Background. DICER1 syndrome is an autosomal dominant disorder predisposing to a broad spectrum of malignant and benign neoplasms, caused by germline pathogenic variants (PVs) in the DICER1 gene. We aimed to characterize the clinical features of DICER1 syndrome in a national referral cohort and to estimate neoplasm risk.Materials and Methods. This retrospective study was conducted in a cohort of 945 patients who underwent DICER1 genetic testing at Institut Curie, Paris, using Sanger sequencing from 2012 to 2014 and Next Generation Sequencing from 2015 to 2023.Results. Among 584 index cases evaluated for DICER1 syndrome, 91 (16%) carried a germline DICER1 PV and 31 (5%) harbored only somatic DICER1 PVs. Several tumors that were not previously part of the DICER1 tumor spectrum were identified. ETMR-like brain tumor and testicular Sertoli cell tumor are now recognized as DICER1-related neoplasms, and schwannoma is a strong candidate. The neoplasm risk was estimated in 170 relatives carrying a germline DICER1 PV. The cumulative incidence of malignant neoplasms was 4.8% [95% CI: 2.1% – 9.1%] at 10 years and 15.8% [95% CI: 8.9% – 24.7%] at 50 years. Overall neoplasm risk was significantly higher in females, primarily driven by the higher incidence of multinodular goiter.Conclusion. This large cohort study provides a comprehensive overview of the distribution of neoplasms associated with DICER1 syndrome. Broader genetic testing identified additional DICER1-related neoplasms, and schwannoma emerged as a candidate association. Finally, this study confirms the moderate penetrance of germline DICER1 PVs.

In this multicenter study, we were able to detect circulating tumor DNA (ctDNA) in 87.5% of patients with the rare disease ALK + ALCL. Moreover, by analyzing ctDNA from samples collected at disease progression, we were able to identify resistance mutations to ALK inhibitors. Furthermore, ctDNA proved to be a valuable and consistent tool for monitoring minimal residual disease.

Single nucleotide polymorphisms (SNPs) of cancer-immunity relevant genes may decide the extent of tumor immunosurveillance and have clinical significance. The Immuno ALCL trial was designed to investigate whether genetic variability in 13 cancer-immunity relevant genes correlated with clinical features and outcome of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) patients. One hundred eighty patients were enrolled and genotyped for 14 SNPs. Age at diagnosis, progression-free survival, histological subtype and anti-ALK antibody titer data were collected. IL10 rs1800872, IL10 rs1800896 and TLR3 rs3775291 variants significantly correlated with age at diagnosis. TLR3 rs3775291 was associated with progression-free survival in a recessive model. Combination of multiple genetic variations showed a trend to associate with post-therapeutic relapse. None of the SNP analyzed associated with histological or clinical parameters. Despite the low number of patients, our work uncovered potential associations between certain cancer-immunity relevant genes and clinical features of ALK-positive ALCL patients. Associations do not imply causations. However, our work highlighted a possible contribution of the IL10 and TLR3 pathways to ALK-positive ALCL pathogenesis and suggested that several genetic variants in concert may modulate the risk of post-therapeutic relapse. clinicaltrial.gov NCT02902874. Registered 07 September 2016 https//clinicaltrials.gov/study/NCT02902874.

Bone sarcomas, constituting less than 1% of malignant neoplasms across all age groups, are rare tumours possibly associated with genetic susceptibility syndromes. This review aims to provide recommendations for the detection of cancer predisposition syndromes associated with bone sarcomas and managing affected patients. Recommendations were formulated by a multidisciplinary working and reviewing group from GroupOs and SFCE oncogenetic's group, including geneticists, oncologists, and radiologists. For various bone sarcomas including osteosarcomas, chondrosarcomas and Ewing sarcomas, we delineate tumour presentation, management strategies, and follow-up within the context of cancer predisposition syndromes. The inherited predisposition syndrome, associated with germline TP53 variants, known as the Li-Fraumeni syndrome, is the most frequent implicated in osteosarcoma cases. Other cancer predisposition syndromes, such as RB1, RECQ or CDKN2A disorders in osteosarcomas and Ollier and Maffucci diseases in chondrosarcomas, are also recognized. Additionally, we discuss rarer cancer predisposition syndromes associated with bone sarcomas and suggest tailored treatment approaches in some cancer predisposition syndromes to mitigate severe toxicities or secondary oncological events. Furthermore, we emphasize the role of identification somatic molecular variations in identifying constitutional germline variants and describe national and international screening programs, reference networks and molecular tumour boards available for collegial and collaborative management discussion. This comprehensive review provides insights into the intricate interplay between genetic predisposition, tumour biology, and therapeutic interventions in bone sarcoma patients with cancer predisposition syndrome.

