Comprehensive clinical DNA and RNA sequencing opens door to the promise of precision medicine

St. Jude Children’s Research Hospital study highlights the power of comprehensive whole genome, whole exome and RNA sequencing to better understand and treat each patient’s cancer.

St. Jude Children’s Research Hospital investigators have demonstrated that comprehensive genomic sequencing of all pediatric cancer patients is feasible and essential to capitalize on the lifesaving potential of precision medicine. Results from the St. Jude Genomes for Kids study appear online today in the journal Cancer Discovery.

Whole genome and whole exome sequencing of germline DNA was offered to all 309 patients who enrolled in the study. Whole genome, whole exome and RNA sequencing of tumor DNA was carried out for the 253 patients for whom adequate tumor samples were available.

Overall, 86% of patients had at least one clinically significant variation in tumor or germline DNA. Those included variants related to diagnosis, prognosis, therapy or cancer predisposition. Researchers estimated that 1 in 5 patients had clinically relevant mutations that would have gone undetected using standard sequencing methods.

“Some of the most clinically relevant findings were only possible because the study combined whole genome sequencing with whole exome and RNA sequencing,” said Jinghui Zhang, Ph.D., St. Jude Department of Computational Biology chair and co-corresponding author of the study.

Every tumor is unique. Every patient is unique.

Comprehensive clinical sequencing that includes whole genome, whole exome and RNA sequencing is not widely available. But as the technology becomes less expensive and accessible to more patients, researchers said comprehensive sequencing will become an important addition to pediatric cancer care.

“We want to change the thinking in the field,” said David Wheeler, Ph.D., St. Jude Precision Genomics team director and a co-author of the study. “We showed the potential to use genomic data at the patient level. Even in common pediatric cancers, every tumor is unique, every patient is unique.

“This study showed the feasibility of identifying tumor vulnerabilities and learning to exploit them to improve patient care,” he said.

Tumor sequencing guided the change in treatment for 12 of the 78 study patients for whom standard of care was unsuccessful. In four of the 12 patients, the changes stabilized disease and extended patient lives. Another patient, one with acute myeloid leukemia, went into remission and was cured by blood stem cell transplantation.

“Through the comprehensive genomic testing in this study, we were able to clearly identify tumor variations that could be treated with targeted agents, opening doors for how oncologists manage their patients,” said co-corresponding author Kim Nichols, M.D.St. Jude Cancer Predisposition Division director.

Germline variants and assessment of variant pathogenicity based on RNA data


A. Numbers of germline P/LP variants, broken down by gene and tumor type. B. Proportions of germline P/LP variants, broken down by tumor type. C. BAP1 intron 4 retention in SJEWS030332 compared to other G4K Ewing sarcoma cases. Each blue histogram shows hg19-aligned RNA-Seq coverage relative to the BAP1 gene model in green (note that BAP1 is on the negative strand). The position of the exon five splice acceptor mutation is indicated by the red dotted line. Increased read coverage in the SJEWS030332 (bearing a mutation at the -3 position of exon 5) intron relative to the three other samples indicates intron 4 retention (black arrow). Inset histograms show the relative proportion of reference and variant alleles in tumorderived WGS and RNA-Seq in grey and purple, respectively. Corresponding read counts are WGS: 32G/21T (40% variant allele) and RNA 2G/28T (93% variant allele). Above the RNA coverage plots a schematic of the BAP1 protein is shown with the location of the splice variant leading to protein truncation marked. D. NF1 exon 45 skipping in SJBALL030144. The blue histogram shows RNA-Seq coverage relative to the NF1 gene model in green. Canonical splices are shown as light blue links between exons and a non-canonical splice is shown in mauve. The height of mauve and blue lollypops is proportional to the number of splice junction reads detected plotted on a log scale on the y-axis. The purple bar indicates the position of the NF1 exon 45 splice acceptor mutation. Exon 45 expression is diminished relative to flanking exons and a non-canonical splice linking exons 44 and 46 is observed indicating an exon skipping event.

Additional findings and details

  • Genomes for Kids enrolled patients between August 2015 and March 2017.
  • Eighteen percent of patients carried germline variations in one of 156 known, cancer-predisposition genes.
  • Almost two-thirds of the germline variations identified would not have been detected based on current screening guidelines.

Next steps

Genomes for Kids helped launch the hospital’s clinical genomics program, which has enrolled about 2,700 cancer patients to date.

Meanwhile, data generated through the Genomes for Kids study are available at no cost to the international research community. By sharing the data, St. Jude aims to speed advances in understanding and treatment of pediatric cancer. The data are available in St. Jude Cloud.

“Even the most treatable cancers are not curable in all patients. For example, relapse remains the leading cause of death for the most common childhood cancer, acute lymphoblastic leukemia,” Nichols said. “Being able to understand and predict which patients will respond to treatment and which won’t requires collecting comprehensive genomic data on all patients.”

SourceSt. Jude Children’s Research Hospital

Newman S, Nakitandwe J, Kesserwan CA, Azzato EM, Wheeler DA, Rusch M, Shurtleff S, Hedges DJ, Hamilton KV, Foy SG, Edmonson MN, Thrasher A, Bahrami A, Orr BA, Klco JM, Gu J, Harrison LW, Wang L, Clay MR, Ouma A, Silkov A, Liu Y, Zhang Z, Liu Y, Brady SW, Zhou X, Chang TC, Pande M, Davis E, Becksfort J, Patel A, Wilkinson MR, Rahbarinia D, Kubal M, Maciaszek JL, Pastor V, Knight J, Gout AM, Wang J, Gu Z, Mullighan CG, McGee RB, Quinn EA, Nuccio R, Mostafavi R, Gerhardt EL, Taylor LM, Valdez JM, Hines-Dowell SJ, Pappo AS, Robinson G, Johnson LM, Pui CH, Ellison DW, Downing JR, Zhang J, Nichols KE. (2021)  Genomes for Kids: The scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing. Cancer Discov [Epub ahead of print]. [abstract]

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