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Atypical 11q deletions identified by array CGH may be missed by FISH panels for prognostic markers in chronic lymphocytic leukemia

Leukemia volume 23, pages 1011–1017 (2009)Cite this article

Genomic alterations have increasingly gained importance as prognostic markers in B-cell chronic lymphocytic leukemia (CLL). The identification of genetic alterations of prognostic importance in CLL is accomplished currently using commercially available fluorescence in situ hybridization (FISH) panels that can detect the most common recurrent aberrations in CLL, involving chromosomes 11q, 13q, 14q, 17p and whole chromosome 12.1, 2, 3, 4 Although the use of FISH analysis has improved the detection rate of genomic alterations in CLL from ∼50% using conventional cytogenetics to >80%,5 there is a need for improved methods to identify prognostic markers that can aid in the risk-stratification of these patients. The identification of high-risk patients is essential for treatment planning and is of particular importance in early-stage, asymptomatic CLL patients, for whom rapid disease progression and a poor prognosis can be predicted by the presence of specific genomic abnormalities such as 11q and 17p deletions.6, 7, 8 Recently, array comparative genomic hybridization (array CGH) has been gaining acceptance as a diagnostic tool that can also be applied to detect genomic gains and losses of prognostic importance in CLL, because of the advantages afforded by simultaneous genome-wide and locus-specific assessment of the leukemia with a single assay.9, 10, 11, 12, 13, 14

Array CGH is well suited for the identification of genomic alterations of prognostic importance in CLL, because the most common and important aberrations are comprised of genomic losses and gains, whereas chromosomal translocations are relatively rare. Although translocations do occur in CLL, their prognostic significance is currently controversial. In a number of recent studies evaluating the use of array CGH as a clinical tool for genomic alteration detection in CLL, array CGH results have exhibited a high concordance with parallel FISH studies, except when FISH aberrations are present in less than ∼25–30% of the cells.9, 10, 11, 12, 13, 14 In a recent report from our laboratory, we analyzed 174 cases of CLL by bacterial artificial chromosome (BAC)-based array CGH and found that we could identify correctly the aberrations identified by FISH 96% of the time.12 The discordant results were because of small clonal cell populations that comprised <25–30% of the total sample. Interestingly, two CLL cases with cryptic (∼1 Mb) 13q14 deletions detected by array CGH were missed by both of the 13q14 region FISH probes used in this study. These findings suggested that array CGH had advantages over FISH for the identification of certain types of genomic alterations in CLL. In this study, we present four additional CLL cases with atypical 11q deletions, including two cases that were not identified properly by a commercially available five-probe FISH panel that also included an 11q22.3 Vysis LSI ATM probe (Abbott Molecular, Des Plaines, IL, USA). This study is also the first to report CLL cases with large 11q deletions that do not include the ATM (Ataxia telangiectasia mutated) gene, suggesting that additional genes in this region may be important for the pathogenesis of CLL.

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References

  1. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kober A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.

    Article  Google Scholar 

  2. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) updating the National Cancer Institute Working Group (NCI-WG) 1996 guidelines. Blood 2008; 111: 5446–5456.

    Article  CAS  Google Scholar 

  3. Zenz T, Döhner H, Stilgenbauer S . Genetics and risk-stratified approach to therapy in chronic lymphocytic leukemia. Best Pract Res Clin Haematol 2007; 20: 439–453.

    Article  CAS  Google Scholar 

  4. Glassman AB, Hayes KJ . The value of fluorescence in situ hybridization in the diagnosis and prognosis of chronic lymphocytic leukemia. Cancer Genet Cytogenet 2005; 158: 88–91.

    Article  CAS  Google Scholar 

  5. Juliusson G, Oscier DG, Fitchett M, Ross FM, Stockdill G, Mackie MJ et al. Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. N Engl J Med 1990; 323: 720–724.

    Article  CAS  Google Scholar 

  6. Kay NE, O’Brien SM, Pettit AR, Stilgenbauer S . The role of prognostic factors in assessing ‘high-risk’ subgroups of patients with chronic lymphocytic leukemia. Leukemia 2007; 21: 1885–1891.

    Article  CAS  Google Scholar 

  7. Dickinson JD, Smith LM, Sanger WG, Zhou G, Townley P, Lynch JC et al. Unique gene expression and clinical characteristics with the 11q23 deletion in chronic lymphocytic leukemia. Br J Haematol 2005; 128: 460–461.