BACKGROUND:Methotrexate-associated leukoencephalopathy is poorly documented in osteosarcoma. Since 2007, our institution has monitored osteosarcoma patients with sequential magnetic resonance imaging (MRI) and neuropsychological evaluations during treatment and follow-up. METHODS:We analyzed data from consecutive osteosarcoma patients younger than 25 years enrolled at Gustave Roussy in the OS2006 study (2007-2015) and treated with high-dose methotrexate (MTX) and etoposide-ifosfamide. Eligible patients received four or more MTX courses and at least one brain MRI. MTX-related neurotoxicity was defined as neurological symptoms attributed to MTX after excluding other causes. RESULTS:MTX-related neurotoxicity occurred in seven (13%) of 53 eligible patients. Additionally, 12 had severe depression, nine reported attention/memory deficits, and 25 had headaches during MTX infusion. Acute symptoms resolved in all but one. Forty-nine patients had an MRI during treatment, and 47 after. Leukoencephalopathy was found in 44 (83%): Grade 1 in six, Grade 2 in 15, and Grade 3 in 23. Grade 2-3 leukoencephalopathy was more frequent in patients with severe depression (p = 0.02) and those receiving more than 12 MTX courses (p = 0.03); no association was found with age, sex, MTX-related neurotoxicity, or cognitive complaints. Among 24 patients with MRI ≥3 years post-treatment, 20 still showed leukoencephalopathy (12 Grade 1, eight Grade 2). Neurocognitive evaluations showed IQ scores consistent with norms, except for lower processing speed, which improved post-treatment. At last follow-up (median 8.5 years), most patients had integrated into school or work. CONCLUSION:MTX-associated leukoencephalopathy is frequent in osteosarcoma, even in asymptomatic patients, and often persists after treatment. Serious neurocognitive sequelae appear uncommon, but long-term cognitive monitoring is essential to detect subtle deficits.

The access to next-generation sequencing, primarily performed for therapeutic purposes, has considerably increased in the real-time clinical practice in pediatric malignancies. Using germline DNA as a matched reference, this approach is also a unique opportunity to detect alterations in medically actionable genes (named "additional data"). The main objective of this project was to estimate the frequency of such genetic predisposition discoveries among children and adolescents with relapsing or refractory cancer. Among 791 children included in MAPPYACTS “MoleculAr Profiling for Pediatric and Young Adult Cancer Treatment Stratification” study, germline DNA exome sequencing was available for 674 patients with many distinct cancer types. Informed consent was obtained to disclose genetic findings if an actionable predisposition was detected. A multidisciplinary germline molecular board established the list of genes to be looked at, including 184 cancer predisposition genes with consensual surveillance guidelines, and 49 non cancer genes belonging to the ACMG Secondary Findings v3.1 list. Bioinformatic analysis included two different indel variant calling (Varscan and Haplotypecaller), quality controls and filters to ensure high-confidence variant calls, ClinVar annotations for pathological classification and in-silico function assessment by computational prediction (with several tools including CADD, SpliceAI and SPiP). Expert biologists have evaluated the pathogenicity of genetic variations with the use of genetic databases, computational predictions and medical literature. Among 184 cancer genes, 16 607 genetic variants have emerged. Twenty-five per cent of them were classified as unknown significance corresponding to a median of 7 (0;47) variants/patient and 8% of variants were retained as likely pathogenic or pathogenic variant (LPV/PV). Thus, 132 patients (19.6%) carried one LPV/PV variant among 53 cancer genes. According to inheritance patterns (we retained heterozygous variant for dominant disease and only biallelic events for recessive disease), genetic counselling was recommended for 58 patients (8.6%). Only two patients had two different cancer predisposition. The most frequently involved genes were TP53 (n=16), DICER1 (n=5), NF1 (n=4) and BRCA1 (n=4). Those identified genetic predispositions to cancer corresponded to the expected tumor spectrum in 50% of cases and were previously known in 38% of families. Furthermore, 10 patients (1.5%) were germline carriers of LPV/PV in genes involved in other genetic conditions (n=6 for cardiopathy; n=2 familial hypercholesterolemia; n=2 transthyretin amyloidosis). A specific evaluation of exome sequenced for therapeutic purposes provides germline information that could be actionable for 10.1% of families to improve cancer prevention or manage some other genetic condition. The psychological impact induced by the return of secondary findings to families will be investigated. Tiphaine Adam de Beaumais, Yahia Adnani, Léa Guerrini-Rousseau, Samuel Abbou, Cécile Acquaviva-Bourdain, Pablo Berlanga, Adeline Bonnard, Gaelle Bougeard, Franck Bourdeaut, Nelly Burnichon, Sandrine Caputo, Alain Carrié, Olivier Caron, Hélène Cavé, Albain Chansavang, Nadège Corradini, Sophie Cotteret, Philippe Denizeau, Alice Fievet, Mathilde Filser, Marion Gauthier-Villars, Birgit Geoerger, Nadim Hamzaoui, Edwige Kasper, Florence Kyndt, Ludovic Lacroix, Jessica Le Gall, Julien Masliah-Planchon, Laurence Pacot, Cécile Pagan, Mélanie Pagès, Béatrice Parfait, Eric Pasmant, Gaelle Pierron, Pascale Richard, Nathalie Roux-Buisson, Cécile Saint-Martin, Hela Sassi, Gudrun Schleiermacher, Renaud Touraine, Nancy Uhrhammer, Dominique Vidaud, Laurence Brugières, Gilles Vassal, Etienne Rouleau, Yoann Vial, Lisa Golmard, Odile Cabaret. Genetic predisposition discoveries of clinical utility by exome sequencing performed for therapeutic purposes in children with relapsing or refractory cancer in the MAPPYACTS study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr A006.

