Compendium of Cancer Genome Aberrations

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Table 1 - Recurrent Genomic Alterations in AML Detected by Chromosomal Microarray (Literature Review). This is a comprehensive list of CNAs and CN-LOH detectable by CMA testing with strong diagnostic, prognostic and treatment implications in AML. Table derived from Xu et al., 2018 [PMID 30344013] with permission from Cancer Genetics.

Chromosome AML Subtype Abnormality Type (Amplification, Loss, CN-LOH) Region Relevant Genes (if known) Clinical Significance Level of Evidence References
1 AML including NK-AML CN-LOH 1p D 3 [1][2][3][4][5][6][7][8][9]
2 AML CN-LOH 2p DNMT3A D 3 [1][10][11]
3 NK-AML, sAML Loss 3p14.1 FOXP1 D 3 [3][12][13]
4 sAML, pAML CN-LOH 4q24 TET2 D 3 [4][14][15]
4 AML, NK-AML, sAML Loss 4q24 TET2 D, P 3 [13][16][17]
5 pAML, sAML Loss 5q D 1 [12][13][17][18][19][20][21][22][23][24][25][26]
6 AML including NK-AML CN-LOH 6p D 3 [2][3][7][9]
7 AML including NK-AML CN-LOH 7q EZH2 D 3 [4][7][27]
7 NK-AML, pAML, sAML Loss 7q EZH2, CUX1 D 1 [12][13][28][29]
8 AML with complex karyotype Amplification 8q24 MYC D, P 3 [18][20][30]
9 NK-AML, sAML CN-LOH 9p JAK2 D 3 [4][9][13]
11* AML with complex karyotype Amplification 11q23 MLL (KMT2A) D, P 3 [20][31]
11* AML CN-LOH 11p WT1 D 3 [1][3][7][10]
11 pAML, sAML, NK-AML CN-LOH 11q CBL D 3 [1][4][7][10][13]
12 AML, NK-AML, AML with complex karyotype, sAML Loss 12p13.2 ETV6 D 3 [3][9][12][13][18][19][20][21][26][31][32][33][34][35]
13* pAML, NK-AML, NPM1 mutated AML, FLT3-ITD positive AML, sAML CN-LOH 13q FLT3 D, P 2 [1][2][3][4][5][6][7][9][10][13][27][28][36][37][38][39]
16 NK-AML, AML with complex karyotype, pAML, sAML Loss 16q CBFB D 3 [2][20][26][30]
17 AML, NK-AML, pAML, sAML CN-LOH 17p TP53 D 3 [1][2][4][7][10][25][28]
17 sAML, NK-AML, AML with complex karyotype, de novo AML Loss 17p TP53 D, P 1 [2][18][13][20][23][24][25][26][28][30][34]
17 NK-AML, pAML Loss 17q11.2 NF1, SUZ12 D, P 3 [2][9][13][18][20][28][30][31][40][41]
19* AML, NK-AML, sAML CN-LOH 19q CEBPA D 3 [1][2][3][6][7][15]
20 sAML Loss 20q D 3 [13][18][42][43]
21* pAML, AML with complex karyotype Amplification 21q22 ERG, ETS2 D, P, T 3 [12][20][30][44][45]
21* AML, NK-AML, sAML CN-LOH 21q RUNX1 D 3 [1][2][4][7][8][9][15][46]
21* sAML Loss 21q22.12 RUNX1 D 3 [12]

D = diagnostic significance; P = prognostic significance; T = therapeutic significance. Classification of levels of evidence: Level 1 = WHO classification or professional practice guidelines; Level 2 = well-powered studies with consensus from experts in the field; Level 3 = multiple small studies without any contradicting data; Level 4 = individual small studies, case reports, preclinical studies.

Abrreviations: CMA = chromosomal microarray; CNA = copy number aberration; CN-LOH = copy-neutral loss-of-heterozygosity; AML = acute myeloid leukemia; NK-AML = normal karyotype AML; pAML = primary AML; and sAML = secondary AML.

