Defining the Topography of Deletion 5q Using SNP-A Identifies Patients with More Aggressive Disease and Correlates with Additional Lesions

Abstract 2795

Interstitial deletions of chromosome 5q are common in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), pointing towards 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. In order to better address the genetic and genomic complexity of 5q abnormalities in myeloid malignances, we analyzed a large series of 1,155 clinically well-annotated patients with malignant myeloid disorders with SNP-A-based karyotyping to define: i) the extent of the 5q deletion, investigating whether loss of genes is different among 5q disorders; ii) minimally deleted region(s); iii) associated non-5q genomic lesions with 5q abnormalities; and iv) the association of genomic abnormalities with clinical features. We identified chromosome 5q deletions in 142/1155 patients (12%) and uniparental disomy segments (UPD) in 4/1155 patients (0.35%).

With increased resolution there was a shift towards more complex karyotypes and increased identification of additional lesions among the patients with 5q aberrations. By SNP-A, previously cryptic lesions were identified in 52% of the patients who otherwise showed a singular del(5q) lesion by metaphase cytogenetics (MC). The presence of chromosome 5q material in all our cases with apparent monosomy 5 (N=11) by conventional MC serves as an illustration for SNP array-based mapping allowing for a more precise definition of the breakpoints; in addition, 48% of MC results localized both the beginning and end of the deletion to a different band than SNP-A, and in only 9% of cases, MC and SNP-A boundaries coincided. The CDR defined in our 5q-syndrome, though with wider limits (145,279,940–153,809,148), encompasses the CDR described by Boultwood et al; the CDR in advanced del(5q) MDS and AML patients is centered on a sub-section of bands 5q31.2 and 5q31.3 (137,528,564–139,451,907) and includes the defect initially mapped by Le Beau et al. Patients with MDS and deletions involving the centromeric and telomeric extremes of 5q have a more aggressive disease phenotype (median overall survival: 32 months, p=0.04, HR 1.9; median number of chromosome lesions: 5.8 vs. 1.1, p<0.001:; median time to progression: 30 months vs not reached, p<0.001). Moreover, 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 (25% vs 11% of cases, respectively). We closely investigated the outlying cases of aggressive disease and shorter interstitial deletions. We chose to test for 6 possible tumor suppressor genes, located within the extremes of 5q and related to the TP53 pathway that, if defective, might explain a clonal advantage. In our AML cohort only 5 patients showed a deletion not involving the 5q extremes: 4/5 of them displayed either NPM1 and/or MAML1 heterozygous mutations. In summary, the present study of 5q disorders shows that SNP-A can complement traditional MC, not only by finding cryptic abnormalities, but also by precisely defining the extent of the lesions. Moreover, we have perfomed whole exon sequencing but to date the analysis did not identify genes mutated on 5q rather the ones described above. Our results strongly suggest that while genes widely deleted among 5q disorders may be responsible for the characteristics of the dysplastic clone, the loss of an additional gene or genes in the proximal and telomeric extremes of 5q may be responsible of increasing genomic instability, favoring AML transformation.