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Letters to the Editor
Structural aberrations are associated with poor survival in patients with clonal cytopenia of undetermined significance
Many patients referred to the hematological depart- ment with unexplained cytopenia are diagnosed with idiopathic cytopenia of undetermined significance (ICUS) when diagnostic bone marrow (BM) morphological find- ings or cytogenetic abnormalities defining myelodysplas- tic syndromes (MDS) are absent.1 Approximately half of ICUS patients harbor MDS-related somatic mutations, a condition known as clonal cytopenia of undetermined significance (CCUS), associated with a >13-fold higher risk of progression to MDS or acute myeloid leukemia (AML) than ICUS patients without detectable mutations (i.e., ICUS non-clonal).1,2 Still, the natural history of ICUS varies considerably; thus, additional prognostic markers remain to be identified.
Single nucleotide polymorphism-based array analysis (SNP-A) in patients with myeloid malignancies allows the identification of chromosomal aberrations beyond the resolution of metaphase cytogenetics (≤5 Mb), i.e., focal copy number aberrations (CNA) and copy-neutral loss of heterozygosity (CNLOH) (Online Supplementary Figure S1), that correlate with clinical features and out- come (reviewed by Kanagal-Shamanna et al.,3 Xu et al.4 and Ronaghy et al5).
In this study, we investigated whether CNA and CNLOH were also present in ICUS patients and, if so, whether they had prognostic impact.
Patients (n=153) diagnosed with ICUS after routine work-up in Denmark between 2009-2017 were included upon first visit to the Department of Hematology and fol- lowed prospectively until death or study cut-off date (Online Supplementary Methods).
The study was approved by the Danish Science Ethics Committee and conducted in accordance with the
Table 1. Structural aberrations, including relevant genes affected, in the cohort of 153 patients with idiopathic cytopenia that are also recur- rently detected in myeloid malignancies.
A
Chromosomal Region
1p34
1q
Abnormality type
CNLOH
CNLOH
Relevant gene(s) (if known)*
MPL
No. and disorder of cases
1 (CCUS)
1 (ICUS non-clonal)
Relation*
MDS, MDS/MPN, MPN, AML
MDS, MPN
2p23 Deletion DNMT3A 1 (ICUS non-clonal) MDS, AML 4q12-q24 CNLOH, Deletion TET2, PDGFRA, FIP1L1 2, CNLOH (CCUS); 1, Deletion (CCUS) MDS, MDS/MPN, MPN, AML
7q22 Deletion CUX1 1 (CCUS) MDS, MDS/MPN, MPN, AML 11q13-q23 CNLOH CBL, CCND1 1 (CCUS) MDS, MDS/MPN, MPN, AML
19p13
20q
B
Gene Chr
TET2‡ 4 CUX1 7
CNLOH CNLOH
Start, bp
106,067,032
101,458,959
DNMT1, PRDX2
1 (ICUS non-clonal) 1 (CCUS)
MDS MDS
Relation
MDS, MPN, AML
MDS, MPN, AML
End, bp
106,200,973
101,927,250
OMIM
612839
116896
Abnormality
Deletion CNLOH Deletion
Patient ID†
36 22, 34 34
Disorder of patient
CCUS CCUS CCUS
DNMT3A‡ 2 25,455,845 25,565,459 602769 Deletion 6 ICUS non-clonal MDS, MPN, AML IDH2‡ 15 90,626,277 90,645,736 147650 CNLOH§ 11 CCUS MDS, MPN, AML
CALR 19 13,049,392 13,055,304 109091 CNLOH 13 ICUS non-clonal MPN GNAS 20 57,414,773 57,486,250 139320 CNLOH 1 CCUS MDS, AML
CBL‡ 11 119,076,752 119,178,859 165360 CNLOH 1 MDS, MPN, AML MLL 11 118,307,205 118,397,539 159555 CNLOH 1 AML
SF1 11 64,532,076 64,546,316 601516 CNLOH 1 MDS, AML GNB1 1 1,716,725 1,822,526 139380 CNLOH 14 CCUS MDS, AML
MPL 1 43,803,475 43,820,135 159530 CNLOH 14 MDS, MPN, AML FBXW7 4 153,242,410 153,457,253 606278 CNLOH 22, 34 CCUS AML
KIT 4 55,524,085 55,606,881
-Y
164920
CNLOH
34 CCUS MDS, MPN, AML
[10 patients] ICUS MDS, MPN, AML
non-clonal/CCUS
(A) List of copy number aberrations (CNA) and copy neutral loss of heterozygosity (CNLOH) in our study cohort of patients with idiopathic cytopenia of undetermined significance (ICUS),that are also recurrently detected in patients with myeloid malignancies.These include ten CNA and CNLOH in eight chromosomal regions identified in eight patients (two patients had more than one).The cases listed in this table are all included in (B) except for chromosome 1q abnormality,as the gene(s) at this loca- tion that is relevant for myeloid malignancies is unknown. (B) List of genes recurrently affected in myelodysplastic syndromes, myeloproliferative neoplasms and/or acute myeloid leukemia that were involved in CNA and/or CNLOH in the ICUS patients.The cases listed in this table are all included in (A),except for the one marked by a section sign (§) as CNLOH(15q) is not reported as a recurrent lesion in myeloid malignancies.*From reviews by Kanagal-Shamanna et al.3 and Xu et al.4 †Patient ID in accordance with Online Supplementary Tables S2, S3. ‡Genes included in the 20-gene panel and sequenced in the study. §Not included in (A). CNLOH: copy-neutral loss of heterozy- gosity; CCUS: clonal cytopenia of undetermined significance; ICUS: idiopathic cytopenia of unknown significance; MDS: myelodysplastic syndromes; MPN: myeloprolifera- tive neoplasms; AML: acute myeloid leukemia; Chr: chromosome; bp: base pairs; OMIM: online Mendelian inheritance in man.
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