The prognostic significance of single-nucleotide polymorphism array-based whole-genome analysis and uniparental disomy in myelodysplastic syndrome

Abstract

Introduction: Myelodysplastic syndrome (MDS) is a group of heterogeneous hematological diseases characterized by ineffective hematopoiesis and dysplastic morphology. Single nucleotide polymorphism array (SNP-A)-based whole genome analysis has a much higher resolution for chromosomal alterations when compared with conventional cytogenetic tools. In the present study, we evaluated the diagnostic value and prognostic significance of SNP-A in MDS patients with normal karyotypes.

Methods: A total of 127 patients with MDS and myeloproliferative neoplasms or acute myeloid leukemia with myelodysplasia-related changes were included in our study. The advantages and disadvantages of SNP-A were compared with those of traditional metaphase cytogenetic analysis (MC). The Kaplan-Meier analysis and COX regression analysis were used to investigate the prognostic value of SNP-A and uniparental disomy (UPD) in MDS patients with normal karyotype. Furthermore, the chromosomal abnormalities detected by SNP-A in patients with specific gene mutations were explored.

Results: SNP-A was more sensitive toward meaningful chromosomal aberrations (58.2% vs 36.9%; P < .05) than MC. Among the patients with normal karyotype, those who were detected with new chromosomal abnormalities via SNP-A presented with inferior survival compared with those without the abnormalities (P = .003). Additionally, the presence of UPD was an independent prognostic factor in patients with normal karyotype (P = .01). TP53 and RUNX1 mutations often occurred with abnormalities in chromosomes 17p and 21q, respectively.

Conclusions: Compared with MC, SNP-A capable of detecting UPD can offer more diagnostic and prognostic information; TP53 and RUNX1 gene mutations are often accompanied by abnormalities in their chromosomes (17p, 22q).

Keywords: metaphase cytogenetic analysis; myelodysplastic syndrome; uniparental disomy.

FIGURE 1

The diagnostic information of patients included in the present study: A, The diagnostic composition of all 127 patients and the classification of all 110 patients with MDS. B, MC results of patients included in the present study. SLD: MDS‐SLD, myelodysplastic syndromes with single lineage dysplasia; MLD: MDS‐MLD, myelodysplastic syndromes with multilineage dysplasia; RS‐SLD: MDS‐RS‐SLD, myelodysplastic syndrome with ring sideroblasts with single lineage dysplasia; RS‐MLD: MDS‐RS‐MLD, myelodysplastic syndrome with ring sideroblasts with multiple lineage dysplasia; EB1: MDS‐EB‐1, myelodysplastic syndromes with single lineage dysplasia with excess blasts 1; EB2: MDS‐EB‐2, myelodysplastic syndromes with single lineage dysplasia with excess blasts 2; U: MDS‐U, myelodysplastic syndromes unclassifiable; 5q‐: myelodysplastic syndrome with isolated del(5q)

FIGURE 2

Summary of genomic alterations detected by SNP‐A. Gain: duplication or duplicated alteration; Loss: deletion or deleted alteration; UPD: uniparental disomy; and Complex: complex changes or chromothripsis)

FIGURE 3

Overall survival (OS) of MDS patients with normal karyotype. A, Survival curves in 41 patients without novel chromosomal defects found by SNP‐A (red line) and 22 patients with novel chromosomal defects found by SNP‐A (blue line) using the KM method (P = .003). B, Survival curves in 41 patients without chromosomal structural abnormalities or UPDs (red line) and 15 patients with UPDs (blue line) using the KM method (P = .008). C, Survival curves in 41 patients without chromosomal structural abnormalities or UPDs (red line) and 15 patients with UPDs (blue line) using the COX multivariate regression model (adjusted for the average age, P = .01)

FIGURE 4

The heatmap of the correlation between significant gene mutations and genomic alterations detected by SNP‐A