Skip to main content
Top
Published in: Annals of Hematology 10/2017

01-10-2017 | Original Article

Quantitative PCR: an alternative approach to detect common copy number alterations in multiple myeloma

Authors: M. C. Chillón, C. Jiménez, R. García-Sanz, M. Alcoceba, I. Prieto, M. García-Alvarez, A. Antón, R. Maldonado, M. Hernández-Ruano, M. González, N. C. Gutiérrez, M. E. Sarasquete

Published in: Annals of Hematology | Issue 10/2017

Login to get access

Abstract

Chromosome 1q gains and 13q deletions are common cytogenetic aberrations in multiple myeloma (MM) that confer a poor prognosis. There are several techniques for the targeted study of these alterations, but interphase fluorescence in situ hybridization (FISH) is the current gold standard. The aim of the present study was to validate quantitative PCR (qPCR) as an alternative to FISH studies in CD138+-enriched plasma cells (PCs) from MM patients at diagnosis. We analyzed 1q gains and 13q deletions by qPCR in 57 and 60 MM patients, respectively. qPCR applicability was 84 and 88% for 1q and 13q, respectively. The qPCR and FISH methods had a sensitivity and specificity of 88 and 71% for 1q gains, and 79 and 100% for 13q deletions. A second qPCR assay for each region was carried out to confirm the previous results. Paired qPCR (two assays) and FISH results were available from 53 MM patients: 26 for 1q amplification and 27 for 13q deletion. qPCR assays gave concordant results (qPCR-consistent) in 20 of the 26 (77%) 1q gains and 25 of the 27 (93%) 13q deletions. Considering only the consistent data, the overall concordance among qPCR and FISH was 85 and 100% for 1q gains and 13q deletions, respectively. Our results show a substantial agreement between qPCR and the gold standard FISH technique, indicating the potential of qPCR as an alternative approach, particularly when the starting material is too scarce or cells are too damaged to obtain accurate results from FISH studies.
Literature
1.
go back to reference Weinhold N, Kirn D, Seckinger A, Hielscher T, Granzow M, Bertsch U et al (2016) Concomitant gain of 1q21 and MYC translocation define a poor prognostic subgroup of hyperdiploid multiple myeloma. Haematologica 101(3):e116–e119CrossRefPubMedPubMedCentral Weinhold N, Kirn D, Seckinger A, Hielscher T, Granzow M, Bertsch U et al (2016) Concomitant gain of 1q21 and MYC translocation define a poor prognostic subgroup of hyperdiploid multiple myeloma. Haematologica 101(3):e116–e119CrossRefPubMedPubMedCentral
2.
go back to reference Avet-Loiseau H, Attal M, Campion L, Caillot D, Hulin C, Marit G et al (2012) Long-term analysis of the IFM 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival. J Clin Oncol: Off J Am Soc Clin Oncol 30(16):1949–1952CrossRef Avet-Loiseau H, Attal M, Campion L, Caillot D, Hulin C, Marit G et al (2012) Long-term analysis of the IFM 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival. J Clin Oncol: Off J Am Soc Clin Oncol 30(16):1949–1952CrossRef
3.
go back to reference Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C et al (2007) Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood 109(8):3489–3495CrossRefPubMed Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C et al (2007) Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myelome. Blood 109(8):3489–3495CrossRefPubMed
4.
go back to reference Gutierrez NC, Castellanos MV, Martin ML, Mateos MV, Hernandez JM, Fernandez M et al (2007) Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia 21(1):143–150CrossRefPubMed Gutierrez NC, Castellanos MV, Martin ML, Mateos MV, Hernandez JM, Fernandez M et al (2007) Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia 21(1):143–150CrossRefPubMed
5.