    Article  CAS  Google Scholar 

  8. Zent CS, Call TG, Hogan WJ, Shanafelt TD, Kay NE . Update on risk-stratified management for chronic lymphocytic leukemia. Leuk Lymphoma 2006; 47: 1738–1746.

    Article  Google Scholar 

  9. Schwaenen C, Nessling M, Wessendorf S, Salvi T, Wrobel G, Radlwimmer B et al. Automated array-based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations. Proc Natl Acad Sci USA 2004; 101: 1039–1044.

    Article  CAS  Google Scholar 

  10. Patel A, Kang S-H, Lennon PA, Li YF, Rao PN, Abruzzo L et al. Validation of a targeted DNA microarray for clinical evaluation of recurrent abnormalities in chronic lymphocytic leukemia. Am J Hematol 2008; 83: 540–546.

    Article  CAS  Google Scholar 

  11. Gunn SR, Mohammed MS, Mellink CHM, Abruzzo LV, Robetorye RS . The HemeScan test for genomic prognostic marker assessment in chronic lymphocytic leukemia. Expert Opin Med Diagn 2008; 2: 731–740.

    Article  CAS  Google Scholar 

  12. Gunn SR, Mohammed MS, Gorre ME, Cotter PD, Kim J, Bahler DW et al. Whole-genome scanning by array comparative genomic hybridization as a clinical tool for risk assessment in chronic lymphocytic leukemia. J Mol Diagn 2008; 10: 442–451.

    Article  CAS  Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. Higgins RA, Gunn SR, Robetorye RS . Clinical application of array-based comparative genomic hybridization arrays for the identification of prognostically important genetic alterations in chronic lymphocytic leukemia. Mol Diagn Ther 2008; 12: 271–280.

    Article  Google Scholar 

  15. Stilgenbauer S, Liebisch P, James MR, Schroder M, Schlegelberger B, Fischer K et al. Molecular cytogenetic delineation of a novel critical genomic region in chromosome band 11q22.3-q23.1 in lymphoproliferative disorders. Proc Natl Acad Sci USA 1996; 93: 11837–11841.

    Article  CAS  Google Scholar 

  16. Eclache V, Caulet-Maugendre S, Poirel HA, Djemai M, Robert J, Lejeune F et al. Cryptic deletion involving the ATM locus at 11q22.3-q23.1 in B-cell chronic lymphocytic leukemia and related disorders. Cancer Genet Cytogenet 2004; 152: 72–76.

    Article  CAS  Google Scholar 

  17. Stilgenbauer S, Sander S, Bullinger L, Benner A, Leupolt E, Winkler D et al. Clonal evolution in chronic lymphocytic leukemia: acquisition of high-risk genomic aberration associated with unmutated VH, resistance to therapy and short survival. Haematology 2007; 92: 1242–1245.

    Article  Google Scholar 

  18. Vallee RB, Varma D, Dujardin DL . ZW10 function in mitotic checkpoint control, dynein targeting and membrane trafficking: is dynein the unifying theme? Cell Cycle 2006; 5: 2447–2451.

    Article  CAS  Google Scholar 

  19. Gao K, Lockwood WW, Li J, Lam W, Li G . Genomic analyses identify gene candidates for acquired irinotecan resistance in melanoma cells. Int J Oncol 2008; 32: 1343–1349.

    CAS  PubMed  Google Scholar 

  20. Shaknovich R, Yeyati PL, Ivins S, Melnick A, Lempert C, Waxman S et al. The promyelocytic leukemia zinc finger protein affects myeloid cell growth, differentiation, and apoptosis. Mol Cell Biol 1998; 18: 5533–5545.

    Article  CAS  Google Scholar 

  21. Yeyati PL, Shaknovich R, Boterashvili S, Li J, Ball HJ, Waxman S et al. Leukemia translocation protein PLZF inhibits cell growth and expression of cyclin A. Oncogene 1999; 18: 925–934.

    Article  CAS  Google Scholar 

  22. McConnell MJ, Chevallier N, Berkofsky-Fessler W, Giltnane JM, Malani RB, Staudt LM et al. Growth suppression by acute promyelocytic leukemia-associated protein PLZF is mediated by repression of c-myc expression. Mol Cell Biol 2003; 23: 9375–9388.

