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Pediatric Cancer Neoepitope Analysis May Aid Immunotherapy Development

NEW YORK (GenomeWeb) – A new sequencing study in hundreds of pediatric cancer cases has revealed potential targets for cancer vaccines, adoptive T cell therapy, or other forms of immunotherapy.

Researchers from St. Jude Children's Research Hospital used genomic and transcriptomic profiles for tumors from 540 children to look for somatic mutations and fusions that might produce new antigen targets, or neoepitopes. As they reported in Genome Medicine yesterday, the search led to predicted neoepitopes in 90 percent of the solid tumors considered and 88 percent of leukemia cases.

"To the best of our knowledge, this is the first comprehensive analysis of neoepitopes in pediatric cancers, which we hope will enable a broader range of research and open up new avenues for the treatment of pediatric cancer," St. Jude computational biology researcher Jinghui Zhang, the study's corresponding author, and her colleagues wrote. 

As part of the Pediatric Cancer Genome Project, the investigators performed paired-end whole-genome sequencing on tumor and matched normal samples from 540 children with pediatric cancer, spanning 23 cancer subtypes. More than half of those cases were leukemias, they noted, while 123 involved central nervous system tumors and 133 were solid tumors occurring outside the central nervous system.

Using an Optitype algorithm developed by investigators in Germany, the team teased out human leukocyte antigen haplotype patterns in the pediatric cancer cases. It also produced RNA sequence data for 270 primary tumors and a dozen relapsed tumors to track transcript expression profiles in relation to the mutations and fusions observed in the genome.

From a collection of more than 5,600 somatic missense mutations detected in primary tumor samples, the researchers narrowed in on 2,336 candidate neoepitopes — potential antigen targets that turned up in 90 percent of the solid tumors, just over 88 percent of leukemia cases, and around 78 percent of solid tumors falling in the central nervous system category.

Along with follow-up analyses of potential neoepitope expression in a subset of the tumors, the team went on to explore the distribution of these candidate antigen-coding alterations, identifying recurrent changes found within and across cancer types.

The search led to recurrent neoepitope candidates involving mutations in the KRAS or NRAS genes, for example, as well as fusions leading to possible neoepitopes in several cancer subtypes. Not surprisingly, tumors marked by DNA mismatch repair gene glitches were far more mutation-prone, containing thousands of proposed neoepitopes apiece, on average.

"Neoepitopes identified from oncogenic mutations are ideal targets for immunotherapy, including tumor vaccines and adoptively transferred tumor-reactive T cells," Zhang and co-authors wrote. "Alternatively, checkpoint blockade therapy might facilitate cytotoxic T lymphocyte recognition of these neoepitopes in a subset of patients."