MDS, MDS/MPN and MPN Tables: Recurrent Genomic Alterations Detected by Chromosomal Microarray

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Table 1. Evidence for the clinical utility of chromosomal microarray testing (CMA) in myeloid disorders excluding acute myeloid leukemia

Disease Overall CMA detection rate Key and unique

CMA aberrations

Altered

gene(s)

Impact References
MDS 28-83%

(Normal karyotype only: 11-39%)

Total genomic alteration Prognostic poor survival [1][2][3][4][5]
1p CN-LOH Prognostic for progression to AML [6][7][8][9][10]
1q gain Recurrent [6][11]30[10]
4q loss TET2 Prognostic for poor survival [6]21, 23, 24, 47]
4q CN-LOH TET2 Prognostic for poor survival [12,[6]16, 21, 30,[3][8]38, 46, 64, 111]
5q loss 5q loss “size” prognostic for progression to AML [6]15, 21[1], 33, 63[10]112]
7q loss CUX1, EZH2 Prognostic for poor survival [6]15, 18, 30, 32, 39, 46[9]64, 79, 103[10]109, 112]
7q CN-LOH Recurrent [12, [6]21,[7] 30, [8][5] 92, 111]
11q CN-LOH CBL Prognostic/ recurrent [12, [6] 15, [7] [3][8]64[10]
12p loss ETV6 Recurrent [6]16, 30, 32, 47]
13q loss ?RB1 Recurrent [6] 21, 32,[3][10]
17p loss TP53 Recurrent [6]30, 34, 47, 103]
17p CN-LOH TP53 Diagnostic for advanced MDS/sAML [21, 30,[3][8] 39]
20q loss Recurrent [6][9]62, 65, 103, 109, 112]
21q CN-LOH or deletion RUNX1 Prognostic for progression to AML [6]18, 32, 47[9]92]
MDS/MPN 73%/NA 4q CN-LOH TET2 Recurrent [12, 20, 23, 64, 65]
7q CN-LOH Likely CUX1 Recurrent [12, 20[8][9]64]
11q CN-LOH CBL Recurrent [12, 20, 23, [8]44]
MPN >56%/NA 1q gain Recurrent [40, 55, 56]
4q loss TET2 Prognostic for progression to AML [24, 58]
9p CN-LOH JAK2 Predictive for JAK2 inhibitors; Prognostic for PV progression to MF [40, 44, 55, 56, 113]
14q CN-LOH Presence of CNAs/CN-LOH prognostic for progression to AML [40, 55, 56[9]
20q loss Recurrent [40, 55, 114]
CML 21-24%/NA 17p loss TP53 Recurrent, progression, associated with TKI resistance [51, 52]
2q CN-LOH Diagnostic (only seen in BC) [52]
8p CN-LOH Diagnostic (only seen in BC) [52]
BMFS 19% (AA) 6p CN-LOH ?HLA genes Recurrent [78-80]

Table 2.  A comprehensive list of CNAs and CN-LOH of known or likely clinical significance in MDS detected by CMA testing

Chromosome Disease Abnormality Type (Gain, Loss, CN-LOH) Region Relevant Genes (if known) Clinical Significance* Level of Evidence References
1 MDS Gain 1p36.33-p33 MPL Recurrent 3

[15]

[6]62]