    Article  CAS  Google Scholar 

  23. Nowacki S, Skowron M, Oberthuer A, Fagin A, Voth H, Brors B et al. Expression of the tumour suppressor gene CADM1 is associated with favourable outcome and inhibits cell survival in neuroblastoma. Oncogene 2008; 27: 3329–3338.

    Article  CAS  Google Scholar 

  24. Lung HL, Cheung AK, Xie D, Cheng Y, Kwong FM, Murakami Y et al. TSLC1 is a tumor suppressor gene associated with metastasis in nasopharyngeal carcinoma. Cancer Res 2006; 66: 9385–9392.

    Article  CAS  Google Scholar 

  25. Fukuhara H, Kuramochi M, Fukami T, Kasahara K, Furuhata M, Nobukuni T et al. Promoter methylation of TSLC1 and tumor suppression by its gene product in human prostate cancer. Jpn J Cancer Res 2002; 93: 605–609.

    Article  CAS  Google Scholar 

  26. Heller G, Geradts J, Ziegler B, Newsham I, Filipits M, Markis-Ritzinger EM et al. Downregulation of TSLC1 and DAL-1 expression occurs frequently in breast cancer. Breast Cancer Res Treat 2007; 103: 283–291.

    Article  CAS  Google Scholar 

  27. Goto A, Niki T, Chi-Pin L, Matsubara D, Murakami Y, Funata N et al. Loss of TSLC1 expression in lung adenocarcinoma: relationships with histological subtypes, sex and prognostic significance. Cancer Sci 2005; 96: 480–486.

    Article  CAS  Google Scholar 

  28. Houshmandi SS, Surace EI, Zhang HB, Fuller GN, Gutmann DH . Tumor suppressor in lung cancer-1 (TSLC1) functions as a glioma tumor suppressor. Neurology 2006; 67: 1863–1866.

    Article  CAS  Google Scholar 

  29. Jansen M, Fukushima N, Rosty C, Walter K, Altink R, Heek TV et al. Aberrant methylation of the 5’ CpG island of TSLC1 is common in pancreatic ductal adenocarcinoma and is first manifest in high-grade PanlNs. Cancer Biol Ther 2002; 1: 293–296.

    Article  CAS  Google Scholar 

  30. Allinen M, Peri L, Kujala S, Lahti-Domenici J, Outila K, Karppinen SM et al. Analysis of 11q21-24 loss of heterozygosity candidate target genes in breast cancer: indications of TSLC1 promoter hypermethylation. Genes Chromosomes Cancer 2002; 34: 384–389.

    Article  CAS  Google Scholar 

  31. Ito T, Shimada Y, Hashimoto Y, Kaganoi J, Kan T, Watanabe G et al. Involvement of TSLC1 in progression of esophageal squamous cell carcinoma. Cancer Res 2003; 63: 6320–6326.

    CAS  PubMed  Google Scholar 

  32. Honda T, Tamura G, Waki T, Jin Z, Sato K, Motoyama T et al. Hypermethylation of the TSLC1 gene promoter in primary gastric cancers and gastric cancer cell lines. Jpn J Cancer Res 2002; 93: 857–860.

    Article  CAS  Google Scholar 

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Acknowledgements

SRG, ELE, MEG and MSM are employees of Combimatrix Molecular Diagnostics. RSR is a clinical consultant for Combimatrix Molecular Diagnostics. MKH is an employee of Clarient Diagnostics.

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Authors and Affiliations

  1. Combimatrix Molecular Diagnostics, Irvine, CA, USA

    S R Gunn, E L Enriquez, M E Gorre & M S Mohammed

  2. Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    S R Gunn, S H Ismail & R S Robetorye

  3. Clarient Diagnostics Laboratory, Aliso Viejo, CA, USA

    M K Hibbard

  4. Molecular Pathology and Cancer Cytogenetics, Louisiana State University Health Sciences Center, Shreveport, LA, USA

    M Lowery-Nordberg

  5. Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands

    C H M Mellink

  6. Department of Pathology and ARUP Institute for Clinical and Experimental Pathology, University of Utah, Salt Lake City, UT, USA

    D W Bahler

  7. Department of Hematopathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    L V Abruzzo

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Gunn, S., Hibbard, M., Ismail, S. et al. Atypical 11q deletions identified by array CGH may be missed by FISH panels for prognostic markers in chronic lymphocytic leukemia. Leukemia 23, 1011–1017 (2009). https://doi.org/10.1038/leu.2008.393

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