The role of cancer predisposition syndrome in children and adolescents with very rare tumours

Germline predisposing pathogenic variants (GPVs) are present in approximately 8 to 10% of children with all cancer types. Very rare tumours (VRTs) represent many different diseases, defined with an annual incidence < 2 / 1,000,000, and correspond to 11% of all cancers in patients aged 0-14 years. Some of these VRTs, including cancer typical for adults, develop in children with a cancer predisposition syndrome (CPS). Classically, three situations lead to consider this association: Some patients develop a VRT for which histology itself strongly suggests a GPV related to a CPS; others are referred for germline genetic testing because of a family or personal history and finally, a systematic molecular genomic tumour analysis, reveals a PV typical to a CPS. Depending on the samples tested and type of analysis performed, information can be directly available about the germline status of such a PV. Depicting the association between CPS and VRT is clinically important as some of these tumour types require adapted therapy, sometimes in the frontline setting, and the proposal of a specific surveillance programme to detect other malignancies. The diagnosis of CPS necessitates a careful familial evaluation and genetic counselling regarding the risks faced by the child or other family members. The aim of this paper is to propose a literature review of solid VRTs occurring in paediatric and young adult patients associated with CPSs

Cancer risk and tumour spectrum in 172 patients with a germline SUFU pathogenic variation : a collaborative study of the SIOPE Host Genome Working Group

Background Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome. Methods To study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germline SUFU PV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives with SUFU PV (89 patients) using the Nelson-Aalen estimator. Results Overall, 117/172 (68%) SUFU PV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entire SUFU gene and inherited in 73% of cases in which inheritance could be evaluated. Conclusion Germline SUFU PV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes.Peer reviewe

Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas

Diffuse intrinsic pontine glioma (DIPG) is one of the most frequent malignant pediatric brain tumor and its prognosis is universaly fatal. No significant improvement has been made in last thirty years over the standard treatment with radiotherapy. To address the paucity of understanding of DIPGs, we have carried out integrated molecular profiling of a large series of samples obtained with stereotactic biopsy at diagnosis. While chromosomal imbalances did not distinguish DIPG and supratentorial tumors on CGHarrays, gene expression profiling revealed clear differences between them, with brainstem gliomas resembling midline/thalamic tumours, indicating a closely-related origin. Two distinct subgroups of DIPG were identified. The first subgroup displayed mesenchymal and pro-angiogenic characteristics, with stem cell markers enrichment consistent with the possibility to grow tumor stem cells from these biopsies. The other subgroup displayed oligodendroglial features, and appeared largely driven by PDGFRA, in particular through amplification and/or novel missense mutations in the extracellular domain. Patients in this later group had a significantly worse outcome with an hazard ratio for early deaths, ie before 10 months, 8 fold greater that the ones in the other subgroup (p = 0.041, Cox regression model). The worse outcome of patients with the oligodendroglial type of tumors was confirmed on a series of 55 paraffin-embedded biopsy samples at diagnosis (median OS of 7.73 versus 12.37 months, p = 0.045, log-rank test). Two distinct transcriptional subclasses of DIPG with specific genomic alterations can be defined at diagnosis by oligodendroglial differentiation or mesenchymal transition, respectively. Classifying these tumors by signal transduction pathway activation and by mutation in pathway member genes may be particularily valuable for the development of targeted therapies

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

BACKGROUND: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. METHODS: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. FINDINGS: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. INTERPRETATION: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. FUNDING: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario

Relapsing intracranial germ cell tumours warrant retreatment

International audienc

End of life care in children and adolescents with cancer: perspectives from a French pediatric oncology care network

International audienceBackground: In developed countries, cancer remains the leading cause of pediatric death from illness after the neonatal period. Objective: To describe the end-of-life care characteristics of children and adolescents with solid tumors (ST) or hematologic malignancies (HM) who died from tumor progression in the Île-de-France area. Methods: This is a regional, multicentric, retrospective review of medical files of all children and adolescents with cancer who died over a 1-year period. Extensive data from the last 3 months of life were collected. Results: A total of 99 eligible patients died at a median age of 9.8 years (range, 0.3–24 years). The most frequent terminal symptoms were pain (n = 86), fatigue (n = 84), dyspnea (n = 49), and anorexia (n = 41). Median number of medications per patient was 8 (range, 3–18). Patients required administration of opioids (n = 91), oxygen (n = 36), and/or sedation (n = 61). Decision for palliative care was present in all medical records and do-not-resuscitate orders in 90/99 cases. Symptom prevalence was comparable between children and adolescents with ST and HM. A wish regarding the place of death had been expressed for 64 patients and could be respected in 42 cases. Death occurred in hospital for 75 patients. Conclusions: This study represents a large and informative cohort illustrating current pediatric palliative care approaches in pediatric oncology. End-of-life remains an active period of care requiring coordination of multiple care teams

HGG-41. Glioma oncogenesis in the constitutional mismatch repair deficiency (CMMRD) syndrome

International audienceAbstract PURPOSE: Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS: A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS: Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden. CONCLUSION: CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors

Description of the oligodendroglial/proneural type of DIPG.

<p>Panel A: Radial plot showing the expression of oligodendroglial markers in the two groups of DIPG, in log2 ratios related each other. The red circle represent the median expression level of the whole population of DIPG. Group 1 expresses higher levels of oligodendroglial markers than group 2 DIPG. Panel B: Morphological oligodendroglial differenciation in group 1 tumors (HES staining, ×40). Panel C: Morphological astrocytic differenciation in group 2 tumors (HES staining ×40). Panel D: Olig2 immunohistochemistry in a group 1 DIPG showing that probably not all cells in the biopsy are tumoral (×40). Panel E: Dual immunohistochemistry for Olig2 and GFAP showing that tumor cells in mitosis are GFAP negative but Olig2 positive (×100). Panel F: Overall survival of 55 DIPG according to the presence (red) or absence (blue) of oligodendroglial differenciation. Median OS was shorter in patients with oligodendroglial type of tumors (7.73 vs 12.37, p = 0.045, log rank test).</p

PDGFRA amplification/mutation is driving the oncogenesis of the oligodendroglial/proneural type of DIPG.

<p>Panel A: GSEA graph showing the enrichment of group 1 DIPG for the gene set describing the gene expression profile of PDGFRA amplified glioblastomas. Panel B: PDGFRA immunohistochemistry in the infiltrative part of a DIPG. Panel C: PDGFRA immunohistochemistry in the tumoral part of a DIPG. Panel D: FISH analysis of a DIPG using a FIP1L1/PDGFRA probe showing the amplification of the locus encompassing the two genes (most frequently seen). Panel E: Dual-FISH analysis of a DIPG with two probes one for PDGFRA and one for MET showing that the two oncogenes may be gained/amplified in different cells within the tumor. Panel F: Integrative genomic analysis using DR-Integrator (R package). Seven genes are present in the minimal common region (MCR) gained on chromosomal location 4q12 in DIPG. Boxplots represent the distribution of GE data and circles represent CNA data. The circles are centered on the corresponding GE measure on the distribution and their radii are proportional to the absolute value of CNA, red ones being losses and green ones gains. CNA and GE were highly correlated for four of these seven genes (<i>CHIC2, KIT, KDR, PDGFRA</i>). Panel G: Diagram of the PDGFRA gene showing the mutations discovered in DIPG samples and xenografts.</p