1 MDS CN-LOH 1p MPL Recurrent 2 [6][7][8][9]
1 MDS Gain 1q Recurrent 2 [6]21, 30[10]
2 MDS CN-LOH 2pter-2p13.3 DNMT3A Recurrent 2 [6] 63, 64, 115]
3 MDS CN-LOH 3q21.3-qter MECOM, GATA2 Recurrent 3 [6]16, 19, 35, 61]
4 MDS Loss 4q24 TET2 T*** 2 [6]18, 21, 23, 24, 32, 47]
4 MDS CN-LOH 4q12-qter TET2 Recurrent 2 [12, [6]16, 21, 29, 30, [8]38, 46, 64, 111]
5 MDS Gain 5p Suggestive of i(5p) with 5q del Recurrent 3 [6]
5 MDS Loss 5q RPS14 D, P (Good when isolated) 1 [6], 15,16, 18, 19, 21[1], 30, 33, 34, [3], 39, 43, 46, [5] 62-65, 103[10]112, 116]
7 MDS Loss 7q EZH2, CUX1 D, P (Intermediate) 1 [6]15, 18, 19,[1] 30, 32, 34, 39, 46, [5][9]79, 103[10]112]
7 MDS CN-LOH 7q21.11-qter EZH2, CUX1 Recurrent 2 [12, [6]16, 19, 21,[7] 30[8][5]92, 111]
7 MDS Loss (Monosomy) 7 Whole Chromosome D, P (Poor) 1 [34, 39, 46, 64, 79, 103[10]109, 112]
8 MDS Gain (Trisomy) 8 Whole Chromosome P (Intermediate)** 1 [6]21, 30, 34, 47, [5][9] 62, 74, 79, 103, 112]
9 MDS Gain 9p JAK2 Recurrent 3 [6]30, 47]
9 MDS CN-LOH 9pter-p24.2 JAK2 Recurrent 2 [6]31,[3]]
11 MDS Loss 11q14.1-q24.3 CBL D, P (Very Good) 1 [6] 62]
11 MDS CN-LOH 11q13.3-qter CBL Recurrent 2 [12,[6] 15, 25,[3][8] 64[10]109]
11 MDS Gain (Trisomy and q-arm) 11 / 11q CBL Recurrent 3 [6] 16[1]30, 64]
12 MDS Loss 12p ETV6 D, P (Good) 1 [6]16, 30, 32, 47]
12 MDS CN-LOH 12pter-p11.23 ETV6 Recurrent 2 [3], 64]
13 MDS Loss 13q RB1 D, P (Intermediate) 2 [6]21,[3][10]
13 MDS CN-LOH 13q12.3-qter FLT3, RB1 Recurrent 3 [6][8]64]
13 MDS Gain (Trisomy) 13 Whole Chromosome Recurrent 3 [6]
14 MDS CN-LOH 14q24.2-qter CHGA Recurrent 3 [6]15, 25, 29[8]
16 MDS Loss (Monosomy and q-arm) 16 / 16q CDH1 Recurrent 3 [6]47[10]
16 MDS CN-LOH 16q22.1-qter CDH1 Recurrent 3 [6]92]
17 MDS Loss 17p TP53 P (Poor) 1 [6]30, 34, 43, 47, [5] 103]
17 MDS CN-LOH 17pter-p11.2 TP53 Recurrent 2 [16, 21, 30, 33,[3][8]39[5]]
17 MDS Loss 17q11.2 NF1 Recurrent 3 [32, 47]
17 MDS CN-LOH 17q11.2-qter SRSF2, NF1 Recurrent 2 [6]19, 25]
19 MDS CN-LOH 19pter-p13.11 DNMT1, PRDX2 Recurrent 3 [9]64]
19 MDS Loss 19p13.13 PRDX2 Recurrent 3 [1]
19 MDS Gain (Trisomy) 19 Whole Chromosome Recurrent 2 [6][9]
20 MDS Gain 20p Suggestive of ider(20p) with 20q del Recurrent 3 [6]
20 MDS Loss 20q ASXL1 P (Good)** 1 [6] 21[1] 43,[5][9]62, 65, 92, 103, 109, 112]

[15, 30, 46, 114, 117]

20 MDS CN-LOH 20q11.21-qter ASXL1 Recurrent 2 [5]92]
21 MDS Loss 21q22.12 RUNX1 D, P (Poor) 2 [6] 16, 18, 21, 32, 34, 47]
21 MDS CN-LOH 21q21.1-qter RUNX1, U2AF1 Recurrent 2 [6] 25, [5]111, 116]
21 MDS Gain (Trisomy) 21 Whole Chromosome Recurrent 2 [6]30, 103]
22 MDS CN-LOH 22q11.23-qter MN1, SF3A1, EP300 Recurrent 3 [6][10]

