Topography, clinical, and genomic correlates of 5q myeloid malignancies revisited

Abstract

Purpose: Interstitial deletions of chromosome 5q are common in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), pointing toward the pathogenic role of this region in disease phenotype and clonal evolution. The higher level of resolution of single-nucleotide polymorphism array (SNP-A) karyotyping may be used to find cryptic abnormalities and to precisely define the topographic features of the genomic lesions, allowing for more accurate clinical correlations.

Patients and methods: We analyzed high-density SNP-A karyotyping at diagnosis for a cohort of 1,155 clinically well-annotated patients with malignant myeloid disorders. results: We identified chromosome 5q deletions in 142 (12%) of 1,155 patients and uniparental disomy segments (UPD) in four (0.35%) of 1,155 patients. Patients with deletions involving the centromeric and telomeric extremes of 5q have a more aggressive disease phenotype and additional chromosomal lesions. Lesions not involving the centromeric or telomeric extremes of 5q are not exclusive to 5q- syndrome but can be associated with other less aggressive forms of MDS. In addition, larger 5q deletions are associated with either del(17p) or UPD17p. In 31 of 33 patients with del(5q) AML, either a deletion involving the centromeric and/or telomeric regions or heterozygous mutations in NPM1 or MAML1 located in 5q35 were present.

Conclusion: Our results suggest that the extent of the affected region on 5q determines clinical characteristics that can be further modified by heterozygous mutations present in the telomeric extreme.

Fig 1.

Frequency of detection of 5q abnormalities by metaphase cytogenetics (MC) and single-nucleotide polymorphism array (SNP-A). (A) Distribution of 142 patients with 5q deletion, among the 1,155 SNP-A–tested patients with myeloid malignancies, according to WHO classification. (B) Number of patients with 5q loss of heterozygosity seen on MC and SNP-A. Lesions were observed in 132 of 1,155 and 142 of 1,155 patients when using MC and SNP-A, respectively. Additional 5q lesions were found in noninformative MC (n = 6) or presence of uniparental disomy (UPD; n = 4). (C) Percentage of patients with a sole 5q lesion versus accompanied by other abnormalities as identified by MC and SNP-A. Sole 5q lesions were observed in 44 of 142 versus 21 of 142 patients by MC and SNP-A, respectively. AA, aplastic anemia; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasms.

Fig 2.

Identification of commonly retained regions and their association with disease subtypes. Mapping of deletions detected by single-nucleotide polymorphism array in the cohort separated according the involvement (right) or not (left) of 5q– syndrome commonly retained regions. Deletions have been colored depending on the International Prognostic Scoring System (IPSS) risk group at diagnosis (myelodysplastic syndrome; MDS) or de novo or secondary origin (acute myeloid leukemia; AML). Low-risk MDS includes low and intermediate-1 IPSS groups. High-risk MDS includes intermediate 2 and high-risk IPSS groups.

Fig 3.

Differences in survival outcomes and progression-free survival in patients with myelodysplastic syndrome (MDS) with del(5q). P values presented correspond to the Cox regression between the groups indicated. (A) Comparison of survival outcomes between 5q- syndrome and other forms of del(5q) MDS. (B, C) Patients with other forms of del(5q) MDS were divided according to the involvement of the 5q– syndrome (5qSy) commonly retained region (CRR). (D) There was no difference in survival when comparing 5q syndrome patients with those patients with del(5q) whose lesions did not involve CRR but who could not be classified as 5q– syndrome because of the presence of an additional cytogenetic aberration or more than 5% bone marrow blasts (intermediate-1 International Prognostic Scoring System score).

Fig A1.

(A) Mapping of 5q deletions detected by single-nucleotide polymorphism array (SNP-A) in our cohort. Blue lines indicate the deleted regions in each case. On the left, 5q– syndrome subset deletions are shown with a lighter red rectangle encompassing the commonly deleted region (CDR) in our subset. In darker red, Boultwood's^, CDR and genes involved are shown as reference. The blue rectangles highlight the two commonly retained regions along the long arm of chromosome 5. On the right, other forms of deletions of patients with del(5q) myelodysplastic syndrome (MDS) and del(5q) acute myeloid leukemia (AML) are shown. Again, the lighter red rectangle indicates the CDR in this subset and the darker red rectangle references Le Beau's CDR. (B) For patient 30, metaphase cytogenetics (MC) detected three copies of chromosome 5: one normal homolog and two copies with a segmental deletion of 5q. However, SNP-A (left) demonstrated that although the p-arm portion had been duplicated, the q arm, with the exception of two small microdeletions approximately 1.35 Mb and 1.92 Mb in length, showed a normal diploid set. We hypothesized that fragments of the q arm had been translocated to other regions in the genome before duplication had occurred and had remained undetectable in the MC analysis. To confirm these results, we performed multicolor SKY (upper right) and found that chromosome 5 material (red) had indeed been displaced to both chromosomes 3 (light blue) and 7 (pink) with a reciprocal translocation of chromosome 3 material occurring on the abnormal chromosome 5. In addition, when we performed fluorescent in situ hybridization analysis (bottom right) using probes for early growth response protein 1 (EGR1) at 5q31.2 (red signal) and for D5S23 at 5p15.2 on the short arm (green signal), the results of SNP-A karyotyping were confirmed, showing only one hybridization signal for EGR1 located in the region affected by the microdeletion. Chr, chromosome.

Fig A2.

(A, B) Distribution of disease subtype among patients with deletions (B) involving the 5q - syndrome CRRs or (A) not. (C, D) Additional single-nucleotide polymorphism–detected genomic lesions separated according the same criteria as previously stated. UPD, uniparental disomy.