The * indicates CNAs and CN-LOH regions that are predominantly seen in AML.

Reference

1. Xu X, Bryke C, Sukhanova M, Huxley E, Dash DP, Dixon-Mciver A, Fang M, Griepp PT, Hodge JC, Iqbal A, Jeffries S, Kanagal-Shamanna R, Quintero-Rivera F, Shetty S, Slovak ML, Yenamandra A, Lennon PA, Raca G. (2018). Assessing copy number abnormalities and copy-neutral loss-of-heterozygosity across the genome as best practice in diagnostic evaluation of acute myeloid leukemia: An evidence-based review from the cancer genomics consortium (CGC) myeloid neoplasms working group. Cancer Genet [Epub ahead of print], PMID 30344013.

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Gronseth CM, McElhone SE, Storer BE, Kroeger KA, Sandhu V, Fero ML, Appelbaum FR, Estey EH, Fang M. Prognostic significance of acquired copy-neutral loss of heterozygosity in acute myeloid leukemia. Cancer 2015;121:2900–8, PMID 26033747
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Yi JH, Huh J, Kim HJ, Kim SH, Kim HJ, Kim YK, Sohn SK, MoonJH, Kim SH, Kim KH, Won JH, Mun YC, Kim H, Park J, Jung CW, Kim DH. Adverse prognostic impact of abnormal lesions detected by genome-wide single nucleotide polymorphism array-based karyotyping analysis in acute myeloid leukemia with normal karyotype. J Clin Oncol Offic J Am Soc Clin Oncol, 29 (2011), pp. 4702-4708, PMID 2208437
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 L Bullinger, J Kronke, C Schon, I Radtke, K Urlbauer, UBotzenhardt, V Gaidzik, A Cario, C Senger, RF Schlenk, JRDowning, K Holzmann, K Dohner, H Dohner. Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis. Leukemia, 24 (2010), pp. 438-449, PMID 20016533
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 AJ Dunbar, LP Gondek, CL O'Keefe, H Makishima, MS Rataul, HSzpurka, MA Sekeres, Wang XF, MA McDevitt, JP Maciejewski 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. Cancer Res, 68 (2008), pp. 10349-10357, PMID 19074904
  5. ↑ 5.0 5.1 Kronke J, Bullinger L, Teleanu V, Tschurtz F, Gaidzik VI, Kuhn MW, Rucker FG, Holzmann K, Paschka P, Kapp-Schworer S, Spath D, Kindler T, Schittenhelm M, Krauter J, Ganser A, Gohring G, Schlegelberger B, Schlenk RF, Dohner H, Dohner K. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood 2013;122:100–8, PMID 23704090
  6. ↑ 6.0 6.1 6.2 M Koren-Michowitz, A Sato-Otsubo, A Nagler, T Haferlach, S Ogawa, HP Koeffler. Older patients with normal karyotype acute myeloid leukemia have a higher rate of genomic changes compared to young patients as determined by SNP array analysis. Leukem Res, 36 (2012), pp. 467-473, PMID 22071139
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 L Bullinger, S Frohling. Array-based cytogenetic approaches in acute myeloid leukemia: clinical impact and biological insights. Sem Oncol, 39 (2012), pp. 37-46, PMID 22289490
  8. ↑ 8.0 8.1 Barresi V, Romano A, Musso N, Capizzi C, Consoli C, Martelli MP, Palumbo G, DiRaimondo F, Condorelli DF. Broad copy neutral loss of heterozygosity regions and rare recurring copy number abnormalities in normal karyotype acute myeloid leukemia genomes. Genes Chromos Cancer 2010;49:1014–23., PMID 20725993