BACKGROUND:Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare childhood cancer predisposition syndrome associated with a broad spectrum of malignancies, including non-Hodgkin lymphomas (NHL). Most patients die due to cancer before the age of 20 years. Limited data exist on CMMRD-associated lymphomas and their outcome. METHODS:We conducted a retrospective study including all CMMRD-associated NHL patients registered before 2020 in the European and North American databases or reported by members of the European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL). Events considered to define event-free survival included relapse/progression, second malignancy (SML), or death, whichever occurred first. FINDINGS:The analysis included 74 patients, with 20 having multiple metachronous NHL. The median age at diagnosis was 9.4 years. Previous malignancies were reported in 36% of the patients, café au lait spots in 96%, and consanguinity in 54%. The initial lymphoma subtypes were 53 T-cell lymphoblastic lymphomas (T-LBL), four B-lymphoblastic lymphomas, and 17 mature B-cell non-Hodgkin lymphoma (B-NHL). All patients were treated with curative intent, with current chemotherapy regimens adapted to their subtype. The median follow-up was 8.7 years. After the first lymphoma, the 5-year event-free and overall survival rates were, respectively, 23.5% [95% confidence interval (CI): 14.9-35.1] and 61.5% [95% CI: 49.6-72.1]. The 5-year cumulative risk of progression/relapse, SML or death as a first event was 20.8%, 52.9%, and 2.7%. INTERPRETATION:Standard treatments for sporadic NHL are effective in most CMMRD-associated NHL cases, but multiple malignancies, including lymphomas, impair prognosis. Future strategies should evaluate the potential of less genotoxic therapies, including immunotherapy, in preventing SMLs while maintaining effective control of NHL.

Hepatoblastomas (HB) display heterogeneous cellular phenotypes that influence the clinical outcome, but the underlying mechanisms are poorly understood. Here, we use a single-cell multiomic strategy to unravel the molecular determinants of this plasticity. We identify a continuum of HB cell states between hepatocytic (scH), liver progenitor (scLP) and mesenchymal (scM) differentiation poles, with an intermediate scH/LP population bordering scLP and scH areas in spatial transcriptomics. Chromatin accessibility landscapes reveal the gene regulatory networks of each differentiation pole, and the sequence of transcription factor activations underlying cell state transitions. Single-cell mapping of somatic alterations reveals the clonal architecture of each tumor, showing that each genetic subclone displays its own range of cellular plasticity across differentiation states. The most scLP subclones, overexpressing stem cell and DNA repair genes, proliferate faster after neo-adjuvant chemotherapy. These results highlight how the interplay of clonal evolution and epigenetic plasticity shapes the potential of HB subclones to respond to chemotherapy. Hepatoblastoma (HB) is the most frequent paediatric liver tumour with heterogeneous cellular phenotypes that influence clinical outcomes. Here, the authors integrate bulk, single-cell, and spatial multi-omics to characterise HB cells, and find that clonal evolution and epigenetic plasticity shape response to therapy.

