Deep sequencing and SNP array analyses of pediatric T-cell acute lymphoblastic leukemia reveal NOTCH1 mutations in minor subclones and a high incidence of uniparental isodisomies affecting CDKN2A

Abstract

BackgroundPediatric T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that arises in a multistep fashion through acquisition of several genetic aberrations, subsequently giving rise to a malignant, clonal expansion of T-lymphoblasts. The aim of the present study was to identify additional as well as cooperative genetic events in T-ALL.MethodsA population-based pediatric T-ALL series comprising 47 cases was investigated by SNP array and deep sequencing analyses of 75 genes, in order to ascertain pathogenetically pertinent aberrations and to identify cooperative events.ResultsThe majority (92%) of cases harbored copy number aberrations/uniparental isodisomies (UPIDs), with a median of three changes (range 0–11) per case. The genes recurrently deleted comprised CDKN2A, CDKN2B, LEF1, PTEN, RBI, and STIL. No case had a whole chromosome UPID; in fact, literature data show that this is a rare phenomenon in T-ALL. However, segmental UPIDs (sUPIDs) were seen in 42% of our cases, with most being sUPID9p that always were associated with homozygous CDKN2A deletions, with a heterozygous deletion occurring prior to the sUPID9p in all instances. Among the 75 genes sequenced, 14 (19%) were mutated in 28 (72%) of 39 analyzed cases. The genes targeted are involved in signaling transduction, epigenetic regulation, and transcription. In some cases, NOTCH1 mutations were seen in minor subclones and lost at relapse; thus, such mutations can be secondary events.ConclusionsDeep sequencing and SNP array analyses of T-ALL revealed lack of wUPIDs, a high proportion of sUPID9p targeting CDKN2A, NOTCH1 mutations in subclones, and recurrent mutations of genes involved in signaling transduction, epigenetic regulation, and transcription.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0138-0) contains supplementary material, which is available to authorized users.

Translocation t(8;14)(q24;q11) with concurrentPTENalterations and deletions ofSTIL/TAL1andCDKN2A/Bin a pediatric case of acute T-lymphoblastic leukemia: A genetic profile associated with adverse prognosis

“…PTEN loss‐of‐function mutations result in MYC overexpression via upregulation of the PI3K/AKT pathway and stabilized MYC protein levels . The fact that diagnostic and relapse bone marrow samples of our patient shared some PTEN deletions, while a relapse sample harbored a new mutation, also supports the hypothesis of subclone selection and may indicate relapse from the preleukemic clone . The genetic profile of our leukemia case with t(8;14)(q24;q11) and NOTCH wt / FBXW7 wt / PTEN mut agrees with that of leukemia‐initiating cells (LICs) in Pten ‐null experimental T‐ALL model.…”

Persistent donor derived Vδ4 T cell clones may improve survival for recurrent T cell acute lymphoblastic leukemia after HSCT and DLI

“…This T cell expansion may be enhanced by IL-2 and IFN-γ which were used with DLI [16, 17]. However, even the relapse with the same Vδ5 leukemic clone, whether there was evolution in another molecule that may affect the biological behavior of a leukemic clone remains unclear, this may be identified by deep sequencing of the patient samples, which were collected at each instance of disease recurrence [18–20]. …”

Pediatric T‐cell acute lymphoblastic leukemia

“…Conventional chromosome banding analyses reveal clonal abnormalities in 55–75% of T‐ALL cases (Table ), a frequency clearly lower than that of 85–90% in childhood BCP ALL (Zachariadis et al, ). However, the proportion of aberrant T‐ALL increases quite substantially if interphase fluorescence in situ hybridization (FISH) or single nucleotide polymorphism array (SNP‐A) analyses are performed (Karrman et al, ). Hence, chromosomal changes in T‐ALL often escape cytogenetic detection.…”

“…Whole chromosome UPIDs are very rare (<1%) in T‐ALL (Kawamata et al, ; Karrman et al, ) in contrast to pediatric BCP ALL where such UPIDs are found in 5–10% of cases (Kawamata et al, ; Lundin et al, ). One reason for this frequency discrepancy could be the fact that whole chromosome UPIDs are particularly common in aneuploid malignancies (Lundin et al, ) and that T‐ALL cases only rarely are aneuploid (Fig.…”