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 T Akagi, S Ogawa, M Dugas, N Kawamata, G Yamamoto, YNannya, M Sanada, CW Miller, Yung A, S Schnittger, T Haferlach, C Haferlach, HP Koeffler. Frequent genomic abnormalities in acute myeloid leukemia/myelodysplastic syndrome with normal karyotype. Haematologica, 94 (2009), pp. 213-223, PMID 19144660
  10. ↑ 10.0 10.1 10.2 10.3 10.4 M Gupta, M Raghavan, RE Gale, C Chelala, C Allen, G Molloy, TChaplin, DC Linch, JB Cazier, Young BD. Novel regions of acquired uniparental disomy discovered in acute myeloid leukemia. Genes Chromos Cancer, 47 (2008), pp. 729-739, PMID 18506749
  11. ↑ T McKerrell, T Moreno, H Ponstingl, N Bolli, JM Dias, G Tischler, V Colonna, B Manasse, A Bench, D Bloxham, B Herman, DFletcher, N Park, MA Quail, N Manes, C Hodkinson, J Baxter, JSierra, T Foukaneli, AJ Warren, Chi J, P Costeas, R Rad, B Huntly, C Grove, Ning Z, C Tyler-Smith, I Varela, M Scott, J Nomdedeu, VMustonen, GS Vassiliou. Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies. Blood, 128 (2016), pp. e1-e9, PMID 27121471
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 N Itzhar, P Dessen, S Toujani, N Auger, C Preudhomme, CRichon, V Lazar, V Saada, A Bennaceur, JH Bourhis, S de Botton, ABernheim. Chromosomal minimal critical regions in therapy-related leukemia appear different from those of de novo leukemia by high-resolution aCGH. PloS One, 6 (2011), p. e16623, PMID 21339820
  13. ↑ 13.00 13.01 13.02 13.03 13.04 13.05 13.06 13.07 13.08 13.09 13.10 JD Milosevic, A Puda, L Malcovati, T Berg, M Hofbauer, AStukalov, T Klampfl, AS Harutyunyan, H Gisslinger, B Gisslinger, TBurjanivova, E Rumi, D Pietra, C Elena, AM Vannucchi, MDoubek, D Dvorakova, B Robesova, R Wieser, E Koller, NSuvajdzic, D Tomin, N Tosic, J Colinge, Z Racil, M Steurer, SPavlovic, M Cazzola, R Kralovics. Clinical significance of genetic aberrations in secondary acute myeloid leukemia. Am J Hematol, 87 (2012), pp. 1010-1016, PMID 22887079
  14. ↑ B Parkin, H Erba, P Ouillette, D Roulston, A Purkayastha, J Karp, M Talpaz, L Kujawski, S Shakhan, Li C, K Shedden, SN Malek. Acquired genomic copy number aberrations and survival in adult acute myelogenous leukemia. Blood, 116 (2010), pp. 4958-4967, PMID 20729466
  15. ↑ 15.0 15.1 15.2 J Flach, F Dicker, S Schnittger, S Schindela, A Kohlmann, THaferlach, W Kern, C Haferlach. An accumulation of cytogenetic and molecular genetic events characterizes the progression from MDS to secondary AML: an analysis of 38 paired samples analyzed by cytogenetics, molecular mutation analysis and SNP microarray profiling. Leukemia, 25 (2011), pp. 713-718, PMID 21233836
  16. ↑ S Weissmann, T Alpermann, V Grossmann, A Kowarsch, NNadarajah, C Eder, F Dicker, A Fasan, C Haferlach, T Haferlach, WKern, S Schnittger, A Kohlmann. Landscape of TET2 mutations in acute myeloid leukemia. Leukemia, 26 (2012), pp. 934-942, PMID 22116554
  17. ↑ 17.0 17.1 U Bacher, S Weissmann, A Kohlmann, S Schindela, T Alpermann, S Schnittger, W Kern, T Haferlach, C Haferlach. TET2 deletions are a recurrent but rare phenomenon in myeloid malignancies and are frequently accompanied by TET2 mutations on the remaining allele. Br J Haematol, 156 (2012), pp. 67-75, PMID 22017486