go back to reference Avet-Loiseau H, Soulier J, Fermand JP, Yakoub-Agha I, Attal M, Hulin C et al (2010) Impact of high-risk cytogenetics and prior therapy on outcomes in patients with advanced relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone. Leukemia 24(3):623–628CrossRefPubMed Avet-Loiseau H, Soulier J, Fermand JP, Yakoub-Agha I, Attal M, Hulin C et al (2010) Impact of high-risk cytogenetics and prior therapy on outcomes in patients with advanced relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone. Leukemia 24(3):623–628CrossRefPubMed
6.
go back to reference Walker BA, Wardell CP, Melchor L, Brioli A, Johnson DC, Kaiser MF et al (2014) Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia 28(2):384–390CrossRefPubMed Walker BA, Wardell CP, Melchor L, Brioli A, Johnson DC, Kaiser MF et al (2014) Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia 28(2):384–390CrossRefPubMed
7.
go back to reference Magrangeas F, Lode L, Wuilleme S, Minvielle S, Avet-Loiseau H (2005) Genetic heterogeneity in multiple myeloma. Leukemia 19(2):191–194CrossRefPubMed Magrangeas F, Lode L, Wuilleme S, Minvielle S, Avet-Loiseau H (2005) Genetic heterogeneity in multiple myeloma. Leukemia 19(2):191–194CrossRefPubMed
8.
go back to reference Cremer FW, Bila J, Buck I, Kartal M, Hose D, Ittrich C et al (2005) Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics. Genes, Chromos Cancer 44(2):194–203CrossRef Cremer FW, Bila J, Buck I, Kartal M, Hose D, Ittrich C et al (2005) Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics. Genes, Chromos Cancer 44(2):194–203CrossRef
9.
go back to reference An G, Li Z, Tai YT, Acharya C, Li Q, Qin X et al (2015) The impact of clone size on the prognostic value of chromosome aberrations by fluorescence in situ hybridization in multiple myeloma. Clin Cancer Res: Off J Am Assoc Cancer Res 21(9):2148–2156CrossRef An G, Li Z, Tai YT, Acharya C, Li Q, Qin X et al (2015) The impact of clone size on the prognostic value of chromosome aberrations by fluorescence in situ hybridization in multiple myeloma. Clin Cancer Res: Off J Am Assoc Cancer Res 21(9):2148–2156CrossRef
10.
go back to reference Puig N, Conde I, Jimenez C, Sarasquete ME, Balanzategui A, Alcoceba M et al (2015) The predominant myeloma clone at diagnosis, CDR3 defined, is constantly detectable across all stages of disease evolution. Leukemia 29(6):1435–1437CrossRefPubMed Puig N, Conde I, Jimenez C, Sarasquete ME, Balanzategui A, Alcoceba M et al (2015) The predominant myeloma clone at diagnosis, CDR3 defined, is constantly detectable across all stages of disease evolution. Leukemia 29(6):1435–1437CrossRefPubMed
11.
go back to reference Walker BA, Boyle EM, Wardell CP, Murison A, Begum DB, Dahir NM et al (2015) Mutational Spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. J Clin Oncol: Off J Am Soc Clin Oncol 33(33):3911–3920CrossRef Walker BA, Boyle EM, Wardell CP, Murison A, Begum DB, Dahir NM et al (2015) Mutational Spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. J Clin Oncol: Off J Am Soc Clin Oncol 33(33):3911–3920CrossRef
12.
go back to reference Homig-Holzel C, Savola S (2012) Multiplex ligation-dependent probe amplification (MLPA) in tumor diagnostics and prognostics. Diagnos Mol Pathol: Am J Surg Pathol, Part B 21(4):189–206CrossRef Homig-Holzel C, Savola S (2012) Multiplex ligation-dependent probe amplification (MLPA) in tumor diagnostics and prognostics. Diagnos Mol Pathol: Am J Surg Pathol, Part B 21(4):189–206CrossRef
14.
go back to reference Ceulemans S, van der Ven K, Del-Favero J (2012) Targeted screening and validation of copy number variations. Methods Mol Biol 838:311–328CrossRefPubMed Ceulemans S, van der Ven K, Del-Favero J (2012) Targeted screening and validation of copy number variations. Methods Mol Biol 838:311–328CrossRefPubMed
