The KMT2A recombinome of acute leukemias in 2023.

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.

Current recommendations for clinical surveillance and genetic testing in rhabdoid tumor predisposition: a report from the SIOPE Host Genome Working Group.

The rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pathogenic variants (PV) in genes encoding constituents of the BAF chromatin remodeling complex, i.e. SMARCB1 (RTPS1) and SMARCA4 (RTPS2). In contrast to other genetic disorders related to PVs in SMARCB1 and SMARCA4 such as Coffin-Siris Syndrome, RTPS1&2 are characterized by a predominance of truncating PVs, terminating transcription thus explaining a specific cancer risk. The penetrance of RTPS1 early in life is high and associated with a poor survival. However, few unaffected carriers may be encountered. Beyond RT, the tumor spectrum may be larger than initially suspected, and cancer surveillance offered to unaffected carriers (siblings or parents) and long-term survivors of RT is still a matter of discussion. RTPS2 exposes female carriers to an ill-defined risk of small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT), which may appear in prepubertal females. RT surveillance protocols for these rare families have not been established. To address unresolved issues in the care of individuals with RTPS and to propose appropriate surveillance guidelines in childhood, the SIOPe Host Genome working group invited pediatric oncologists and geneticists to contribute to an expert meeting. The current manuscript summarizes conclusions of the panel discussion, including consented statements as well as non-evidence-based proposals for validation in the future.

Analysis of somatic hypermutations of immunoglobulin gene rearrangements in childhood acute lymphoblastic leukemia.

The current study investigated the presence, frequency, and status of somatic hypermutations as well as their role in children with B lineage ALL. The obtained sequences were analyzed using IMGT/V-QUEST. Totally, 150 IGH sequences were evaluated; 139 from the 111 patients at the time of diagnosis and 11 from 8/111 patients at the time of relapse. The findings of the current report revealed the presence of somatically mutated V genes in childhood B lineage ALL. A higher frequency of somatic hypermutations was noted in unproductive rearrangements and was generally attributed to nucleotide mutation type, region, and IGHV gene subgroup biases.

Blood stream infections throught the entire course of acute lymphoblastic leukemia treatment.

The incidence, type and mortality of bacteremias were evaluated in a pediatric patient cohort, during the entire course of treatment for acute lymphoblastic leukemia (ALL). Eighty-six patients with newly diagnosed ALL were studied. A bacteremic episode was defined as blood isolation of a pathogen in the presence of clinical symptomatology of septicaemia. Bacteremias were analyzed according to the treatment element being delivered and the degree of neutropenia. A central venous catheter (CVC) was inserted at diagnosis in all patients. Fifty-two episodes of bacteremias were encountered in 38/86 (44%) patients, while 48/86 patients had no positive blood culture. Three out of the 38 patients had bacteremia and CVC area infection, simultaneously. Most blood stream infections (29/52, 56%) were documented during the induction phase. Isolated Gram-positive organisms were 48%, Gram-negative 50% and 2% of the positive blood cultures represented fungaemias. The most common Gram-positive isolates were Staphylococcus species (N=22) and the commonest Gram-negative isolated pathogens were Escherichia coli and Pseudomonas aeruginosa. The majority of bacteremias (75%) occurred during neutropenia. The initial antibiotic treatment was ceftazidime or piperacillin/tazobactam and amikacin or tobramycin. CVC was not removed in the majority of bacteremias (94%). No infection related fatality was recorded. Bacteremias constituted a severe and common complication in our patient cohort. However, infection-related fatality rate was negligible, most probably due to the prompt initiation of broad coverage antimicrobial therapy.

Frequency of FLT3 mutations in childhood acute lymphoblastic leukemia.

FLT3 mutations are occasionally observed in acute lymphoblastic leukemia (ALL). These most frequently manifest as internal tandem duplications (ITD) and activation loop (AL) mutations. This study investigated the incidence of FLT3 mutations in 86 pediatric patients diagnosed with ALL and the co-presence of common RAS mutations. A 2.3% (2/86) FLT3/AL mutation rate in terms of total ALL cases and a 22% (2/9) incidence in hyperdiploid cases was observed. This is in accordance to previous studies indicating a higher incidence in the patient subgroup associated with hyperdiploidy.