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 R Bajaj, Xu F, Xiang B, K Wilcox, AJ Diadamo, R Kumar, APietraszkiewicz, S Halene, Li P. Evidence-based genomic diagnosis characterized chromosomal and cryptic imbalances in 30 elderly patients with myelodysplastic syndrome and acute myeloid leukemia. Mol Cytogenet, 4 (2011), p. 3, PMID 21251322
  19. ↑ 19.0 19.1 B Parkin, P Ouillette, M Yildiz, K Saiya-Cork, K Shedden, SN Malek. Integrated genomic profiling, therapy response, and survival in adult acute myelogenous leukemia. Clin Cancer Res Offic J Am Assocr Cancer Res, 21 (2015), pp. 2045-2056, PMID 25652455
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 MJ Walter, JE Payton, RE Ries, WD Shannon, H Deshmukh, ZhaoY, J Baty, S Heath, P Westervelt, MA Watson, MH Tomasson, RNagarajan, BP O'Gara, CD Bloomfield, K Mrozek, RR Selzer, TARichmond, J Kitzman, J Geoghegan, PS Eis, R Maupin, RS Fulton, M McLellan, RK Wilson, ER Mardis, DC Link, TA Graubert, JFDiPersio, TJ Ley. Acquired copy number alterations in adult acute myeloid leukemia genomes. Proc Natl Acad Sci USA, 106 (2009), pp. 12950-12955, PMID 19651600
  21. ↑ 21.0 21.1 FG Rucker, RF Schlenk, L Bullinger, S Kayser, V Teleanu, H Kett, MHabdank, CM Kugler, K Holzmann, VI Gaidzik, P Paschka, GHeld, M von Lilienfeld-Toal, M Lubbert, S Frohling, T Zenz, JKrauter, B Schlegelberger, A Ganser, P Lichter, K Dohner, HDohner. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood, 119 (2012), pp. 2114-2121, PMID 22186996
  22. ↑ A Jerez, LP Gondek, AM Jankowska, H Makishima, B Przychodzen, Tiu RV, CL O'Keefe, AM Mohamedali, D Batista, MA Sekeres, MAMcDevitt, GJ Mufti, JP Maciejewski. Topography, clinical, and genomic correlates of 5q myeloid malignancies revisited. J Clin Oncol Offic J Am Soc Clin Oncol, 30 (2012), pp. 1343-1349, PMID 22370328
  23. ↑ 23.0 23.1 M Mehrotra, R Luthra, F Ravandi, RL Sargent, BA Barkoh, RAbraham, BM Mishra, LJ Medeiros, KP Patel. Identification of clinically important chromosomal aberrations in acute myeloid leukemia by array-based comparative genomic hybridization. Leukemia Lymph, 55 (2014), pp. 2538-2548, PMID 24446873
  24. ↑ 24.0 24.1 Kim MH, J Stewart, C Devlin, Kim YT, E Boyd, M Connor. The application of comparative genomic hybridization as an additional tool in the chromosome analysis of acute myeloid leukemia and myelodysplastic syndromes. Cancer Genet Cytogen, 126 (2001), pp. 26-33, PMID 11343775
  25. ↑ 25.0 25.1 25.2 Rumi E, Harutyunyan A, Elena C, Pietra D, Klampfl T, Bagien-ski K, Berg T, Casetti I, Pascutto C, Passamonti F, Kralovics R, Cazzola M. Identification of genomic aberrations associated with disease transformation by means of high resolution SNP array analysis in patients with myeloproliferative neoplasm. Am J Hematol 2011;86:974–9, PMID 21953568
  26. ↑ 26.0 26.1 26.2 26.3 LP Gondek, Tiu R, CL O'Keefe, MA Sekeres, KS Theil, JPMaciejewski. Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood, 111 (2008), pp. 1534-1542, PMID 17954704
