Editorial: [New Insights into Cancer Predisposition Syndromes in Pediatric Hematology-Oncology]

ROBERTO CARTA ^1* Davide Leardini ^2* Angela Mastronuzzi ^1*

• ¹ Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital (IRCCS), Rome, Italy
• ² Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

Hereditary predisposition is a relevant cause of hematologic and solid cancer in children and adolescents. It has been estimated that at least 10% of all pediatric tumors are due to germline mutations in cancer predisposition genes, and recent evidence are demonstrating that this data may be also higher (1;2). In recent years, the advances in molecular biology and genetic technologies, such as large-scale genome sequencing analysis, have improved the biological and molecular understanding of Cancer Predisposition Syndromes (CPS) (3). However, many grey areas are still present, such as in the case of interpreting the role of an identified genetic variant. Indeed, one of the most significant burdens is represented by Variants of Uncertain Significance (VUSs) detection, with their uncertain role and impact on the pathogenesis of neoplasms. For individuals who have already been diagnosed with cancer, knowing that a specific mutation is present can help choose targeted and effective treatment. In addition, the detection of a genetic variant in the patient can be important not only for organizing follow-up strategies, but also for the adoption of possible surveillance strategies in family members. The purpose of the Research Topic "New Insights into Cancer Predisposition Syndromes in Pediatric Hematology-Oncology", which includes seven articles, is to highlight the most recent advances concerning epidemiological, clinical, biological, molecular, and therapeutic aspects of CPS in pediatric and adolescent populations and provide new insights that may be useful to further improve the diagnosis, treatment and follow-up of CPS.Vinci et al. present five instructive cases of GATA2-related diseases, offering a clinically valuable analysis of current knowledge and treatment approaches presented with useful learning points. GATA2 is highly emerging gene in pediatric hematology with a strong association with malignancies (4;5). The authors in this paper highlighted the expanding phenotype of GATA2 deficiency, which extends beyond hematologic involvement to include immunological and pulmonary manifestations. The authors appropriately emphasize the need for heightened awareness of this condition among hemato-oncology specialists to avoid delays in diagnosis. Among the open questions, we particularly stress the role of preemptive allogeneic transplantation-an approach with curative potential but significant risks. Importantly, patient perception should be a key factor in decision-making.Di Benedetto et al. provide a valuable retrospective analysis of 23 pediatric and adolescent patients with RET-mutated medullary thyroid carcinoma, highlighting genotype-phenotype correlations and disease outcomes. Their findings reinforce the critical role of early detection through genetic screening and timely intervention. Notably, they emphasize the impact of RET mutations on prognosis, with M918T confirming its aggressive course. The study underscores the importance of monitoring first-degree relatives to optimize preventive strategies. While limited by its retrospective nature, this work enhances our understanding of hereditary medullary thyroid carcinoma and informs clinical decision-making regarding timing and extent of surgical management.Rees et al. conducted exome sequencing on 160 medulloblastoma survivors, focusing on rare variants in 239 cancer susceptibility genes (CSGs). They identified pathogenic/likely pathogenic (P/LP) variants in CSGs in 12.5% of pediatric medulloblastoma survivors, compared to 5% in controls. Notably, ELP1 and SUFU were among the most enriched CSGs. The study also identified two novel genes, CHEK2 and AGL, which had not previously been linked to medulloblastoma. These findings highlight the high prevalence of P/LP variants in CSGs in medulloblastoma survivors and have important implications for genetic testing, guiding risk assessment and personalized treatment strategies.Fabozzi et al. in their article describe a rare case of a 5-year-old girl carrying a VUS in the Succinate Dehydrogenase Complex Subunit C (SHDC) gene, which developed a therapy-related acute myeloid leukemia as a second neoplasm after being treated for high-risk neuroblastoma. Their case report highlights the importance of performing genetic study in patients who develop a second malignancy to identify both constitutional and somatic mutations. This case report also highlights the importance of functional studies to further investigate the potential impact and causative role on the tumor history of the genetic variant identified.Ling et al. in their paper describe a rare case of paraneoplastic juvenile dermatomyositis (JDM) and Hodgkin's lymphoma in an adolescent female patient. The authors emphasize the uniqueness of the case described and highlight the differences in cancer risk compared to patients with adult-onset dermatomyositis. Ling et al. demonstrate the importance of a detailed physical examination, which lead them to detect two distinct and rarely related clinical entities and how treating the underlying neoplasm can also improve the associated paraneoplastic condition. The authors emphasize the need for tumor screening in patients with JDM and unusual clinical findings and for careful long-term follow-up even in cases in which an underlying malignancy is not detected when JDM is diagnosed. Mak et al. present three pediatric cases of medulloblastoma with subsequent development of therapyrelated myeloid neoplasms as potential complication of treatment for primary tumor. The authors emphasize the importance of discovering a cancer predisposition syndrome which may play a causal role, have significant prognostic implications, and predict treatment response. They also highlight the relevance of surveillance for hematological abnormalities in long-term medulloblastoma survivors. Greene et al. describe the importance of performing molecular testing on somatic samples from pediatric CNS neoplasms using a multiplexed targeted next-generation sequencing panel validated to detect genetic alterations in various cancer-related genes. They describe how obtaining information about the somatic molecular sequencing of the tumor can help select a subpopulation of patients who deserve to be considered for germline analysis. Confirmation of a germline variant for some patients can be important in clarifying the diagnosis, for informing a patient's own cancer risk, can lead to life-saving monitoring and risk reduction interventions for themselves and family members, and can sometimes directly impact their treatment plan. Indeed, the application of molecular sequencing methods still has some hurdles to overcome. As mentioned by Green et al., the application of somatic sequencing in tumor tissue samples at diagnosis or relapse of the disease may provide insights and help to select a subpopulation of patients in whom germline testing should be recommended. However, the criteria for such selection have not been universally defined and may vary from laboratory to laboratory. A useful parameter for recommending germline variant detection from somatic sample is the variant allele frequency, but it may be influenced by other variables such as tumor tissue heterogeneity and copy number alterations. Selecting patients for germline variant detection from somatic data can be time-consuming, depending on the laboratory, and sometimes the results may come too late, once the patient's treatment has already been performed, not allowing to avoid potential treatment-related complications. For this reason, some authors have suggested performing paired somatic and germline testing at the time of primary tumor diagnosis. While this proposal is certainly advantageous and provides accurate pretreatment information, it may be too expensive for centers with more limited financial resources. It is important to underline that once genetic information has been acquired, the explanation of the results need to be done as part of structured genetic counselling. To conclude, CPS remain a challenging issue in pediatric hematology and oncology, and much is still needed to better understand the impact of molecular sequencing on patient clinical management and outcomes, and on psychological aspects of all family members.