Table 3.  A comprehensive list of CNAs and CN-LOH of known or likely clinical significance in MDS/MPN detected by CMA testing

Chromosome Disease Abnormality Type (Gain, Loss, CN-LOH) Region Relevant Genes (if known) Clinical Significance* Level of Evidence References
1 MDS/MPN CN-LOH 1p21.3 MPL Recurrent 2 [37]
4 MDS/MPN Loss 4q24 TET2 Recurrent** 2 [23]
4 MDS/MPN CN-LOH 4q12.4-qter TET2 Recurrent 2 [12, 20, 23[8] 64, 65]
5 MDS/MPN Loss (Monosomy and q-arm) 5 / 5q RPS14 P (Intermediate) 1 [23, 28, 33, 44, 56, 63]
7 MDS/MPN Loss 7q EZH2, CUX1 P (Poor) 1 [12, 44]
7 MDS/MPN CN-LOH 7q21.11-qter EZH2, CUX1 Recurrent 2 [12, 20[8][9]64]
8 MDS/MPN Gain (Trisomy) 8 Whole chromosome P (Poor) 1 [56, 64]
9 MDS/MPN CN-LOH 9pter-p13.3 JAK2 Recurrent 2 [8]
11 MDS/MPN CN-LOH 11q13.2-qter CBL Recurrent 2 [12, 20, 23[8]
12 MDS/MPN Loss 12p ETV6 P (Intermediate) 1 [20, 28]
13 MDS/MPN Loss 13q RB1 P (Intermediate) 1 [44, 56]
14 MDS/MPN CN-LOH 14q CHGA Recurrent 3 [8]
17 MDS/MPN Loss 17p TP53 P (Poor)*** 1 [56]
20 MDS/MPN Loss 20q ASXL1 P (Intermediate) 2 [44]
21 MDS/MPN Gain 21q22.12 RUNX1 P (Intermediate) 2 [20, 23]
21 MDS/MPN CN-LOH 21q22-qter RUNX1 Recurrent 2 [20[8]

Table 4. A comprehensive list of CNAs and CN-LOH of known or likely clinical significance in