Background ELP1 pathogenic variants (PV) have been recently identified as the most frequent variants predisposing to Sonic Hedgehog (SHH) medulloblastomas (MB); however, guidelines are still lacking for genetic counseling in this new syndrome.Methods We retrospectively reviewed clinical and genetic data of a French series of 29 ELP1-mutated MB.Results All patients developed SHH-MB, with a biallelic inactivation of PTCH1 found in 24 tumors. Other recurrent alterations encompassed the TP53 pathway and activation of MYCN/MYCL signaling. The median age at diagnosis was 7.3 years (range: 3-14). ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups and similar outcomes (5 y - OS = 86%); no unusual side effect of treatments was noticed. Remarkably, a germline ELP1 PV was identified in all patients with available constitutional DNA (n = 26); moreover, all tested familial trio (n = 11) revealed that the PVs were inherited. Two of the 26 index cases from the French series had a family history of MB; pedigrees from these patients and from 1 additional Dutch family suggested a weak penetrance. Apart from MB, no cancer was associated with ELP1 PVs; second tumors reported in 4 patients occurred within the irradiation fields, in the usual time-lapse for expected radiotherapy-induced neoplasms.Conclusions The low penetrance, the "at risk' age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with SHH-MB, depending on the parents" request.

Background Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition due to biallelic mutations in one of the mismatch repair (MMR) genes associated with early onset of cancers, especially high-grade gliomas. Our aim was to decipher the molecular specificities of these gliomas.Methods Clinical, histopathological, and whole exome sequencing data were analyzed in 12 children with genetically proven CMMRD and a high-grade glioma.Results PDL1 expression was present in immunohistochemistry in 50% of the samples. In 9 patients, the glioma harbored an ultra-hypermutated phenotype (104-635 coding single nucleotide variants (SNV) per Mb, median 204). Driver mutations in POLE and POLD1 exonuclease domains were described for 8 and 1 patients respectively and were always present in the mutation burst with the highest variant allele frequency (VAF). The mutational signatures were dominated by MMR-related ones and similar in the different mutation bursts of a same patient without subsequent enrichment of the mutation signatures with POL-driven ones. Median number of coding SNV with VAF above one of the driving polymerase mutation per Mb was 57 (17-191). Our findings suggest that somatic polymerase alterations does not entirely explain the ultra-hypermutant phenotype. SETD2, TP53, NF1, EPHB2, PRKDC, and DICER1 genes were frequently mutated with higher VAF than the deleterious somatic polymerase mutation.Conclusions CMMRD-associated gliomas have a specific oncogenesis that does not involve usual pathways and mutations seen in sporadic pediatric or adult glioblastomas. Frequent alterations in other pathways such as MAPK may suggest the use of other targeted therapies along with PD1 inhibitors. Patients with mutations in genes responsible for repairing damaged DNA are at a higher risk of developing cancer at an early age. Gliomas are a type of aggressive brain cancer that can occur in these patients. The authors of this study wanted to understand the differences between gliomas in patients with and without this specific genetic condition. To do this, they reviewed 12 children with the genetic condition who developed gliomas. Their results showed that 9 patients had tumors with a higher than expected number of mutations (ultra-mutated). The genes that are commonly mutated in these patients were not identical to those that are commonly known to occur without this genetic condition.

