Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Precision medicine and systems biology


1

What is precision medicine, and how does it relate to pediatric oncology?

Precision medicine refers to approaching the treatment and prevention of disease by tailoring patients’ care based on their individual variability in genes, environment, and lifestyle. Oncology has been at the forefront of applying precision medicine principles to the care of patients supported by a rapid expansion in genomic technologies and large-scale databases along with the computational tools for analyzing them. The application of precision medicine is emerging within pediatric oncology as we shift from directing the diagnosis, classification, and management of tumors from the site of tumor origin alone to incorporating individual tumor information at the gene, protein, and environment level. Clinical, histological, and molecular data are integrated with the goal of selecting the most appropriate treatment for an individual patient and the unique biological profile of that patient’s tumor. This includes molecularly based classification, use of clinical and molecular features for risk stratification and therapy selection, and the growing use of genomically driven targeted therapies relying on individualized tumor genomic analyses. The goal of precision medicine in pediatric oncology is to select more precise and personalized therapies to cure more patients while minimizing short- and long-term side effects from treatment.

2

How is the pediatric cancer genome different from that in adults? How does this affect the way precision medicine is applied in pediatric versus adult oncology?

Compared with adult cancers, pediatric cancers are much rarer, more often induced by inherited or sporadic errors in development rather than environmental exposures, and typically of mesenchymal rather than epithelial origin. This leads to significant differences in the frequency and spectrum of mutations seen in pediatric cancers compared with adult cancers, including:

  • Lower mutational burden

  • Higher prevalence of structural variations (chromosomal rearrangements, gene fusions)

  • More frequent epigenetic alterations: heritable changes that affect gene expression and activity without underlying nucleotide changes (DNA methylation, histone modifications)

  • Rare occurrence of targetable kinase alterations, such as epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)

  • More frequent germline mutations in cancer predisposition genes

These differences highlight the need for precision medicine in pediatric oncology to:

  • Use more comprehensive sequencing approaches beyond targeted gene panels, including gene expression and DNA methylation analyses.

  • Aggregate clinical and molecular data across institutions to support discovery research and guide clinical decision making in the setting of a rare disease.

  • Focus on inherited cancer susceptibility including the added clinical, computational, and ethical complexity of incorporating routine germline testing into clinical care.

3

Define next-generation sequencing (NGS). Describe the main NGS methods used clinically in pediatric oncology and their advantages and limitations.

NGS, also described as massively parallel or deep sequencing, refers to a newer, fast technology for sequencing of DNA or RNA that is done in a highly parallel, high-throughput, scalable fashion. This has allowed for the sequencing of the entire human genome within a single day and greatly reduced the cost so that routine genomic analysis in the clinical setting to direct patient care is now possible. The main NGS methods used in pediatric oncology clinical practice, along with their advantages and limitations, are detailed in Table 14.1 and Figure 14.1 . In addition to the detection of point mutations, these NGS methodologies can identify insertions, deletions, copy number changes, novel gene fusions, and relative gene expression. Compared with older sequencing technologies, NGS can also identify subclonal mutations (present in a low proportion of tumor cells) that can be responsible for therapy resistance and relapse in certain tumors.

Table 14.1
Next-Generation Sequencing (NGS) Methods Used in Pediatric Oncology
NGS Method Description Advantages Limitations
Targeted gene/ fusion panel sequencing

  • Deep sequencing of a panel of preselected genes or regions associated with cancer

  • High sequencing depth to identify rare variants or those at low allele frequency

  • Commercially available

  • Cost-effective

  • Faster, easier, more reliable data analysis

  • Often designed for adult cancers (miss important pediatric tumor gene regions)

  • Limit detection of novel cancer-associated genes not included in the panel

Whole-exome sequencing (WES)

  • Sequencing of the protein-coding region of the genome (< 2% of entire genome but contains the majority of disease-related variants)

  • Can identify novel cancer-associated genes and variants

  • Relatively cost-effective with smaller, more manageable data compared with whole-genome sequencing (WGS)

  • May miss some rare or subclonal variants because of lower depth

  • Complex interpretation (i.e., variants of unknown significance)

  • Requires paired sequencing of normal tissue to determine which changes are tumor-related

Whole-genome sequencing (WGS)

  • Sequencing of the entire genome, including chromosomal and mitochondrial DNA

  • Increased yield for identifying pathogenic variants, including noncoding regions

  • Higher coverage better identifies copy number changes, structural variants, high focal amplifications, and deletions that can be missed using fragmented data

  • Costly

  • Large amounts of complex data, difficult interpretation (noncoding regions less conserved)

  • Requires sequencing and data storage systems that are not readily available for everyday clinical practice

Whole transcriptome sequencing (RNAseq)

  • Sequencing of coding and multiple forms of noncoding RNA

  • Whole transcriptome-based biomarkers have prognostic or therapeutic significance

  • Important for discovery of novel fusions, allele-specific expression

  • Relatively cost-effective

  • Complicated interpretation and high potential for bias: results are tissue-and time-specific and can vary significantly with the exact sequencing platform

Figure 14.1, Clinical applications of next-generation sequencing (NGS) in pediatric oncology.

4

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here