Kids Cancer Center

Abstract Adult-type diffuse gliomas exhibit poor prognosis with limited treatment options. Although copper-targeted therapies have been previously explored in these tumors, they have yet to show significant benefits. To understand the role of copper in glioma biology we performed an in silico data analysis on the TCGA glioma cohorts to identify copper-homeostasis related genes (CHRG) with prognostic significance. This was done to enable patient stratification into appropriate treatment arms for future clinical trials involving copper targeted therapies. Furthermore, in vitro experimentation was performed to validate the functional outcomes observed from the in silico results. 19 CHRGs were identified to have prognostic association from the TCGA glioma cohorts. This gene signature regulates a broad range of cellular processes, including metal homeostasis, metabolism, extracellular matrix organization, and immune cell function. The CHRG signature enabled the development of a predictive model that allowed stratification of patients between high and low risk groups. In vitro spheroid growth assays in both U87 cell lines with or without IDH mutation elicited sustained growth inhibition after 6 days post treatment. Furthermore, copper chelation therapy modified the energy potential of these glioma cells in vitro leading to growth inhibition. This study established a predictive model using 19 CHRGs that enable patient stratification between high and low risk glioma patients. Furthermore, our in vitro experiments show the suitability of targeting intracellular copper to inhibit tumor growth. Further research is needed to understand the underlying mechanisms and explore optimal treatment combinations for improved outcomes. We aim to extend this approach to pediatric gliomas for improved risk assessment and personalized medicine.

ObjectiveTo examine academic outcomes among children hospitalised with a chronic health condition.DesignPopulation-level birth cohort.SettingNew South Wales, Australia.Participants397 169 children born 2000–2006 followed up to 2014.Intervention/exposureHospitalisations with a chronic condition.Main outcome measuresAcademic underperformance was identified as ‘below the national minimum standard’ (BNMS) in five literacy/numeracy domains using the national assessment (National Assessment Program-Literacy and Numeracy) data. Multivariable logistic regression assessed the adjusted ORs (aORs) of children performing BNMS in each domain at each grade (grades 3, 5 and 7, respectively).ResultsOf children hospitalised with a chronic condition prior to National Assessment Program-Literacy and Numeracy (NAPLAN) (16%–18%), 9%–12% missed ≥1 test, with a maximum of 37% of those hospitalised ≥7 times, compared with 4%–5% of children not hospitalised. Excluding children who missed a NAPLAN test, more children hospitalised with a chronic condition performed BNMS across all domains and grades, compared with children not hospitalised (eg, for BNMS in reading at grade 3: n=2588, aOR 1.35 (95% CI 1.28 to 1.42); for BNMS in numeracy at grade 3: n=2619, aOR 1.51 (95% CI 1.43 to 1.59)). Increasing frequency and bed-days of hospitalisation were associated with 2–3 fold increased odds of performing BNMS across all domains and grades. Children hospitalised with mental health/behavioural conditions had the highest odds of performing BNMS across all domains at each grade.ConclusionsChildren hospitalised with a chronic condition underperform academically across literacy/numeracy domains at each school grade. Health and educational supports are needed to improve these children’s academic outcomes.

ObjectivesDisclosure of a hereditary condition in the family poses notable challenges for patients who often seek the assistance of genetic health professionals (GHPs). This study aimed to investigate GHPs’ opinions about the ideal time for disclosure to offspring and their responsibility to at-risk relatives.DesignCross-sectional qualitative study.SettingGenetic familial cancer clinics related to mostly secondary and tertiary care hospitals and centres in urban, regional and rural areas across all states of Australia.ParticipantsGHPs (N=73) including clinical geneticists, genetic counsellors, medical specialists, nurses, surgeons and mental health specialists (eg, psychiatrists, psychologists) who had worked with BRCA1 and BRCA2 families for an average of 9 years.ResultsFocus groups and interviews were transcribed and analysed thematically. GHPs perceived that life stage, maturity, parents’ knowledge and capacity to disseminate information influenced parent–offspring disclosure. In general, GHPs recommended early informal conversations with offspring about a family illness. GHPs considered that facilitation of disclosure to relatives using counselling strategies was their responsibility, yet there were limitations to their role (eg, legal and resource constraints). Variability exists in the extent to which genetic clinics overcome challenges to disclosure.ConclusionsGHPs’ views on the ideal time for the disclosure of genetic risk are generally dependent on the patient’s age and relative’s ability to disclose information. A responsibility towards the patient and their at-risk relative was widely accepted as a role of a GHP but views vary depending on legislative and specialty differences. Greater uniformity is needed in genetic procedural guidelines and the role of each discipline (eg, geneticists, genetic counsellors, oncologists, nurses and mental health specialists) in genetic clinics to manage disclosure challenges.

The etiology of severe hemolytic anemia in most patients with recessive hereditary spherocytosis (rHS) and the related disorder hereditary pyropoikilocytosis (HPP) is unknown. Whole exome sequencing of DNA from probands of 24 rHS or HPP kindreds identified numerous mutations in erythrocyte membrane α-spectrin (SPTA1). Twenty-eight mutations were novel, with null alleles frequently found in trans to missense mutations. No mutations were identified in a third of SPTA1 alleles (17/48). Whole genome sequencing revealed linkage disequilibrium between the common rHS-linked α-spectrinBug Hill polymorphism and a rare intron 30 variant in all 17 mutation-negative alleles. In vitro minigene studies and in vivo splicing analyses revealed the intron 30 variant changes a weak alternate branch point (BP) to a strong BP. This change leads to increased utilization of an alternate 3' splice acceptor site, perturbing normal α-spectrin mRNA splicing and creating an elongated mRNA transcript. In vivo mRNA stability studies revealed the newly created termination codon in the elongated transcript activates nonsense mediated decay leading to spectrin deficiency. These results demonstrate a unique mechanism of human genetic disease contributes to the etiology of a third of cases of rHS, facilitating diagnosis and treatment of severe anemia, and identifying a new target for therapeutic manipulation.