BACKGROUND:Previous studies have shown that neutrophil-to-lymphocyte (NLR) ratio at diagnosis and early lymphocytes recovery on doxorubicin-based chemotherapy, may impact the outcome in patients with osteosarcoma (OST). This study aimed to evaluate the prognostic value of hemogram parameters in patients with OST treated with high-dose methotrexate and etoposide/ifosfamide (M-EI) chemotherapy.MATERIALS AND METHODS:We retrospectively analyzed the prognostic value of various hemogram parameters at diagnosis and during therapy in a large consecutive cohort of patients with OST included in the French OS2006 trial and treated with M-EI chemotherapy.RESULTS:A total of 164 patients were analyzed. The median age was 14.7 years (interquartile range [IQR]: 11.7-17). Median follow-up was 5.6 years (IQR: 3.3-7.7 years). Three-year event-free survival (EFS) and overall survival (OS) were 71.5% (95% confidence interval [CI]: 64%-78%) and 86.4% (95% CI: 80%-91%), respectively. In univariate analysis, blood count parameters at diagnosis and early lymphocyte recovery at Day 14 were not found prognostic of survival outcomes. By contrast, an increase of NLR ratio at Day 1 of the first EI chemotherapy (NLR-W4) was associated with reduced OS in univariate (p = .0044) and multivariate analysis (hazards ratio [HR] = 1.3, 95% CI: 1.1-1.5; p = .002), although not with EFS. After adjustment on histological response and metastatic status, an increase of the ratio NLR-W4 of 1 was associated with an increased risk of death of 30%.CONCLUSIONS:We identified NLR-W4 as a potential early biomarker for survival in patients with OST treated with M-EI chemotherapy. Further studies are required to confirm the prognostic value of NLR and better identify immune mechanisms involved in disease surveillance.

Introduction Brigatinib is an orally administered second-generation anaplastic lymphoma kinase (ALK) inhibitor (ALKi) with good central nervous system penetration, approved for the treatment of ALK-positive (ALK+) non-small cell lung cancer in adults. The recommended dose in adults is 180 mg once daily (QD) after a 7-day lead-in at 90 mg QD. This report describes updated results of the phase 1 part of the BrigaPED trial (NCT04925609). This study is part of a Pediatric Investigation Plan, sponsored by the Princess Máxima Center and supported by Takeda Pharmaceuticals International Co. Methods The BrigaPED trial is a multicenter, non-randomized open label phase 1-2 study of brigatinib in pediatric and young adult patients. Patients aged ≥1 to <18 years and a body weight > 10 kg with relapsed or refractory ALK+ malignancies, including ALCL and inflammatory myofibroblastic tumors (IMT), were eligible for enrollment in the phase 1 part of this study. ALK positivity on immunohistochemistry was sufficient to enroll ALCL patients. Frontline ALK+ ALCL patients who were minimal residual disease (MRD) positive after one course of chemotherapy met the definition of refractory disease. Patients with IMT were also eligible in frontline in case of unresectable or metastatic disease. Previous treatment with other ALKi was allowed. Written informed consent and adequate organ function were required for study eligibility. In phase 1, brigatinib was dose escalated using the rolling-six design. The starting dose was allometrically scaled based on the adult approved dose, with one dose escalation, and a lower dose-level (DL) in case of dose-limiting toxicities (DLT). Brigatinib was administered once daily as tablets in 28-day cycles. DLTs were evaluated during the 7-day lead-in and the first cycle, to determine the recommended phase 2 dose (RP2D). Patients were assessed for safety, pharmacokinetics, activity, and efficacy. Response in ALCL was evaluated according to international pediatric non-Hodgkin lymphoma (IPNHL) response criteria and by response evaluation criteria for solid tumors (RECIST) for solid tumors. Qualitative MRD was assessed in ALCL patients using Reverse Transcriptase-PCR and digital PCR. Results Ten patients were enrolled between 08-2022 and 08-2023, 9 ALCL (3 frontline MRD+ and 6 relapsed), and 1 sarcoma NOS with an ALK fusion. Median age at inclusion was 9 years (range: 6-17 years). All patients were pretreated with chemotherapy and 3 with another ALKi. At database cut-off (21 June 2024), patients had received a median of 18 cycles (range 10-23 cycles). No DLT was observed on DL1 (n=4), and 1 on DL2 (n=6, grade (G)3 neutropenia > 7 days). Following dose reduction, this patient could resume brigatinib successfully. Common treatment-related adverse events (AE) were (n any G; n ≥ G3): asymptomatic CPK increase (8;2), nausea/vomiting (7;0), abdominal pain (6;0), and AST/ALT elevation (4;0). Reported AEs of special interest included ophthalmological events (3;0) and weight gain (3;2). No brigatinib related pulmonary toxicity or endocrine AEs were observed. Steady-state PK exposure on DL2 was within the predefined target range. Amongst 9 ALCL patients, 7 were MRD positive at screening and 8 had evaluable disease on imaging. The objective response rate (ORR) was 100%, with all ALCL patients achieving CR (n=6/8) or CRu (n=2/8), and a PR in the sarcoma patient. MRD negativity was obtained in 6/7 patients after a median of 1 cycle (range: 1-16 cycles). All ALCL patients were still on treatment with an ongoing response for a median duration of 18 months (range: 9-21 months). Conclusions Brigatinib monotherapy is well tolerated and demonstrated promising preliminary signs of activity in pediatric ALK+ ALCL, with no signs of cumulative toxicity. All ALCL patients are still on treatment. The RP2D was established at DL2, corresponding to 150 mg QD in patients 18-40 kg, or 240 mg QD in patients > 40 kg, which is higher than the adult approved dose. The phase 2 part of this study is currently open for accrual with disease-specific cohorts for ALK+ ALCL and IMT (age ≥1 - <26 years). An age-appropriate formulation is in development and will be used to confirm the RP2D in smaller children.