15.
go back to reference D'Haene B, Vandesompele J, Hellemans J (2010) Accurate and objective copy number profiling using real-time quantitative PCR. Methods 50(4):262–270CrossRefPubMed D'Haene B, Vandesompele J, Hellemans J (2010) Accurate and objective copy number profiling using real-time quantitative PCR. Methods 50(4):262–270CrossRefPubMed
16.
go back to reference Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P et al (2016) International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 17(8):e328–e346CrossRefPubMed Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P et al (2016) International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 17(8):e328–e346CrossRefPubMed
17.
go back to reference Lopez-Corral L, Sarasquete ME, Bea S, Garcia-Sanz R, Mateos MV, Corchete LA et al (2012) SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status. Leukemia 26(12):2521–2529CrossRefPubMed Lopez-Corral L, Sarasquete ME, Bea S, Garcia-Sanz R, Mateos MV, Corchete LA et al (2012) SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status. Leukemia 26(12):2521–2529CrossRefPubMed
18.
go back to reference Garcia-Sanz R, Orfao A, Gonzalez M, Moro MJ, Hernandez JM, Ortega F et al (1995) Prognostic implications of DNA aneuploidy in 156 untreated multiple myeloma patients. Castelano-Leones (Spain) Cooperative Group for the Study of Monoclonal Gammopathies. Br J Haematol 90(1):106–112CrossRefPubMed Garcia-Sanz R, Orfao A, Gonzalez M, Moro MJ, Hernandez JM, Ortega F et al (1995) Prognostic implications of DNA aneuploidy in 156 untreated multiple myeloma patients. Castelano-Leones (Spain) Cooperative Group for the Study of Monoclonal Gammopathies. Br J Haematol 90(1):106–112CrossRefPubMed
19.
go back to reference Lopez-Corral L, Gutierrez NC, Vidriales MB, Mateos MV, Rasillo A, Garcia-Sanz R et al (2011) The progression from MGUS to smoldering myeloma and eventually to multiple myeloma involves a clonal expansion of genetically abnormal plasma cells. Clin Cancer Res: Off J Am Assoc Cancer Res 17(7):1692–1700CrossRef Lopez-Corral L, Gutierrez NC, Vidriales MB, Mateos MV, Rasillo A, Garcia-Sanz R et al (2011) The progression from MGUS to smoldering myeloma and eventually to multiple myeloma involves a clonal expansion of genetically abnormal plasma cells. Clin Cancer Res: Off J Am Assoc Cancer Res 17(7):1692–1700CrossRef
20.
go back to reference Ross FM, Avet-Loiseau H, Ameye G, Gutierrez NC, Liebisch P, O'Connor S et al (2012) Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders. Haematologica 97(8):1272–1277CrossRefPubMedPubMedCentral Ross FM, Avet-Loiseau H, Ameye G, Gutierrez NC, Liebisch P, O'Connor S et al (2012) Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders. Haematologica 97(8):1272–1277CrossRefPubMedPubMedCentral
21.
go back to reference Mateos MV, Gutierrez NC, Martin-Ramos ML, Paiva B, Montalban MA, Oriol A et al (2011) Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance. Blood 118(17):4547–4553CrossRefPubMed Mateos MV, Gutierrez NC, Martin-Ramos ML, Paiva B, Montalban MA, Oriol A et al (2011) Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance. Blood 118(17):4547–4553CrossRefPubMed
22.
go back to reference Dimopoulos MA, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H et al (2015) Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica 100(10):1327–1333CrossRefPubMedPubMedCentral Dimopoulos MA, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H et al (2015) Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica 100(10):1327–1333CrossRefPubMedPubMedCentral
23.