  27. ↑ 27.0 27.1 A Tyybakinoja, E Elonen, H Vauhkonen, J Saarela, S Knuutila. Single nucleotide polymorphism microarray analysis of karyotypically normal acute myeloid leukemia reveals frequent copy number neutral loss of heterozygosity. Haematologica, 93 (2008), pp. 631-632, PMID 18379011
  28. ↑ 28.0 28.1 28.2 28.3 28.4 Huh J, Jung CW, Kim HJ, Kim YK, Moon JH, Sohn SK, Kim HJ, Min WS, Kim DH. Different characteristics identified by single nucleotide polymorphism array analysis in leukemia suggest the need for different application strategies depending on disease category. Genes Chromos cancer, 52 (2013), pp. 44-55, PMID 23023762
  29. ↑ ME McNerney, CD Brown, X Wang, ET Bartom, S Karmakar, CBandlamudi, Yu S, Ko J, BP Sandall, T Stricker, J Anastasi, RLGrossman, JM Cunningham, MM Le Beau, KP White. CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia. Blood, 121 (2013), pp. 975-983, PMID 23212519
  30. ↑ 30.0 30.1 30.2 30.3 30.4 FG Rucker, L Bullinger, C Schwaenen, DB Lipka, S Wessendorf, SFrohling, M Bentz, S Miller, C Scholl, RF Schlenk, B Radlwimmer, HA Kestler, JR Pollack, P Lichter, K Dohner, H Dohner. Disclosure of candidate genes in acute myeloid leukemia with complex karyotypes using microarray-based molecular characterization. J Clin Oncol Offic J Am Soc Clin Oncol, 24 (2006), pp. 3887-3894, PMID 16864856
  31. ↑ 31.0 31.1 31.2 E Kjeldsen. Oligo-based high-resolution aCGH analysis enhances routine cytogenetic diagnostics in haematological malignancies. Cancer Genom Proteom, 12 (2015), pp. 301-337, PMID 26543079
  32. ↑ Paulsson K, Heidenblad M, Strombeck B, Staaf J, Jonsson G, Borg A, Fioretos T, Johansson B. High-resolution genome-wide array-based comparative genome hybridization reveals cryptic chromosome changes in AML and MDS cases with trisomy 8 as the sole cytogenetic aberration. Leukemia 2006;20:840–6. PMID 16498392
  33. ↑ Feurstein S, Rucker FG, Bullinger L, Hofmann W, Manuk-jan G, Gohring G, Lehmann U, Heuser M, Ganser A, Dohner K, Schlegelberger B, Steinemann D. Haploinsufficiency of ETV6 and CDKN1B in patients with acute myeloid leukemia and complex karyotype. BMC Genom 2014;15:784. PMID 25213837
  34. ↑ 34.0 34.1 Zhang R, Kim YM, Wang X, Li Y, Lu X, Sternenberger AR, Li S, Lee JY. Genomic copy number variations in the myelodysplastic syndrome and acute myeloid leukemia patients with del(5q) and/or -7/del(7q). Int J Med Sci 2015;12:719–26, PMID 26392809
  35. ↑ Wall M, Rayeroux KC, MacKinnon RN, Zordan A, Campbell LJ. ETV6 deletion is a common additional abnormality in patients with myelodysplastic syndromes or acute myeloid leukemia and monosomy 7. Haematologica 2012;97:1933–6., PMID 22875624
  36. ↑ Tiu RV, LP Gondek, CL O'Keefe, Huh J, MA Sekeres, P Elson, MAMcDevitt, Wang XF, MJ Levis, JE Karp, AS Advani, JP Maciejewski. New lesions detected by single nucleotide polymorphism array-based chromosomal analysis have important clinical impact in acute myeloid leukemia. J Clin Oncol Off J Am Soc Clin Oncol, 27 (2009), pp. 5219-5226, PMID 19770377