Abstract BACKGROUND Medulloblastomas (MB) Sonic hedgehog (SHH) subtype are associated with a cancer predisposition syndrome (CPS) in about 15% of cases, the most frequent being related to ELP1 pathogenic variant (PV). The aim of our study is to better evaluate penetrance of this CPS and detail the characteristics of the related tumors. METHODS Twenty-nine ELP1-mutated MB identified in France were retrospectively reviewed. Molecular characteristics of the tumor and clinical features of the patients were collected; whenever possible, the germline DNA from patients and their relatives were sequenced. RESULTS All patients (sex ratio 16/13) presented with SHH-MB, mostly nodular desmoplastic (n=20/28), between 3 and 15 years of age (median 7.3). All mutations are found in the germline when a constitutional DNA sample was available (n=26). Most tumors (93%) showed a biallelic inactivation of PTCH1, other recurrent alterations concerned the TP53 pathway (including 1 somatic TP53 VP) and activation of MYCN/MYCL signaling. We observed that ELP1-mutated MB behave as sporadic cases, with similar distribution within clinical and molecular risk groups of MB, similar outcomes (5y-OS = 85%) and no unusual side effects of treatments. Three patients developed a second tumor (2 high-grade gliomas and 1 thyroid carcinoma) within the irradiation fields. All germline PV were inherited from one asymptomatic parent (11 trio). No specific morphological features were mentioned. Only two index cases from the 29 French patients had a previous familial history of MB (occurring in a cousin), with many asymptomatic carriers. Except the MB, no other cancer was significantly associated with the ELP1 PV. CONCLUSIONS the low penetrance, the ‘at risk’ age window limited to childhood and the narrow tumor spectrum, question the actual benefit of genetic screening in these patients and their family. Our results suggest restricting ELP1 germline sequencing to patients with MB, depending on the parents’ request.

BACKGROUND:Hepatoblastoma is the most frequent pediatric liver cancer. The current treatments lead to 80% of survival rate at 5 years. In this study, we evaluated the clinical relevance of molecular features to identify patients at risk of chemoresistance, relapse and death of disease. METHODS:All the clinical data of 86 children with hepatoblastoma were retrospectively collected. Pathological slides were reviewed, tumor DNA sequencing (by whole exome, whole genome or target) and transcriptomic profiling with RNAseq or 300-genes panel were performed. Associations between the clinical, pathological, mutational and transcriptomic data were investigated. RESULTS:High-risk patients represented 44% of our series and the median age at diagnosis was 21.9 months (range: 0-208). Alterations of the WNT/ß-catenin pathway and of the 11p15.5 imprinted locus were identified in 98% and 74% of the tumors, respectively. Other cancer driver genes mutations were only found in less than 11% of tumors. After neoadjuvant chemotherapy, disease-specific survival and poor response to neoadjuvant chemotherapy were associated with 'Liver Progenitor' (p = 0.00049, p < 0.0001) and 'Immune Cold' (p = 0.0011, p < 0.0001) transcriptomic tumor subtypes, SBS35 cisplatin mutational signature (p = 0.018, p = 0.001), mutations in rare cancer driver genes (p = 0.0039, p = 0.0017) and embryonal predominant histological type (p = 0.0013, p = 0.0077), respectively. Integration of the clinical and molecular features revealed a cluster of molecular markers associated with resistance to chemotherapy and survival, enlightening transcriptomic 'Immune Cold' and Liver Progenitor' as a predictor of survival independent of the clinical features. CONCLUSIONS:Response to neoadjuvant chemotherapy and survival in children treated for hepatoblastoma are associated with genomic and pathological features independently of the clinical features.

