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•The pattern of whole CNAs associates with the kinetics of blasts clearance.•Aberrations of DNA repair genes may promote BCP-ALL chemoresistance.•Chromothripsis occurs in ‘’slow ...responders’’ harboring somatic defects of TP53 or RB1.
We analyzed the pattern of whole-genome copy number alterations (CNAs) and their association with the kinetics of blast clearance during the induction treatment among 195 pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who displayed intermediate or high levels of minimal residual disease (MRD). Using unsupervised hierarchical clustering of CNAs > 5 Mbp, we dissected three clusters of leukemic samples with distinct kinetics of blast clearance A – early slow responders (n=105), B – patients with persistent leukemia (n=24), C – fast responders with the low but detectable disease at the end of induction (n=66) that corresponded with the patients’ clinical features, the microdeletion profile,the presence of gene fusions and patients survival. Low incidence of large CNAs and chromosomal numerical aberrations occurred in cluster A which included ALL samples showing recurrent microdeletions within the genes encoding transcription factors (i.e., IKZF1, PAX5, ETV6, and ERG), DNA repair genes (XRCC3 and TOX), or harboring chromothriptic pattern of CNAs. Low hyperdiploid karyotype with trisomy 8 or hypodiploidy was predominantly observed in cluster B. Whereas cluster C included almost exclusively high-hyperdiploid ALL samples with concomitant mutations in RAS pathway genes. The pattern of CNAs influences the kinetics of leukemic cell clearance and selected aberrations affecting DNA repair genes may contribute to BCP-ALL chemoresistance.
Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCPALL) is a high-risk acute lymphoblastic leukemia subtype characterized by the presence of BCR::ABL1 fusion gene. ...Tyrosine kinase inhibitors (TKIs) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab (RTX), an anti-CD20 monoclonal antibody (mAb) is administered in adult BCP-ALL patients with ≥20% of CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of RTX in combination with TKIs. Consequently, we examined the influence of TKIs on the antitumor effectiveness of anti-CD20 mAbs by evaluating CD20 surface levels and conducting in vitro functional assays. All tested TKIs were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of RTX-mediated complement-dependent cytotoxicity. Interestingly, these TKIs displayed varied effects on NK cell-mediated antibody-dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-mAb-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity within patients' blood, determined by ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKIs for combination therapy with anti-CD20 mAbs.
Ovarian carcinoma is an extremely rare malignancy in children, often developing on the underlying inherited background. Female carriers of pathogenic germline mutations of
SMARCA4
are at risk of an ...aggressive type of undifferentiated ovarian cancer called small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Regardless of age of the patient, stage of the disease, and oncological treatment, the prognosis for SCCOHT is poor. Therefore, early intervention with risk-reducing surgeries is recommended for these patients
.
In this study, we report genetic testing of a family with two children carrying pathogenic germline mutations of
SMARCA4
and summarize the course of SCCOHT in all pediatric patients reported in the literature with constitutional defects identified within the
SMARCA4
locus.
Germline pathogenic variants in the ETV6 gene are associated with type 5 thrombocytopenia and acute lymphoblastic leukemia (ALL). Its involvement in other regulatory pathways and recent case reports ...suggest that it may influence the toxicity of treatment of ALL and incidence of adverse events.
Characterization of patients with ALL and germinal ETV6 mutation regarding course of their treatment.
Between October 2018 and January 2024 consecutive pediatric patients with ALL were screened for germline ETV6 mutations. On confirmation, additional blood and bone marrow samples were taken from subjects and their families for further genetic diagnostics, blood and bone marrow cells subpopulations composition, and immunoglobulin levels analysis. The treatment of patients was monitored through reports to investigators, medical history and medical follow-up.
