Published today in Cancer Cell, co-first author, Samuel Brady, PhD (left), with co-first author, Robert Greenhalgh, PhD, and corresponding author, Jinghui Zhang, PhD (right), curated and analyzed the first and largest dataset of genomic structural variations specific to childhood cancer.
The first and largest dataset of genomic structure variations specific to childhood cancers was published today by scientists from St. Jude Children’s Research Hospital and the National Cancer Institute. The researchers assembled data cohorts from multiple childhood cancer genomic initiatives and conducted a comprehensive analysis of structural variants across pediatric cancers, which comprise 60% of the mutations that drive childhood malignancies. By comparing the pediatric landscapes to adult cancers, the researchers identified which mutational processes drive these structural changes, and their associated genomic features, specific to childhood disease. The findings were published today in Cancer Cell.
Genomic structural variants are like cut-and-paste errors that occur when pieces of the genome are broken in one place and then rejoined in the wrong location, causing disease. However, not much was known about the profile of these variants across pediatric cancers until the new pan-cancer analysis, a cross-cancer assessment that evaluates similarities and differences across the genome.
“We had always assumed that the mutation burden in pediatric cancer is lower than in adults,” said corresponding author Jinghui Zhang, PhD, St. Jude Department of Computational Biology. “But we observed that the structural variant burden in pediatric blood cancer is higher than that of adult counterparts.”
This is because children usually have not had as much time to accumulate small genetic alterations, called point mutations, caused by aging and environmental damage. Yet, by assessing the data for structural variants, the team observed that these errors in the pediatric genome were prevalent, providing new insight into what drives certain types of pediatric cancers.
Homing in on structural variants in pediatric cancer
For their analysis, the scientists curated structural variants from the publicly available whole genome sequencing data of 1,616 patients across 16 major pediatric cancer types. They then compared summarized data from that cohort to 2,203 adult cancer genomes gathered by the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium, finding what is uniquely driving childhood cancers.
The results point to errors in a specific DNA rearrangement type known as RAG-mediated recombination. In this normally occurring DNA rearrangement process, immune cells significantly alter their DNA using RAG1 and RAG2 proteins to create a rich protein repertoire to recognize potential threats, such as infection. The data shows that aberrant RAG-mediated recombination occurs in almost all subtypes of acute lymphoblastic leukemias (ALL), the most common childhood cancer, including both B-cell ALL (B-ALL) and T-cell ALL (T-ALL). This understanding effectively widens the spectrum of possible leukemic drivers and gives new weight to the significance of structural variants in pediatric blood cancers.
Examining the mechanisms of mutational signatures in disease development
The researchers further sought to identify the source of mutational events leading to the development of structural variants. Through an analysis of 10 prevalent mutational signatures across cancer types, they identified mutational signatures that were highly represented across the curated dataset. One signature, SV7, stood out as abundant in B-ALL and T-ALL with significantly elevated RAG1/2 expression, suggesting that RAG-mediated recombination serves as a potential causative mechanism for the SV7 mutational signature in pediatric ALL. The finding was supported by the propensity of SV7 in adult lymphoid cancer, whose mutational basis is also suspected to be caused by a RAG-mediated recombination, providing ample evidence for the investigators to understand the mechanism contributing to this important signature.
The findings demonstrate that there are important mechanisms driving pediatric cancer hidden in the structural variant data and showcase how the dataset and analysis serve as a rich resource for future investigations.
“This comprehensive dataset will provide more opportunities to identify targets and investigate the mechanism behind the structural variations,” Zhang said. “The data is well curated, so there’s a lot of datamining scientists can do to gain insight into the relevance of a target they are interested in studying, making it an incredible resource for the cancer community.”
The database can be access through the St. Jude Cloud GenomePaint portal.
Authors and funding
The study has three lead authors, Robert Greenhalgh, Samuel Brady, and Wentao Yang, all of St. Jude. Other co-authors include Diane Flasch, Michael Edmondson, Nadezhda Terekhanova, Yanling Liu, Jian Wang, Karol Szlachta, Liqing Tian, Daniel Putnam, Delaram Rahbarinia, Pandurang Kolekar, Xin Zhou, Xiaotu Ma, all of St. Jude; and Daniela Gerhard, National Cancer Institute.
The study was supported by grants from the National Institutes of Health, National Cancer Institute (grant R01CA216391 and contract HHSN261200800001E) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children’s Research Hospital is leading the way the world understands, treats, and cures childhood catastrophic diseases. As the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, St. Jude advances groundbreaking research and shares its discoveries worldwide to accelerate progress in pediatric medicine. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to more than 80% since the hospital opened more than 60 years ago. Through collaboration and innovation, St. Jude is working to ensure that children everywhere have access to the best possible care. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.