PURPOSE:Describe clinical characteristics and outcome of Li-Fraumeni syndrome (LFS)-associated osteosarcomas. METHODS:TP53 germline pathogenic/likely pathogenic variant carriers diagnosed with osteosarcoma in France between 1980 and 2019 were identified via the French Li-Fraumeni database at Rouen University Hospital. Sixty-five osteosarcomas in 52 patients with available clinical and histological data were included. The main clinical characteristics were compared with data from National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results) for patients of the same age group. RESULTS:Median age at first osteosarcoma diagnosis was 13.7 years (range: 5.9-36.7). Compared to unselected osteosarcomas, LFS-associated osteosarcomas occurred more frequently in patients less than 10 years of age (23% vs. 9%), and when compared with osteosarcomas in patients less than 25 years were characterized by an excess of axial (16% vs. 10%) and jaw sites (15% vs. 3%) and histology with predominant chondroblastic component and periosteal subtypes (17% vs. 1%). Metastases incidence (25%) was as expected in osteosarcomas. After the first osteosarcoma treatment, the rate of good histologic response (62%) and the 5-year progression-free survival (55%, 95% confidence interval [CI]: 42.6-71.1) were as expected in unselected series of osteosarcomas, whereas the 5-year event-free survival was 36.5% [95% CI: 25.3-52.7] due to the high incidence of second malignancies reaching a 10-year cumulative risk of 43.4% [95% CI: 28.5-57.5]. CONCLUSION:In osteosarcoma, young age at diagnosis, axial and jaw sites, histology with periosteal or chondroblastic subtype, and synchronous multifocal tumors should prompt suspicion of a germline TP53 mutation. Standard treatments are effective, but multiple malignancies impair prognosis. Early recognition of these patients is crucial for tailored therapy and follow-up.

Biallelic germline pathogenic variants in one of the four mismatch repair genes (MSH2, MSH6, MLH1 and PMS2) cause a very rare, highly penetrant, childhood-onset cancer syndrome, called constitutional mismatch repair deficiency (CMMRD). The European consortium “Care for CMMRD” (C4CMMRD) was founded in Paris in 2013 to facilitate international collaboration and improve our knowledge of this rare cancer predisposition syndrome. Following initial publications on diagnostic criteria and surveillance guidelines for CMMRD, several partners collaborating within the C4CMMRD consortium have worked on and published numerous CMMRD-related clinical and biological projects. Since its formation, the C4CMMRD consortium held meetings every 1–2 years (except in 2020 and 2021 due to the Covid 19 pandemic). The sixth C4CMMRD meeting was held in Paris in November 2022, and brought together 42 participants from nine countries involved in various fields of CMMRD healthcare. The aim was to update members on the latest results and developments from ongoing research, and to discuss and initiate new study proposals. As previously done for the fifth meeting of the C4CMMRD group, this report summarizes data presented at this meeting.

Background Rhabdoid tumors (RT) are aggressive, rare tumors predominantly affecting young children, characterized by biallelic SMARCB1 gene inactivation. While most SMARCB1 alterations are acquired de novo, a third of cases exhibit germline alterations, defining Rhabdoid Tumors Predisposition Syndrome. With the increased sensitivity of next-generation sequencing (NGS), mosaicisms in genes linked to genetic diseases are more detectable. This study focuses on exploring SMARCB1 germline alterations, notably mosaicism in blood samples of children with RT and in parents, using a custom NGS panel.Methods A cohort of 280 children and 140 parents with germline analysis was studied. Germline DNA from 111 children with RT and 32 parents were reanalyzed with a custom NGS panel with 1500X average depth targeting the SMARCB1 gene to identify intragenic variants not detected with conventional low-sensitivity methods. Follow-up data was obtained for 77 patients.Results Nine previously undetected mosaicism cases were identified, totaling 17/280 patients with a mosaic variant (6.1%) in the cohort, with variant allele frequencies between 0.9% and 33%, thus highlighting the prior underestimation of its prevalence. Follow-up data showed that 4 out of 7 survivors with mosaic variants developed distinct novel tumors, 2 sharing SMARCB1 alterations with the initial tumor, emphasizing the potential clinical impact of SMARCB1 mosaicism.Conclusions The hitherto underestimated rate of SMARCB1 mosaicism in RT underscores the need for optimized genetic counseling and oncological monitoring. The findings have significant medical implications, considering the dire prognosis of RT. Graphical Abstract

