One or more cancer drivers were identified in the tumors of almost all patients participating in a prospective, Australian-based precision medicine program focused on the extensive molecular characterization of high-risk pediatric cancer, according to findings published in Nature Medicine.

High-risk pediatric cancers in children, adolescents, and young adults are characterized by aggressive disease lacking well-established treatments or relapsed/refractory disease following standard-of-care treatments, and has been associated with a 5-year survival rate of less than 30%.

Although precision medicine initiatives have the potential to identify targeted treatment options for patients with high-risk pediatric cancers, this type of approach is currently complicated by several factors:

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  • Only an estimated 45% of cancer driver genes identified in pediatric cancers are also found in adult cancers.
  • Pediatric cancers are often associated with novel pathogenic molecular alterations that have not been well characterized.
  • Data on the dosing and efficacy of targeted agents for patients with pediatric cancers are limited.

In order to address some of these limitations of precision medicine in the setting of high-risk pediatric cancer, the Zero Childhood Cancer Program was established in Australia, and designed to extensively characterize high-risk pediatric tumor specimens using whole-genome sequencing, RNA sequencing, and methylation profiling for central nervous system (CNS) tumors.

This process, along with the interpretation of results and issuance of recommendations by a molecular tumor board for their application, was performed in real time for the individual patients recruited to the program.

Regarding the use of this comprehensive approach to the molecular characterization of pediatric cancers, the study authors commented that “the discovery of all potentially relevant molecular data in an individual tumor is, we contend, essential for the clinical application of such evidence by [molecular tumor boards] and clinicians.”

They further added that “the genomic complexity of high-risk cancer is such that there is likely to be more than one genomic driving feature that would require targeting for effective treatment. Appreciating the full targetable landscape permits the [molecular tumor board] and clinicians to consider how targeted therapies might be used, alone or in combination.”

Between 2015 and 2019, 247 patients with high-risk or rare pediatric cancers were recruited to the Zero Childhood Cancer Program, and comprehensive molecular profiling was performed on 252 tumor specimens. These tumors were classified as CNS (92 individuals), nonsarcomatous extracranial solid (35 individuals), neuroblastoma (20 individuals), sarcoma (62 individuals) and hematologic cancers (43 individuals). Whole-genome sequencing, RNA sequencing, and methylation arrays were performed on 100%, 90.5%, and 29.3% of tumors, respectively. 

Some of the key findings of this study were as follows:

  • At least 1 pathogenic molecular alteration was detected in 93.7% of tumor specimens, with 35.1% uncovered using whole-genome sequencing only and 25% found with RNA sequencing only.
  • The median number of pathologic molecular alterations per patient was 3.
  • Extensive molecular profiling resulted in a change in the diagnosis of 5.2% of patients, with methylation profiling confirming or changing the diagnosis of a suspected CNS tumor in 71.1% and 2.6% of cases, respectively.
  • A high rate (16.2%) of germline mutations associated with increased cancer risk were uncovered.
  • Actionable therapeutic molecular targets were identified in 71.4% of tumor specimens.
  • Approximately two-thirds of patients received at least 1 molecular tumor board-based recommendation for an accessible treatment for which pediatric safety data were available.
  • Of the 38 evaluable patients who were treated with an approach recommended by the molecular tumor board, the best overall response was complete responses (11.4%), partial responses (20%), stable disease (40%) and progressive disease (28.6%).

In their concluding remarks, the study authors commented that “in high-risk childhood cancer, [whole-genome sequencing] and [RNA sequencing] both contributed significantly to the identification of the full spectrum of germline and somatic driver variants and to clinical therapeutic recommendations. Whether this holds true in standard-risk pediatric cancers remains to be determined, but it seems likely that the optimal molecular profiling approach might vary by disease type and stage. Our experience demonstrates that [whole-genome sequencing] and [RNA sequencing] offer the best opportunity to identify targetable driver genomic lesions in high-risk pediatric cancer.”


Wong M, Mayoh C, Lau LMS, et al. Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer. Nat Med. Published online October 5, 2020. doi:10.1038/s41591-020-1072-4