The Zero Childhood Cancer Program is a precision medicine program to benefit children with poor-outcome, rare, relapsed or refractory cancer. Using tumor and germline whole genome sequencing (WGS) ...and RNA sequencing (RNAseq) across 252 tumors from high-risk pediatric patients with cancer, we identified 968 reportable molecular aberrations (39.9% in WGS and RNAseq, 35.1% in WGS only and 25.0% in RNAseq only). Of these patients, 93.7% had at least one germline or somatic aberration, 71.4% had therapeutic targets and 5.2% had a change in diagnosis. WGS identified pathogenic cancer-predisposing variants in 16.2% of patients. In 76 central nervous system tumors, methylome analysis confirmed diagnosis in 71.1% of patients and contributed to a change of diagnosis in two patients (2.6%). To date, 43 patients have received a recommended therapy, 38 of whom could be evaluated, with 31% showing objective evidence of clinical benefit. Comprehensive molecular profiling resolved the molecular basis of virtually all high-risk cancers, leading to clinical benefit in some patients.
Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid ...high‐throughput drug screening (HTS) and patient‐derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high‐risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found. Screens also provided orthogonal proof of drug efficacy suggested by molecular analyses and negative results for some molecular findings. We identified treatment options across the whole testing platform for 70% of patients. Only molecular therapeutic recommendations were provided to treating oncologists and led to a change in therapy in 53% of patients, of whom 29% had clinical benefit. These data indicate that in vitro and in vivo drug screening of tumor cells could increase therapeutic options and improve clinical outcomes for high‐risk pediatric cancer patients.
Synopsis
A precision diagnostic platform integrating genomics and transcriptomics with drug testing of patient's primary tumor cells in high throughput drug screening (HTS) and patient‐derived xenograft (PDX) was established to improve identification of therapies in high‐risk pediatric cancer patients.
Treatment options could be identified for 70% of patients across the four‐part platform.
HTS provided orthogonal proof of drug efficacy suggested by molecular analyses and identified many new drug responses without prior molecular hallmarks.
Effective treatments were observed in more than half of PDX models.
There was a strong correlation between HTS and PDX results, and the clinical responses in patients.
A precision diagnostic platform integrating genomics and transcriptomics with drug testing of patient's primary tumor cells in high throughput drug screening (HTS) and patient‐derived xenograft (PDX) was established to improve identification of therapies in high‐risk pediatric cancer patients.
IntroductionIdentifying an underlying germline cancer predisposition (CP) in a child with cancer has potentially significant implications for both the child and biological relatives. Cohort studies ...indicate that 10%–15% of paediatric cancer patients carry germline pathogenic or likely pathogenic variants in cancer predisposition genes, but many of these patients do not meet current clinical criteria for genetic testing. This suggests broad tumour agnostic germline testing may benefit paediatric cancer patients. However, the utility and psychosocial impact of this approach remain unknown. We hypothesise that an approach involving trio whole-genome germline sequencing (trio WGS) will identify children and families with an underlying CP in a timely fashion, that the trio design will streamline cancer risk counselling to at-risk relatives if CP was inherited, and that trio testing will not have a negative psychosocial impact on families.Method and analysisTo test this, we present the Cancer PREDisposition In Childhood by Trio sequencing study (PREDICT). This study will assess the clinical utility of trio WGS to identify CP in unselected patients with cancer 21 years or younger in New South Wales, Australia. PREDICT will perform analysis of biological parents to determine heritability and will examine the psychosocial impact of this trio sequencing approach. PREDICT also includes a broad genomics research programme to identify new candidate genes associated with childhood cancer risk.Ethics and disseminationBy evaluating the feasibility, utility and psychosocial impact of trio WGS to identify CP in paediatric cancer, PREDICT will inform how such comprehensive testing can be incorporated into a standard of care at diagnosis for all childhood cancer patients.Trial registration numberNCT04903782.
Precision medicine is changing cancer care and placing new demands on oncology professionals. Precision medicine trials for high-risk childhood cancer exemplify these complexities. We assessed ...clinicians' (
= 39) and scientists' (
= 15) experiences in the first year of the PRecISion Medicine for Children with Cancer (PRISM) trial for children and adolescents with high-risk cancers, through an in-depth semi-structured interview. We thematically analysed participants' responses regarding their professional challenges, and measured oncologists' knowledge of genetics and confidence with somatic and germline molecular test results. Both groups described positive early experiences with PRISM but were cognisant of managing parents' expectations. Key challenges for clinicians included understanding and communicating genomic results, balancing biopsy risks, and drug access. Most oncologists rated 'good' knowledge of genetics, but a minority were 'very confident' in interpreting (25%), explaining (34.4%) and making treatment recommendations (18.8%) based on somatic genetic test results. Challenges for scientists included greater emotional impact of their work and balancing translational outputs with academic productivity. Continued tracking of these challenges across the course of the trial, while assessing the perspectives of a wider range of stakeholders, is critical to drive the ongoing development of a workforce equipped to manage the demands of paediatric precision medicine.
