Henrik Hasle

The European LeukemiaNet has periodically issued guidelines for the diagnosis and management of acute myeloid leukemia (AML) in adults. These consensus recommendations, most recently updated in 2022, incorporate recent advances in genomic testing, disease detection methods, target identification, and response assessment. Although similarities exist between AML in children and adults, pediatric AML is frequently characterized by unique cytogenetic and molecular features, which require distinct genetic and immunophenotypic diagnostics, therapeutic approaches, response assessment criteria, and supportive care strategies. To address these specific needs, an international panel of pediatric hematologist-oncologists, biologists, geneticists, and laboratory medicine scientists convened to develop recommendations for the diagnosis and management of AML in children, adolescents, and young adults (hereafter termed pediatric AML) that are discussed in this special report.

Background As larger population-based studies assessing neoplasm risk in neurofibromatosis 1 (NF1) are limited, we aimed to evaluate overall neoplasm risk, specific cancer types, and second primary cancers. Methods Using Danish registries and clinical databases, we identified 2053 individuals with NF1 and 20,530 population comparisons. We calculated cumulative incidences for first and second primary neoplasms for the study population born 1971–2020 and for adult-onset cancers in the study population born 1951–2020. We used multistate models to estimate the probabilities of being neoplasm-free, having one neoplasm, having ≥two neoplasms or being dead at a certain age. Results The 50-year cumulative incidence of any first neoplasm was 27.2% (95% confidence interval [CI] 23.1–31.4%) for NF1 individuals and 5.0% (4.0–6.0%) for comparisons. Moreover, the cumulative incidence of second primary neoplasm was 21.1% (14.4–27.8%) for NF1 individuals and 6.4% (0.0–15.0%) for comparisons 20 years after the first neoplasm. A person born with NF1 had a 69.8% (65.6–74.2%) probability of being alive and without neoplasm history at age 50 compared to 93.5% (92.4–94.6%) for a person without NF1. Conclusion The highly increased risks for primary and secondary neoplasms and mortality warrant close clinical surveillance of individuals with NF1.

Supplementary Dataset combined

Supplementery Results and Methods

Background: As survival after Wilms tumor has markedly improved, focus on potential long‐term consequences is necessary. We investigated the metabolic profile among Danish survivors of Wilms tumor >20 years from cancer diagnosis. Methods: As of January 15, 2015, we established a cohort of 20‐plus‐year survivors of Wilms tumor identified through the national cancer registries. Siblings contributed as controls. Participation included clinical examination with anthropometric measurements, blood samples, blood pressure measurements, and a comprehensive health questionnaire. Using logistic regression, we identified risk factors for diabetes mellitus (DM). Results: With a response rate of 64%, we included 99 survivors of Wilms tumor with a median of 37 years since diagnosis (median age of 41, range: 24–70), and 38 sibling controls (median age of 41, range: 24–66). An increased prevalence of DM was found in the survivors as compared with their siblings (15% vs. 0%). A logistic regression analysis adjusted for age at follow‐up showed that left‐sided versus right‐sided abdominal radiation therapy was a risk factor for the development of DM (odds ratio [OR] 7.9, 95% confidence interval [CI]: 1.4–44). A larger fraction of the survivors was in active treatment for hypertension compared to siblings (42% vs. 37%), but with no significant difference in body mass index, hip, or waist circumferences. Furthermore, Wilms tumor survivors were more likely to be in active treatment with lipid‐lowering agents (8% vs. 3%). Conclusion: Left‐sided abdominal radiation is a major risk factor for DM in long‐term survivors of Wilms tumor. Patients may benefit from surveillance with increased focus on metabolic risk profile to decrease the risk of DM and cardiovascular events.

Purpose: Cancer predisposition syndromes (CPS) with pediatric onset are the leading known cause of childhood malignancies and are increasingly guiding clinical strategies in pediatric oncology. CPS are placed under evolutionary negative selective pressure, but pediatric pancancer studies have so far failed to investigate genomic evolutionary metrics as a guide to predict penetrance and reveal novel CPS. Experimental Design: Germline whole-genome sequencing was performed in a 5-year prospective, registry-validated, nationwide cohort of individuals diagnosed with cancer before age 18. Evolution-guided burden analysis of private germline variants in constrained genes was compared with 125,748 gnomAD exomes. Results: Across a total of 1,127 participants, 16% carried a pathogenic variant in at least one CPS gene. After genotype–phenotype matching, 9% of children in the prospective cohort (n = 651) carried a variant considered causative, a rate deemed significantly higher than in previous studies [RR, 1.54, 95% confidence interval (CI), 1.37–1.75, P = 1 × 10−14]. As predicted for a disease subject to negative Darwinian selective pressure, compared with reference adults, we found a significant excess of loss-of-function (LoF) variants in the 1,500 most constrained genes (RR, 1.54, 99% CI, 1.21–1.95, P = 4 × 10−6). Surprisingly, this excess was greater than expected, leaving a significant residual enrichment of predicted LoF variants in genes evolutionarily considered the least tolerant to damage (RR, 1.41, 99% CI, 1.09–1.80, P = 4 × 10−4). Conclusions: The high frequency of LoF variants, including in known CPS, emphasizes the need for systematic and extensive germline genomic mapping as part of the diagnostic workup of patients with childhood cancer and the linkage of such data to disease and response phenotypes to guide future pediatric oncological care and ultimately pave the way for prediagnostic interventional measures.

GATA2 deficiency is an autosomal dominant transcriptopathy disorder with high risk for myelodysplastic syndrome (MDS). To elucidate genotype-phenotype associations and identify new genetic risk factors for MDS, we analyzed 218 individuals with germline heterozygous GATA2 variants. We observed striking age-dependent incidence patterns in GATA2-related MDS (GATA2-MDS), with MDS being absent in infants, rare before age 6 years, and steeply increasing in older children. Among 108 distinct GATA2 variants (67 novel), null mutations conferred a 1.7-fold increased risk for MDS, had earlier MDS onset compared to other variants (12.2 vs. 14.6 years, p = 0.009) and were associated with lymphedema and deafness. In contrast, intron 4 variants exhibited reduced penetrance and lower risk for MDS development. Analysis of the somatic landscape revealed unique patterns of clonal hematopoiesis. SETBP1 mutations occurred exclusively in patients with monosomy 7 and their frequency decreased with age. Conversely, the frequency of STAG2 mutations and trisomy 8 increased with age and appeared protective against early development of advanced MDS. Overall, the majority (73.9%) of mutation-positive cases harbored monosomy 7, suggesting it serves as a major driver in malignant progression. Our findings provide evidence for age-appropriate surveillance, and a foundation for genotype-driven risk stratification in GATA2 deficiency.

The aim was to identify treatment‐related risk factors for diabetes in 5‐year survivors of childhood cancer (CCS). This case‐cohort study within Adult Life after Childhood Cancer in Scandinavia (ALiCCS) included 140 CCS with diabetes and a subcohort of 390 randomly selected CCS. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated to assess the association between treatment exposures and diabetes. Radiotherapy was the most important risk factor, with increased IRR after total body irradiation (TBI) (9.8, 95% CI = 2.9–33.7), abdominal radiation (4.8, 95% CI = 2.2–10.4), and cranial radiation (4.3, 95% CI = 2.1–8.8). Continued follow‐up with regard to diabetes is indicated after TBI, abdominal radiation, and cranial radiation in CCS.