The recent advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS) –– with increasingly efficient and lower costs –– has led to studies such as these cancer-screening analyses presented here [attached]. In the main article (page 321), authors examined sequences of whole exomes (all the protein-coding regions in the genome), as well as whole genomes for 961 pediatric cancers representing 24 tumor-types, with emphasis on central nervous system tumors. In the Letter article (page 371), authors used similar analyses to characterize 1,699 pediatric cancers across six types of cancer, emphasizing leukemias. The data in these two papers provide valuable insights into the mechanisms that shape the genomic landscape of childhood cancers.
Adult cancers frequently involve multiple genetic changes that together drive cancer progression, including mutations of one or a few DNA bases, and larger changes called structural variants (insertions & deletions; indels) that span more than 1,000 bases. Such drivers can be shared across cancer types. One of the most meaningful and exciting outcomes of the current studies is their confirmation that the genomic landscape of childhood cancers differs from that of adult cancers. Previous studies of individual pediatric cancer types have shown they have fewer mutations and structural variants, on average, than do adult cancers.
However, these current pan-cancer analyses (genome-wide screen of numerous cancer types in many patients) take this theme further –– systematically highlighting four key differences between childhood and adult cancer genomes. [a] There are fewer mutations and structural variants in pediatric cancers than in adult cancers. [b] Pediatric cancers are frequently defined by a single driver gene. [c] Different genes are mutated in pediatric, compared with adult, cancers. [d] Perhaps most intriguingly, driver mutations tend to be specific to individual pediatric cancer types, with minimal overlap across tumor types (this is in contrast to adult cancers, which more frequently share mutations across types).
These exciting data provide a comprehensive genomic architecture for pediatric cancers and emphasize the need for childhood-cancer-specific development of precision therapies. Moreover, almost half of the pediatric tumors harbor a potentially druggable intracellular signaling-pathway –– which should be highly relevant for the design of future childhood clinical trials.
Nature 15 Mar 2018; 555: 321–327 [full article] & 371–376 [Letter] & 316–317 [News-N-Views]