Gene Synthesis Accelerates Cancer Biology Research
Getting Closer to Precise Therapies for Pediatric Cancers with Integrated Sequencing Analysis
The first step in achieving the promise of precision medicine is realizing that each patient is unique. Recognizing the uniqueness of cancer patients and in an effort to move towards personalized therapies, scientists at St. Jude Children's Hospital took a leap forward in patient-centric care by leveraging not one but several tumor sequencing approaches, including whole genome, whole exome, and RNA sequencing.
Genomes for Kids
Based on the SEER (Surveillance, Epidemiology, and End Results) Program's Cancer Statistic Review (1975-2018), hematological (e.g., leukemia) and central nervous system (CNS) malignancies had the highest incidence in children (Ages 0-19), occurring each with a frequency of over 20%.
Motivated by the paucity of sequencing approaches for pediatric cancer patients diagnosed with low or standard risk cancer types, the team at St. Jude's designed the study "Genomes for Kids" to perform next-generation sequencing analysis of tumor biopsies from over 250 pediatric cancer patients (Newman et al. 2021). Most patients were children with new cancers (85%), with a minority having cancer recurrence. Additionally, the study group represented a broad range of cancer types, with blood and brain malignancies predominating.
Following a workflow that integrated whole genome, whole exome, and RNA sequencing, the team at St. Jude identified a diverse range of somatic genomic alterations, such as single nucleotide variants, insertions, and deletions (indels), and loss of heterozygosity. Additionally, Newman and colleagues identified various structural variations, including fusions, enhancer hijacking, internal tandem duplications, and altered copy numbers. Among these, Newman et al. point out the utility of whole genome sequencing to identify structural variations (e.g., gene fusions and enhancer hijacking), often occurring within non-coding sequences.
Because non-coding regions constitute a significant portion (98%) of the human genome, cancer associated mutations are frequently found in these regions (He et al. 2020).
Genome structural variations involve the rearrangement of large DNA segments. The inclusion of whole genome sequencing in the Genome for Kids study enabled Newman and colleagues to identify gene fusions in 90 tumors, enhancer hijacking translocations in 21 tumors, and intragenic deletions in 38 tumors. Adapted from "Genome Structural Variations", by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates
Leveraging their integrated sequencing platform enabled Newman and colleagues to identify gene fusions, enhancer hijack, and microdeletion events potentially valuable in the diagnosis, prognosis, or treatment of various cancer types. Additionally, investigators showed how this strategy may help establish the role of germline mutations in the development of different tumor types.
Significantly, investigators were able to identify actionable targets that could either help in diagnosis, prognosis, or treatment of tumors in the majority of participants. For example, among Genome for Kids study participants, 78 children were experiencing cancer recurrence or metastasis. Within this group, integrated sequencing enabled the identification of targetable variations in 32 patients and supported therapies for 12 patients, according to their identified variants.
Compared to the use of commercially available gene analysis panels (e.g., Foundation One CDx, Foundation One Heme, Oncomine v3, and Oncokids Hotspots), this integrated sequencing approach provides better coverage allowing the identification of more variants, which maximizes the opportunities for targeted and precise pediatric cancer therapy.
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He, B. et al. Diverse noncoding mutations contribute to deregulation of cis-regulatory landscape in pediatric cancers. Sci. Adv. (2020) doi:10.1126/sciadv.aba3064.
Newman, S. et al. Genomes for Kids: The scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing. Cancer Discov. (2021) doi:10.1158/2159-8290.cd-20-1631.