  37. ↑ Serrano E, Carnicer MJ, Orantes V, Estivill C, Lasa A, Brunet S, Aventin AM, Sierra J, Nomdedeu JF. Uniparental disomy may be associated with microsatellite instability in acute myeloid leukemia (AML) with a normal karyotype. Leukem Lymph 2008;49:1178–83, PMID 18452069
  38. ↑ Koh KN, Lee JO, Seo EJ, Lee SW, Suh JK, Im HJ, Seo JJ. Clinical significance of previously cryptic copy number alterations and loss of heterozygosity in pediatric acute myeloid leukemia and myelodysplastic syndrome determined using combined array comparative genomic hybridization plus single nucleotide polymorphism microarray analyses. J Korean Med Sci 2014;29:926–33, PMID 25045224
  39. ↑ Stirewalt DL, Pogosova-Agadjanyan EL, Tsuchiya K, Joaquin J, Meshinchi S. Copy neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML.Blood Cancer J 2014;4:e208, PMID 24786392
  40. ↑ C Haferlach, V Grossmann, A Kohlmann, S Schindela, W Kern, SSchnittger, T Haferlach. Deletion of the tumor-suppressor gene NF1 occurs in 5% of myeloid malignancies and is accompanied by a mutation in the remaining allele in half of the cases. Leukemia, 26 (2012), pp. 834-839, PMID 22015770
  41. ↑ Boudry-Labis E, Roche-Lestienne C, Niboure lO, Boisse lN, Terre C, Perot C, Eclache V, Gachard N, Tigaud I, Plessis G, Cuccuini W, Geffroy S, Villenet C, Figeac M, Lepretre F, Renneville A, Cheok M, Soulier J, Dombret H, Preudhomme C, Ag F. Neurofibromatosis-1 gene deletions and mutations in de novo adult acute myeloid leukemia. Am J Hematol 2013;88:306–11, PMID 23460398
  42. ↑ Barresi V, Palumbo GA, Musso N, Consoli C, Capizzi C, Meli CR, Romano A, DiRaimondo F, Condorelli DF. Clonal selection of 11q CN-LOH and CBL gene mutation in a serially studied patient during MDS progression to AML. Leukemia Res 2010;34:1539–42, PMID 20674974
  43. ↑ Huh J, Tiu RV, Gondek LP, O’Keefe CL, Jasek M, Makishima H, Jankowska AM, Jiang Y, Verma A, Theil KS, McDevitt MA, Maciejewski JP. Characterization of chromosome arm 20q abnormalities in myeloid malignancies using genome-wide single nucleotide polymorphism array analysis. Genes Chromos Cancer 2010;49:390–9, PMID 20095039
  44. ↑ O Nibourel, S Guihard, C Roumier, N Pottier, C Terre, A Paquet, PPeyrouze, S Geffroy, S Quentin, A Alberdi, RB Abdelali, ARenneville, C Demay, K Celli-Lebras, P Barbry, B Quesnel, SCastaigne, H Dombret, J Soulier, C Preudhomme, MH Cheok. Copy-number analysis identified new prognostic marker in acute myeloid leukemia. Leukemia, 31 (2017), pp. 555-564, PMID 27686867
  45. ↑ CD Baldus, S Liyanarachchi, K Mrozek, H Auer, SM Tanner, MGuimond, AS Ruppert, N Mohamed, RV Davuluri, MA Caligiuri, CD Bloomfield, A de la Chapelle. Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci USA, 101 (2004), pp. 3915-3920, PMID 15007164
  46. ↑ FP Silva, I Almeida, B Morolli, G Brouwer-Mandema, H Wessels, RVossen, H Vrieling, EW Marijt, PJ Valk, HC Kluin-Nelemans, WRSperr, WD Ludwig, M Giphart-Gassler. Genome wide molecular analysis of minimally differentiated acute myeloid leukemia. Haematologica, 94 (2009), pp. 1546-1554, PMID 19773259
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