Anaplastic sarcoma of the kidney (ASK) is a tumor found in the pediatric age group and shows many histopathological similarities to pleuropulmonary blastoma (PPB). We present a 12-year-old girl ...diagnosed with ASK and, three years later, with thyroid follicular carcinoma (TFC) with DICER1 abnormalities. Germline insertion/deletion (p.G1809_S1814delinsA) and independent somatic mutations (p.E1705K in ASK, p.E1813D in TFC) were identified. All of these abnormalities are in the catalytic domain of RNase IIIb. Single-nucleotide polymorphism genotyping microarray revealed independent copy number alterations (trisomy 8, monosomy 10, loss of 17p and partial gain of 17q in ASK; trisomy 5 and partial loss of Xq in TFC). The copy number alteration pattern of ASK was similar to the pattern previously reported in PPB. The present case implies that ASK is a renal counterpart of PPB, and that ASK with DICER1 abnormalities should be suspected in a broader age group than PPB.
Assuming that the time-evolution of the self-consistent mean field is determined by five pairs of collective coordinate and collective momentum, we microscopically derive the collective Hamiltonian ...for low-frequency quadrupole modes of excitation. We show that the five-dimensional collective Schrödinger equation is capable of describing large-amplitude quadrupole shape dynamics seen as shape coexistence/mixing phenomena. We focus on basic ideas and recent advances of the approaches based on the time-dependent mean-field theory, but relations to other time-independent approaches are also briefly discussed.
Molecular mechanisms involved in the relapse of T‐cell acute lymphoblastic leukemia (T‐ALL) are not fully understood, although activating NOTCH1 signaling due to NOTCH1/FBXW7 alterations is a major ...oncogenic driver. To unravel the relevance of NOTCH1/FBXW7 mutations associated with relapse, we performed whole–exome sequencing in 30 pediatric T‐ALL cases, among which 11 diagnosis‐relapse paired cases were further investigated to track the clonal evolution of relapse using amplicon–based deep sequencing. NOTCH1/FBXW7 alterations were detected in 73.3% (diagnosis) and 72.7% (relapse) of cases. Single nucleotide variations in the heterodimerization domain were the most frequent (40.0%) at diagnosis, whereas proline, glutamic acid, serine, threonine–rich (PEST) domain alterations were the most frequent at relapse (54.5%). Comparison between non–relapsed and relapsed cases at diagnosis showed a predominance of PEST alterations in relapsed cases (P = .045), although we failed to validate this in the TARGET cohort. Based on the clonal analysis of diagnosis‐relapse samples, we identified NOTCH1 “switching” characterized by different NOTCH1 mutations in a major clone between diagnosis and relapse samples in 2 out of 11 diagnosis‐relapse paired cases analyzed. We found another NOTCH1 “switching” case in a previously reported Berlin‐Frankfurt‐Münster cohort (n = 13), indicating NOTCH1 importance in both the development and progression of T‐ALL. Despite the limitations of having a small sample size and a non–minimal residual disease–based protocol, our results suggest that the presence of NOTCH1 mutations might contribute to the disease relapse of T‐ALL.
As molecular mechanisms involved in the relapse of T‐ALL are not fully understood, we performed clonal analysis of diagnosis‐relapse samples using next–generation sequencing, specifically to establish the relevance of NOTCH1/FBXW7 mutations associated with relapse. We identified mutational “switching” of NOTCH1 showing different NOTCH1 mutations between diagnostic and relapsed specimens in multiple samples, which indicates the importance in development and progression of T‐ALL.