Out of 1276 children with ALL treated according to AIEOP-BFM2017 protocols in Poland, three (aged 10, 11 and 17 years) were diagnosed with germline ETV6 mutations (0.23%), family members of two were diagnosed as well, one presented with de novo mutation. Patients A and B and their families presented the c.641C>T (p.Pro214Leu) variant and patient C the c.1157G>T (pArg386Ile) variant. Patient A additionally was diagnosed with IKZF1plus molecular profile (IKZF1 and PAX5 deletion), patients B and C with hyperdiploidy. All subjects presented elevated MCV (95-101 fL) and mild thrombocytopenia (75 000-100 000/μL). All patients experienced exacerbation of thrombocytopenia during ALL treatment, requiring frequent transfusions and intermissions during treatment (40 to 180 days), mainly in the reinduction and maintenance phase. Patient A experienced acute pancreatitis during the induction phase that required admission to PICU, which was followed by PRES syndrome phase and SIADH, along with C. difficile infection during maintenance therapy that required fecal transplant and bilateral osteonecrosis, requiring mobility aids. Patient B had numerous febrile neutropenia episodes; one of them was complicated with P. aeruginosa infection of tissues surrounding central line and intermediate liver toxicity. Patient C experienced mild sinus tachycardia and febrile neutropenia episodes. All patients are currently in remission.
Germline ETV6 defect is a rare germline condition predisposing to ALL and may become a prognostic factor, considering the complications the subjects experienced and the subsequent intermissions in treatment.
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous disease with multiple molecular subtypes associated with different prognostic significance. High expression of TSLP receptor ...(CRLF2) protein on the leukemic surface has been correlated with poor outcomes and reduced survival.
To determine whether high expression of CRLF2 as a single factor or coexistence of other molecular rearrangements and activation of the JAK/STAT signaling pathway is responsible for poor prognosis in BCP-ALL patients.
Since June 2021, all newly diagnosed patients with ALL from 16 Pediatric Oncology Centers in Poland, treated according to the clinical AIEOP BFM 2017 Poland clinical trial, were enrolled in our study.
Patients from the AIEOP BFM 2017 Poland clinical trial who underwent advanced molecular diagnostics were analyzed (n=426). Patients with the expression of the CRLF2 detected by flow cytometry (FC) were distinguished (n=21). Expression was assessed as positive if >50% (strong) or dim if 10-50%. Gene fusions and point mutations found by fluorescence in situ hybridization (FISH) and RNA next-generation sequencing (RNA-seq) with TruSight RNA Pan-Cancer Panel were assessed.
In ALL patients with the expression of CRLF2, evaluation of other molecular rearrangements and clinical features was performed, and they were subjected to consider applying targeted therapy with JAK/STAT inhibitors (ruxolitinib).
The study group consisted of patients with BCP-ALL in which expression of CRLF2 was found. Seventeen patients had strong, and 4 had a dim expression of CRLF2. In 18 patients, gene fusions as CRLF2::P2RY8, CRLF2::IGH, and NUP214::ABL1 were detected. Point mutations in CRLF2 and JAK2 were identified in 3 and 6 patients, respectively. In 10 patients, more than one rearrangement was noticed, and in 4 patients, neither gene fusion nor point mutations responsible for positive expression of CRLF2 were found. Additionally, 4 patients harbored IKZF1 deletion. Patients were stratified into standard (n=7; 33,3%), medium (n=8; 38,1%), and high (n=6; 28,6%) risk groups. Five patients with poor responses to the standard treatment received targeted therapy (ruxolitinib).
In patients with CRLF2 expression, other molecular rearrangements should be searched to determine the proper risk group.
Adrenocortical carcinoma (ACC) is a rare cancer in childhood. ACC is frequently associated with germline TP53 variants, with founder effects especially due to the p.Arg337His mutation. ACC leads to ...the secretion of adrenocortical hormones, resulting in endocrine syndromes, which is the usual trigger for establishing the diagnosis. We present a surprising ACC pathology in a non-secreting, ectopic retroperitoneal tumour in a 4-year-old boy, successfully controlled with chemotherapy and mitotane after microscopically incomplete tumour resection with spillage. Genomic analysis (gene panel sequencing and copy-number microarray) demonstrated a novel p.Phe338Leu tetramerisation domain (TD) TP53 variant in the proband and his cancer-free mother and a monoallelic deletion encompassing the TP53 locus in cancer tissue, consistent with cancer-predisposition syndrome. While the recurrent p.Arg337His variant translates into high ACC risk, residue 338 and, in general, TD domain variants drive heterogeneous clinical scenarios, despite generally being considered less disruptive than TP53 DNA-binding domain mutations.
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