MPN detected by CMA testing

Chromosome Disease Abnormality Type (Gain, Loss, CN-LOH) Region Relevant Genes (if known) Clinical Significance* Level of Evidence Reference (PMID)
1 MPN CN-LOH 1p21.3 MPL Recurrent 2 [40]
1 MPN Gain 1q21.2-q32.1 Recurrent 2 [40, 55, 56]
4 MPN Loss 4q24 TET2 Recurrent 2 [24, 58]
5 MPN Loss 5q RPS14 P (Poor) 1 [63]
6 MPN Loss 6p23-22.3 JARID2 Recurrent 3 [56, 60]
7 MPN Loss 7q EZH2, CUX1 P (Poor) 1 [40]
7 MPN CN-LOH 7q22.1-qter EZH2, CUX1 Recurrent 2 [52]
8 MPN Gain (Trisomy) 8 Whole chromosome P (Poor) 1 [51]
9 MPN Gain 9p JAK2 Recurrent 2 [40, 55, 56]
9 MPN CN-LOH 9pter-p13.3 JAK2 Recurrent 2 [40, 44] [55] [56, 113]
9 CML Loss 9q34 Recurrent 3 [50, 51]
9 CML Gain 9q34 (+Ph) ABL1 Recurrent 1 [51]
11 MPN CN-LOH 11q13.4-q25  CBL Recurrent 2 [40, 55]
12 MPN Loss 12p13.3-p12.2 ETV6 P (Poor) 1 [52]
13 MPN Loss 13q RB1 Recurrent 1 [55]
14 MPN CN-LOH 14q CHGA Recurrent 3 [40, 55, 56[9]
17 MPN Loss 17p TP53 P (Poor) 1 [51, 52, 55]
20 MPN Loss 20q ASXL1 Recurrent 1 [40, 55, 114]
22 CML Loss 22q11.2 Recurrent 3 [50, 51]
22 CML Gain 22q11.2 (+Ph) BCR Recurrent 1 [51]
  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Starczynowski DT, Vercauteren S, Telenius A, Sung S, Tohyama K, Brooks-Wilson A, et al. High-resolution whole genome tiling path array CGH analysis of CD34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival. Blood 2008;112:3412-24.[1]
  2. ↑ Yeung CCS, McElhone S, Chen XY, Ng D, Storer BE, Deeg HJ, et al. Impact of copy neutral loss of heterozygosity and total genome aberrations on survival in myelodysplastic syndrome. Mod Pathol 2017.[2]
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 Arenillas L, Mallo M, Ramos F, Guinta K, Barragan E, Lumbreras E, et al. Single nucleotide polymorphism array karyotyping: a diagnostic and prognostic tool in myelodysplastic syndromes with unsuccessful conventional cytogenetic testing. Genes Chromosomes Cancer 2013;52:1167-77.[3]
  4. ↑ Cluzeau T, Moreilhon C, Mounier N, Karsenti JM, Gastaud L, Garnier G, et al. Total genomic alteration as measured by SNP-array-based molecular karyotyping is predictive of overall survival in a cohort of MDS or AML patients treated with azacitidine. Blood Cancer J 2013;3:e155.[4]
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 Ganster C, Shirneshan K, Salinas-Riester G, Braulke F, Schanz J, Platzbecker U, et al. Influence of total genomic alteration and chromosomal fragmentation on response to a combination of azacitidine and lenalidomide in a cohort of patients with very high risk MDS. Leuk Res 2015;39:1079-87.[5]
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 6.15 6.16 6.17 6.18 6.19 6.20 6.21 6.22 6.23 6.24 6.25 6.26 6.27 6.28 6.29 6.30 6.31 6.32 6.33 6.34 6.35 6.36 6.37 6.38 6.39 6.40 6.41 6.42 6.43 6.44 6.45 Tiu RV, Gondek LP, O'Keefe CL, Elson P, Huh J, Mohamedali A, et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood 2011;117:4552-60.[6]
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Gondek LP, Haddad AS, O'Keefe CL, Tiu R, Wlodarski MW, Sekeres MA, et al. Detection of cryptic chromosomal lesions including acquired segmental uniparental disomy in advanced and low-risk myelodysplastic syndromes. Exp Hematol 2007;35:1728-38.[7]
  8. ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 8.12 8.13 8.14 8.15 8.16 8.17 8.18 8.19 Dunbar AJ, Gondek LP, O'Keefe CL, Makishima H, Rataul MS, Szpurka H, et al. 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 2008;68:10349-57.[8]
  9. ↑ 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 9.11 9.12 9.13 Sugimoto Y, Sekeres MA, Makishima H, Traina F, Visconte V, Jankowska A, et al. Cytogenetic and molecular predictors of response in patients with myeloid malignancies without del[5q] treated with lenalidomide. J Hematol Oncol 2012;5:4.[9]
  10. ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 10.12 10.13 Xu X, Johnson EB, Leverton L, Arthur A, Watson Q, Chang FL, et al. The advantage of using SNP array in clinical testing for hematological malignancies--a comparative study of three genetic testing methods. Cancer Genet 2013;206:317-26.[10]
  11. ↑ Evans AG, Ahmad A, Burack WR, Iqbal MA. Combined comparative genomic hybridization and single-nucleotide polymorphism array detects cryptic chromosomal lesions in both myelodysplastic syndromes and cytopenias of undetermined significance. Mod Pathol 2016;29:1183-99.[11]
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