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Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric
Marie Wong1,2,3, Chelsea Mayoh1,2, Loretta M S Lau1,2,4
1Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, Australia.
Abstract:
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.
Insights
The Zero Childhood Cancer Program uses whole genome sequencing to find molecular targets in rare pediatric cancers. This precision medicine approach identified aberrations in most patients, leading to targeted therapies and clinical benefit for some children.
Area of Science:
- Genomics
- Precision Medicine
- Pediatric Oncology
Background:
- Pediatric cancers often have poor outcomes, especially rare, relapsed, or refractory types.
- Precision medicine offers a targeted approach to treatment based on individual molecular profiles.
Purpose of the Study:
- To evaluate the utility of comprehensive molecular profiling in high-risk pediatric cancers.
- To identify molecular aberrations and therapeutic targets in children with poor-prognosis cancers.
Main Methods:
- Whole genome sequencing (WGS) and RNA sequencing (RNAseq) were performed on 252 pediatric tumors.
- Methylome analysis was conducted on 76 central nervous system tumors.
- Identified molecular aberrations, therapeutic targets, and changes in diagnosis.
Main Results:
- 968 molecular aberrations were identified.
- 93.7% of patients had at least one germline or somatic aberration.
- 71.4% of patients had identified therapeutic targets, and 5.2% experienced a diagnostic change.
- 31% of patients receiving recommended therapy showed objective clinical benefit.
Conclusions:
- Comprehensive molecular profiling effectively resolves the molecular basis of high-risk pediatric cancers.
- Precision medicine approaches can identify therapeutic targets and lead to clinical benefit in pediatric cancer patients.
- Genomic and methylome analyses are crucial for diagnosis and treatment selection in pediatric oncology.