Current literature/guidelines regarding the most appropriate term to communicate a cancer-related disease-causing germline variant in childhood cancer lack consensus. Guidelines also rarely address ...preferences of patients/families. We aimed to assess preferences of parents of children with cancer, genetics professionals, and pediatric oncologists towards terminology to describe a disease-causing germline variant in childhood cancer. Using semi-structured interviews we asked participants their most/least preferred terms from; ‘faulty gene,’ ‘altered gene,’ ‘gene change,’ and ‘genetic variant,’ analyzing responses with directed content analysis. Twenty-five parents, 6 genetics professionals, and 29 oncologists participated. An equal number of parents most preferred ‘gene change,’ ‘altered gene,’ or ‘genetic variant’ (n = 8/25). Parents least preferred ‘faulty gene’ (n = 18/25). Half the genetics professionals most preferred ‘faulty gene’ (n = 3/6); however this was least preferred by the remaining genetics professionals (n = 3/6). Many oncologists most preferred ‘genetic variant’ (n = 11/29) and least preferred ‘faulty gene’ (n = 19/29). Participants across all groups perceived ‘faulty gene’ as having negative connotations, potentially placing blame/guilt on parents/children. Health professionals described challenges selecting a term that was scientifically accurate, easily understood and not distressing to families. Lack of consensus highlights the need to be guided by families’ preferred terminology, while providing accurate explanations regarding implications of genetic findings.
Recent studies have identified germline mutations in TP53, PAX5, ETV6, and IKZF1 in kindreds with familial acute lymphoblastic leukemia (ALL), but the genetic basis of ALL in many kindreds is unknown ...despite mutational analysis of the exome. Here, we report a germline deletion of ETV6 identified by linkage and structural variant analysis of whole-genome sequencing data segregating in a kindred with thrombocytopenia, B-progenitor acute lymphoblastic leukemia, and diffuse large B-cell lymphoma. The 75-nt deletion removed the ETV6 exon 7 splice acceptor, resulting in exon skipping and protein truncation. The ETV6 deletion was also identified by optimal structural variant analysis of exome sequencing data. These findings identify a new mechanism of germline predisposition in ALL and implicate ETV6 germline variation in predisposition to lymphoma. Importantly, these data highlight the importance of germline structural variant analysis in the search for germline variants predisposing to familial leukemia.
•ETV6 germline deletions predispose to familial ALL.•Germline deletions may be detected by analysis of whole genome and exome data that retain soft-clipped (partially mapped) reads.
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Li‐Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome caused by germline TP53 mutations. Genetic testing is not routinely offered in asymptomatic children at risk of the ...condition as the benefits are debatable and the attitudes of families and health care professionals (HCPs) may vary. This review assessed the attitudes of families and HCPs towards offering genetic testing to children for LFS, with a focus on perceived advantages and disadvantages and involvement of children in the decision‐making process. We searched three key databases (Medline, PsycINFO and EMBASE) to identify quantitative and qualitative studies. We screened 729 articles identifying eight studies for detailed review. Most parents perceived TP53 genetic testing to be beneficial in childhood, despite previous lack of surveillance guidelines. Parents raised some concerns, including decreased insurability and diminishing the child's autonomy. Most children tested reported no negative emotional concerns after testing, even if tested positive. Despite generally positive interest clinicians remain hesitant. Most families saw the value in involving children in decision‐making. Families' acceptance of TP53 testing in childhood was high. This review highlights the need for research on the long‐term psychosocial impacts of testing and the attitudes of families to be reflected in professional guidelines.