Neuroblastoma, the most common extracranial solid malignancy among children, originates from undifferentiated neural crest cells (NCC). Despite recent intensified treatment, high-risk patients still ...have a high mortality rate. To explore a new therapeutic strategy, we performed an integrated genomic and transcriptomic analysis of 30 high-risk neuroblastoma cases. Based on the expression profiling of RNA sequencing, neuroblastoma was classified into Mesenchymal (MES; n = 5) and Noradrenergic (ADRN; n = 25) clusters, as previously reported in the super-enhancer landscape. The expression patterns in MES-cluster cases were similar to normal adrenal glands, with enrichment in secretion-related pathways, suggesting chromaffin cell-like features built from NCC-derived Schwann cell precursors (SCPs). In contrast, neuron-related pathways were enriched in the ADRN-cluster, indicating sympathoblast features reported to originate from NCC but not via SCPs. Thus, MES- and ADRN-clusters were assumed to be corresponding to differentiation pathways through SCP and sympathoblast, respectively. ADRN-cluster cases were further classified into MYCN- and ATRX-clusters, characterized by genetic alterations, MYCN amplifications and ATRX alterations, respectively. MYCN-cluster cases showed high expression of ALDH18A1, encoding P5CS related to proline production. As reported in other cancers, this might cause reprogramming of proline metabolism leading to tumor specific proline vulnerability candidate for a target therapy of metabolic pathway. In ATRX-cluster, SLC18A2 (VMAT2), an enzyme known to prevent cell toxicity due to the oxidation of dopamine, was highly expressed and VMAT2 inhibitor (GZ-793A) represented significant attenuation of cell growth in NB-69 cell line (high SLC18A2 expression, no MYCN amplification) but not in IMR-32 cell line (MYCN amplification). In addition, the correlation of VMAT2 expression with metaiodobenzylguanidine (MIBG) avidity suggested a combination of VMAT2 inhibitor and MIBG radiation for a novel potential therapeutic strategy in ATRX-cluster cases. Thus, targeting the characteristics of unique neuroblastomas may prospectively improve prognosis.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Therapy-related myeloid neoplasms (tMNs) are severe adverse events that can occur after treatment with autologous hematopoietic stem cell transplantation (ASCT). This study aimed to investigate the ...development of tMNs following ASCT at the molecular level by whole-exome sequencing (WES) and targeted deep sequencing (TDS) in sequential (pre-) tMN samples. WES identified a significantly higher number of mutations in tMNs as compared with de novo myelodysplastic syndrome (MDS) (median 27 vs 12 mutations; P = .001). The mutations found in tMNs did not carry a clear aging-signature, unlike the mutations found in de novo MDS, indicating a different mutational mechanism. In some patients, tMN mutations were identified in both myeloid and T cells, suggesting that tMNs may originate from early hematopoietic stem cells (HSCs). However, the mutational spectra of tMNs and the preceding malignancies did not overlap, excluding common ancestry for these malignancies. By use of TDS, tMN mutations were identified at low variant allele frequencies (VAFs) in transplant material in 70% of the patients with tMNs. Reconstruction of clonal patterns based on VAFs revealed that premalignant clones can be present more than 7 years preceding a tMN diagnosis, a finding that was confirmed by immunohistochemistry on bone marrow biopsies. Our results indicate that tMN development after ASCT originates in HSCs bearing (pre-)tMN mutations that are present years before disease onset and that post-ASCT treatment can influence the selection of these clones. Early detection of premalignant clones and monitoring of their evolutionary trajectory may help to predict the development of tMNs and guide early intervention in the future.
•tMNs after ASCT originate from HSCs bearing (pre-)tMN mutations that are present years before disease onset.•Post-ASCT treatment can influence selection and outgrowth of (pre)leukemic clones.
RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical relevance in pediatric acute myeloid leukemia (AML) is not well ...characterized. We analyzed the frequency, clinical significance, and prognostic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) of 328 patients: NF1 (n=7, 2.1%), PTPN11 (n=15, 4.6%), CBL (n=6, 1.8%), NRAS (n=44, 13.4%), KRAS (n=12, 3.7%). Most of these alterations in the RAS pathway were mutually exclusive also together with other aberrations of signal transduction pathways such as FLT3-ITD (P=0.001) and KIT mutation (P=0.004). NF1 alterations were frequently detected in patients with complex karyotype (P=0.031) and were found to be independent predictors of poor overall survival (OS) in multivariate analysis (P=0.007). At least four of seven patients with NF1 alterations had biallelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favorable outcomes in multivariate analysis (OS, P=0.023; event-free survival EFS, P=0.037). Patients with PTPN11 mutations more frequently received stem cell transplantation (P=0.035) and showed poor EFS than patients without PTPN11 mutations (P=0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.
The prognosis of pediatric acute myeloid leukemia (AML) has improved via stratification therapy. However, relapse or death occurs in 30%–40% of cases. Novel genetic factors for pediatric AML need to ...be elucidated to improve prognosis. We detected recurrent internal tandem duplication in upstream binding transcription factor (UBTF‐ITD) in 1.2% (6/503) of Japanese pediatric patients with de novo AML. No UBTF‐ITD was detected in 175 adult patients with AML or in 65 cell lines that included 15 AML, 39 acute lymphoblastic leukemia, five chronic myeloid leukemia, and six neuroblastoma cell lines. All UBTF‐ITDs were found in exon 13 and shared a duplicated region. UBTF‐ITD was more frequently detected in patients with trisomy 8, FLT3‐ITD, WT1 mutation, and/or high PRDM16 expression (trisomy 8, 3/6; FLT3‐ITD, 5/6; WT1 mutation, 2/6; and high PRDM16 expression, 6/6). Gene expression patterns of patients with UBTF‐ITD were similar to those of patients with NUP98::NSD1 or FUS::ERG. Survival analysis of the AML‐05 cohort revealed that patients with UBTF‐ITD had worse outcomes than those without UBTF‐ITD (3‐year event‐free survival, 20% vs. 55%; 3‐year overall survival, 40% vs. 74%). Moreover, among the 27 patients with trisomy 8, all three patients with UBTF ‐ITD had a poor prognosis resulting in early events (relapse or non‐complete remission) within 1 year. Our findings suggest that UBTF‐ITD may be a novel and significant prognostic factor for pediatric patients with AML.
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