslan V, Ozdemir M, Sahin F, Artan S, et al. Prognostic impact of chromosome alterations detected by FISH in Turkish patients with B-cell chronic lymphocytic leukemia. Cancer Genet Cytogenet. 2009;188:65–9. Durak Aras B, Isik S, Uskudar Teke H, Aslan A, Yavasoglu F, Gulbas Z, et al. Which prognostic marker is responsible for the clinical heterogeneity in CLL with 13q deletion? Mol Cytogenet. 2021;14:2. Edelmann J, Holzmann K, Tausch E, Saunderson EA, Jebaraj BMC, Steinbrecher D, et al. Genomic alterations in high-risk chronic lymphocytic leukemia frequently affect cell cycle key regulators and NOTCH1-regulated transcription. Haematologica. 2020;105:1379–90. Grygalewicz B, Woroniecka R, Rygier J, Borkowska K, Rzepecka I, Łukasik M, et al. Monoallelic and biallelic deletions of 13q14 in a group of CLL/SLL patients investigated by CGH Haematological Cancer and SNP array (8x60K). Mol Cytogenet. 2016;9:1. Hagenkord JM, Monzon FA, Kash SF, Lilleberg S, Xie Q, Kant JA. Array-based karyotyping for prognostic assessment in chronic lymphocytic leukemia: performance comparison of Affymetrix 10K2.0, 250K Nsp, and SNP6.0 arrays. J Mol Diagn. 2010;12:184–96. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131:2745–60. Hernández JA, Rodríguez AE, González M, Benito R, Fontanillo C, Sandoval V, et al. A high number of losses in 13q14 chromosome band is associated with a worse outcome and biological differences in patients with B-cell chronic lymphoid leukemia. Haematologica. 2009;94:364–71. Houldsworth J, Guttapalli A, Thodima V, Yan XJ, Mendiratta G, Zielonka T, et al. Genomic imbalance defines three prognostic groups for risk stratification of patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2014;55:920–8. Kay NE, Eckel-Passow JE, Braggio E, Vanwier S, Shanafelt TD, Van Dyke DL, et al. Progressive but previously untreated CLL patients with greater array CGH complexity exhibit a less durable response to chemoimmunotherapy. Cancer Genet Cytogenet. 2010;203:161–8. Lobry C, Oh P, Mansour MR, Look AT, Aifantis I. Notch signaling: switching an oncogene to a tumor suppressor. Blood. 2014;123:2451–9. Machiela MJ, Zhou W, Caporaso N, Dean M, Gapstur SM, Goldin L, et al. Mosaic 13q14 deletions in peripheral leukocytes of non-hematologic cancer cases and healthy controls. J Hum Genet. 2016;61:411–8. Mian M, Rinaldi A, Mensah AA, Rossi D, Ladetto M, Forconi F, et al. Del(13q14.3) length matters: an integrated analysis of genomic, fluorescence in situ hybridization and clinical data in 169 chronic lymphocytic leukaemia patients with 13q deletion alone or a normal karyotype. Hematol Oncol. 2012;30:46–9. Miao Y, Miao Y, Shi K, Sun Q, Zhao SS, Xia Y, et al. A higher percentage of cells with 13q deletion predicts worse outcome in Chinese patients with chronic lymphocytic leukemia carrying isolated 13q deletion. Ann Hematol. 2018;97:1663–9. Moavero R, Coniglio A, Garaci F, Curatolo P. Is mTOR inhibition a systemic treatment for tuberous sclerosis? Ital J Pediatr. 2013;39:57. Mosca L, Fabris S, Lionetti M, Todoerti K, Agnelli L, Morabito F, et al. Integrative genomics analyses reveal molecularly distinct subgroups of B-cell chronic lymphocytic leukemia patients with 13q14 deletion. Clin Cancer Res. 2010;16:5641–53. O'Reilly A, Murphy J, Rawe S, Garvey M. Chronic Lymphocytic Leukemia: A Review of Front-line Treatment Options, With a Focus on Elderly CLL Patients. Clin Lymphoma Myeloma Leuk. 2018;18:249–56. Ouillette P, Erba H, Kujawski L, Kaminski M, Shedden K, Malek SN. Integrated genomic profiling of chronic lymphocytic leukemia identifies subtypes of deletion 13q14. Cancer Res. 2008;68:1012–21. Ouillette P, Collins R, Shakhan S, Li J, Li C, Shedden K, et al. The prognostic significance of various 13q14 deletions in chronic lymphocytic leukemia. Clin Cancer Res. 2011;17:6778–90. Parker H, Rose-Zerilli MJ, Parker A, Chaplin T, Wade R, Gardiner A, et al. 13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia. Leukemia. 2011;25:489–97. Patel A, Kang SH, Lennon PA, Li YF, Rao PN, Abruzzo L, et al. Validation of a targeted DNA microarray for the clinical evaluation of recurrent abnormalities in chronic lymphocytic leukemia. Am J Hematol. 2008;83:540–6. Rodriguez-Vicente AE, Bikos V, Hernández-Sánchez M, Malcikova J, Hernández-Rivas JS, Pospisilova S. Next-genetration sequencing in chronic lymphocytic leukemia: recent finding and new horizons. Oncotarget. 2017;8:71234–48. Sargent R, Jones D, Abruzzo LV, Yao H, Bonderover J, Cisneros M, et al. Customized oligonucleotide array-based comparative genomic hybridization as a clinical assay for genomic profiling of chronic lymphocytic leukemia. J Mol Diagn. 2009;11:25–34. Setlur SR, Ihm C, Tchinda J, Shams S, Werner L, Cho EK, et al. Comparison of familial and sporadic chronic lymphocytic leukaemia using high resolution array comparative genomic hybridization. Br J Haematol. 2010;151:336–45. Shaffer LG, Beaudet AL, Brothman AR, Hirsch B, Levy B, Martin CL, et al. Microarray analysis for constitutional cytogenetic abnormalities. Genet Med. 2007;9:654–62. Shanafelt TD, Witzig TE, Fink SR, Jenkins RB, Paternoster SF, Smoley SA, et al. Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early-stage chronic lymphocytic leukemia. J Clin Oncol. 2006;24:4634–41. Stevens-Kroef MJ, van den Berg E, Olde Weghuis D, Geurts van Kessel A, Pfundt R, Linssen-Wiersma M, et al. Identification of prognostic relevant chromosomal abnormalities in chronic lymphocytic leukemia using microarray-based genomic profiling. Mol Cytogenet. 2014;7:3. Tyybakinoja A, Vilpo J, Knuutila S. High-resolution oligonucleotide array-CGH pinpoints genes involved in cryptic losses in chronic lymphocytic leukemia. Cytogenet Genome Res. 2007;118:8–12. Article / Publication Details

First-Page Preview

Received: August 11, 2021
Accepted: October 15, 2021
Published online: December 15, 2021

Number of Print Pages: 9
Number of Figures: 2
Number of Tables: 6

ISSN: 1424-8581 (Print)
eISSN: 1424-859X (Online)

For additional information: https://www.karger.com/CGR

Copyright / Drug Dosage / Disclaimer Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.