go back to reference Suda T, Hama T, Kondo S, Yuza Y, Yoshikawa M, Urashima M et al (2012) Copy number amplification of the PIK3CA gene is associated with poor prognosis in non-lymph node metastatic head and neck squamous cell carcinoma. BMC Cancer 12:416CrossRefPubMedPubMedCentral Suda T, Hama T, Kondo S, Yuza Y, Yoshikawa M, Urashima M et al (2012) Copy number amplification of the PIK3CA gene is associated with poor prognosis in non-lymph node metastatic head and neck squamous cell carcinoma. BMC Cancer 12:416CrossRefPubMedPubMedCentral
24.
go back to reference Kim S, Lee J, Hong ME, Do IG, Kang SY, Ha SY et al (2014) High-throughput sequencing and copy number variation detection using formalin fixed embedded tissue in metastatic gastric cancer. PLoS One 9(11):e111693CrossRefPubMedPubMedCentral Kim S, Lee J, Hong ME, Do IG, Kang SY, Ha SY et al (2014) High-throughput sequencing and copy number variation detection using formalin fixed embedded tissue in metastatic gastric cancer. PLoS One 9(11):e111693CrossRefPubMedPubMedCentral
25.
go back to reference Huang WT, Chuang SS (2013) High MET gene copy number predicted poor prognosis in primary intestinal diffuse large B-cell lymphoma. Diagn Pathol 8:16PubMedPubMedCentral Huang WT, Chuang SS (2013) High MET gene copy number predicted poor prognosis in primary intestinal diffuse large B-cell lymphoma. Diagn Pathol 8:16PubMedPubMedCentral
26.
go back to reference De Preter K, Speleman F, Combaret V, Lunec J, Laureys G, Eussen BH et al (2002) Quantification of MYCN, DDX1, and NAG gene copy number in neuroblastoma using a real-time quantitative PCR assay. Modern Pathol: Off J US Can Acad Pathol, Inc 15(2):159–166CrossRef De Preter K, Speleman F, Combaret V, Lunec J, Laureys G, Eussen BH et al (2002) Quantification of MYCN, DDX1, and NAG gene copy number in neuroblastoma using a real-time quantitative PCR assay. Modern Pathol: Off J US Can Acad Pathol, Inc 15(2):159–166CrossRef
27.
go back to reference Guerrera ML TN, Xu L, Yang G, Manning RJ, Demos M, Patterson C, Castillo JJ, Dubeau T, Gustine J, Liu X, Chen J, Chen JG, Arcaini L, Varettoni M, Cazzola M, Treon SP; Hunter ZR. Chromosome 6q deletions are common in Waldenstrom’s Macroglobulinemia, and target regulatory genes for MYD88, CXCR4 and BCL2 signalling. . 9th International WOrkshop on Waldenstrom Macroglobulinemia and Symposium on advances in Multiple Myeloma Abstract Book; October 5–8 20162016 Guerrera ML TN, Xu L, Yang G, Manning RJ, Demos M, Patterson C, Castillo JJ, Dubeau T, Gustine J, Liu X, Chen J, Chen JG, Arcaini L, Varettoni M, Cazzola M, Treon SP; Hunter ZR. Chromosome 6q deletions are common in Waldenstrom’s Macroglobulinemia, and target regulatory genes for MYD88, CXCR4 and BCL2 signalling. . 9th International WOrkshop on Waldenstrom Macroglobulinemia and Symposium on advances in Multiple Myeloma Abstract Book; October 5–8 20162016
28.
go back to reference Olmedillas-Lopez S, Garcia-Arranz M, Garcia-Olmo D (2017) Current and emerging applications of droplet digital PCR in oncology. Mol Diagnos Ther Olmedillas-Lopez S, Garcia-Arranz M, Garcia-Olmo D (2017) Current and emerging applications of droplet digital PCR in oncology. Mol Diagnos Ther
Metadata
Title
Quantitative PCR: an alternative approach to detect common copy number alterations in multiple myeloma
Authors
M. C. Chillón
C. Jiménez
R. García-Sanz
M. Alcoceba
I. Prieto
M. García-Alvarez
A. Antón
R. Maldonado
M. Hernández-Ruano
M. González
N. C. Gutiérrez
M. E. Sarasquete
Publication date
01-10-2017
Publisher
Springer Berlin Heidelberg
Published in
Annals of Hematology / Issue 10/2017
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-017-3083-x

Other articles of this Issue 10/2017

Annals of Hematology 10/2017 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.