Abstract BACKGROUND Diffuse paediatric-type high-grade glioma (HGG), H3-wildtype (WT) and IDH-WT have been recognised as a distinct subgroup in the 5th edition of the World Health Organization (WHO) ...Classification of Tumours of the Central Nervous System (CNS) (2021). METHODS We describe two patients with LFS with conflict between histological and molecular findings. They underwent integrated multi-omics to guide personalised therapy. RESULTS The first patient is a 10-year-old female with a left thalamic diffuse astrocytoma, histologically at least CNS WHO grade 2, with H3K27M, BRAFV600E and IDH1R132H negativity by immunohistochemistry (IHC) and retained H3K27me3, prompting initial management as a low-grade glioma. ZERO2 multi-omics profiling demonstrated no DNA methylation match, (v11b4 and 12.5), but loss of TP53 function (heterozygous germline mutation with tumour whole copy chromosome 17 loss); single copy chromosome X loss with BCOR mutation, and NF1 and FGFR1 mutations. However, tumor aneuploidy, IDH-WT status, co-segregated NF1 alteration and LFS suggested malignant transformation, leading to HGG treatment. The second patient is a 6-year-old boy with LFS, detected on cascade testing, after his brother’s diagnosis of bithalamic diffuse paediatric-type HGG MYCN, following cancer surveillance through Surveillance Study in Multi-organ Cancer Prone Syndrome (SMOC-Junior). Baseline whole-body MRI identified an asymptomatic bithalamic glioma, histopathologically compatible with low-grade astrocytoma except for mosaic loss of H3K27me3. DNA methylation matched (0.99) to diffuse pediatric-type HGG MYCN-subtype, with multiple copy number aberrations, EGFR amplification/overexpression, NF1 mutations and TP53 loss of heterozygosity, without MYCN-alteration or increased expression. He received HGG-specific radiation therapy and is on an NF1-targeted maintenance therapy with trametinib, a MEK inhibitor. In both cases, molecular features suggested early transformation. CONCLUSIONS These patients highlight that integrated multi-omic diagnostic approaches can identify transformation in TP53-altered low grade gliomas and inform development of personalised management guidelines for patients and families with Li Fraumeni syndrome.
Background
Genetic testing in children for hereditary cancer predisposition syndromes (CPSs) involves unique psychosocial and family‐systems considerations. This retrospective study explored the ...perspectives and emotional reactions of parents and young adults about cancer‐related genetic counseling and testing offered to children in the family.
Methods
Families were eligible if they had considered genetic testing for a child (≤18 years) within the family. Parents and young adults ≥16 years participated in semistructured interviews that we coded and identified key themes. We also quantitively assessed emotional distress, quality of life, impact of receiving genetic cancer risk information, and service‐related satisfaction.
Results
From 35 interviews (26 parents, nine young adults), we identified themes spanning families’ experiences from referral to genetic services to the longer term impact of receiving information about family cancer risk from testing of children. Supported by quantitative data, families generally described positive experiences of genetic services and reported benefits to genetic testing. Nevertheless, families faced unique emotional and relational challenges that changed over the family lifecycle. Those challenges differed according to whether the child was asymptomatic or had a cancer diagnosis at testing. Parents of children with cancer described genetic consultations as a secondary concern to the immediate stressors of their child's treatment.
Conclusions
We conclude that the successful integration of cancer genetics into pediatric cancer care requires specialist pediatric genetic counseling and psychosocial support services that are able to respond to families’ changing needs.
Germline genome sequencing in childhood cancer precision medicine trials may reveal pathogenic or likely pathogenic variants in cancer predisposition genes in more than 10% of children. These ...findings can have implications for diagnosis, treatment, and the child's and family's future cancer risk. Understanding parents' perspectives of germline genome sequencing is critical to successful clinical implementation.
A total of 182 parents of 144 children (<18 years of age) with poor-prognosis cancers enrolled in the Precision Medicine for Children with Cancer trial completed a questionnaire at enrollment and after the return of their child's results, including clinically relevant germline findings (received by 13% of parents). Parents' expectations of germline genome sequencing, return of results preferences, and recall of results received were assessed. Forty-five parents (of 43 children) were interviewed in depth.
At trial enrollment, most parents (63%) believed it was at least "somewhat likely" that their child would receive a clinically relevant germline finding. Almost all expressed a preference to receive a broad range of germline genomic findings, including variants of uncertain significance (88%). Some (29%) inaccurately recalled receiving a clinically relevant germline finding. Qualitatively, parents expressed confusion and uncertainty after the return of their child's genome sequencing results by their child's clinician.
Many parents of children with poor-prognosis childhood cancer enrolled in a precision medicine trial expect their child may have an underlying cancer predisposition syndrome. They wish to receive a wide scope of information from germline genome sequencing but may feel confused by the reporting of trial results.
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