In paediatric oncology, genomics raises new ethical, legal and psychological issues, as somatic and constitutional situations intersect throughout the care pathway. The discovery of potential predisposition in this context is sometimes carried out outside the usual framework. This article focuses on the views of children, adolescents, and young adults (AYA) with cancer and their parents about their experience with genomic testing. Forty-eight semi-structured interviews were performed with children or AYAs with cancer and one of their parents, before and/or after receiving the genetic test results. The interviews were fully transcribed, coded and thematically analysed using an inductive method. This analysis revealed several themes that are key issues: perceived understanding and consenting, apprehension about the test outcomes (expectations and fears), perception and attitude towards incidental findings. The main expectation was an aetiological explanation. Children and AYAs also emphasised the altruistic meaning of genetic testing, while parents seemed to expect a therapeutic and preventive approach for their child and the rest of the family. Parents were more concerned about a family risk, while patients were more afraid of cancer relapse or transmission to their descendants. Both groups suggested possible feelings of guilt concerning family transmission and imaginary representations of what genomics may allow. Incidental findings were not understood by patients, while some parents perceived the related issues and hesitated between wanting or not to know. A multidisciplinary approach would be an interesting way to help parents and children and AYAs to better grasp the complexity of genetic and/or genomic testing.

Constitutional mismatch repair deficiency (CMMRD), first described 25 years ago, confers an extremely high and lifelong cancer risk, including haematologic, brain, and gastrointestinal tract malignancies, and is associated with several non-neoplastic features. Our understanding of this condition has improved and novel assays to assist CMMRD diagnosis have been developed. Surveillance protocols need adjustment taking into account recent observational prospective studies assessing their effectiveness. Response to immune checkpoint inhibitors and the effectiveness and toxicity of other treatments have been described. An update and merging of the different guidelines on diagnosis and clinical management of CMMRD into one comprehensive guideline was needed. Seventy-two expert members of the European Reference Network GENTURIS and/or the European care for CMMRD consortium and one patient representative developed recommendations for CMMRD diagnosis, genetic counselling, surveillance, quality of life, and clinical management based on a systematic literature search and comprehensive literature review and a modified Delphi process. Recommendations for the diagnosis of CMMRD provide testing criteria, propose strategies for CMMRD testing, and define CMMRD diagnostic criteria. Recommendations for surveillance cover each CMMRD-associated tumour type and contain information on starting age, frequency, and surveillance modality. Recommendations for clinical management cover cancer treatment, management of benign tumours or non-neoplastic features, and chemoprevention. Recommendations also address genetic counselling and quality of life. Based on existing guidelines and currently available data, we present 82 recommendations to improve and standardise the care of CMMRD patients in Europe. These recommendations are not meant to be prescriptive and may be adjusted based on individual decisions.

OBJECTIVE:To describe treatments and outcomes of French children treated for relapsed/refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL). METHODS:We conducted the analysis of a series of 75 French children treated for a first relapsed/refractory ALK+ ALCL between 1999 and 2017. RESULTS:The median time to first relapse was 8.1 months from initial diagnosis (2.9 after end of treatment), with 12 relapses during frontline treatment or within 1 month of the end of treatment. Treatment of the first relapse varied according to the period of time and risk factors: 48 received multiagent chemotherapy, including 21 and 19 consolidated with allogeneic stem cell transplantation (SCT) and autologous-SCT, respectively. Twenty-one patients received weekly vinblastine, and six received ALK inhibitors (ALKi). Overall, 64/75 patients reached a second complete remission (CR2). Eight out of 11 patients who did not reach CR2 died and the other three were rescued with ALKi, vinblastine, and nivolumab. With a median follow-up of 8.2 years, 60 patients are alive, 43 in CR2, 15 in CR3, two in CR4; and 15 patients died, six from toxicity and nine from disease progression. The 5-year event-free survival and overall survival after first relapse were 51.7% (95% confidence interval [CI]: 39.6%-62.6%) and 80.7% (95% CI: 69.6%-88.1%), respectively. Time to relapse greater than 12 months from initial diagnosis was proven to be a prognostic factor in relapsed/refractory ALK+ ALCL. CONCLUSION:In relapsed ALK+ ALCL, high survival rate can be reached with various therapeutic strategies. The main challenge remains to prevent subsequent relapses, and to lower long-term morbidity.