The development of next generation sequencing (NGS) techniques, including whole genome (WGS),
exome (WES) and RNA sequencing has revolutionized the ability of investigators to query the
molecular mechanisms underlying tumor formation. Through the Pediatric Cancer Genome Project
(PCGP), investigators at St. Jude Children's Research Hospital (SJCRH) have successfully used
NGS approaches to evaluate more than 1,000 pediatric cancers ranging from hematologic
malignancies to central nervous system (CNS) and non-CNS solid tumors. From these and related
studies, it has become clear that genomic approaches can accurately classify tumors into
distinct pathologic and prognostic subtypes and detect alterations in cellular pathways that
may serve as novel therapeutic targets. Collectively, these studies suggest that by
characterizing the genomic make-up of individual tumors, investigators will be able to
develop personalized and potentially more effective cancer treatments and/or preventive
Despite recent advances, NGS approaches are not yet routinely used as part of clinical care
due to their high cost and technical complexity, as well as the many challenges related to
data analysis and translation to the clinical setting. The overarching goal of this protocol
is to establish and test processes by which NGS technologies, including WGS, WES and RNA
sequencing, can be offered to pediatric oncology patients undergoing treatment at SJCRH.
This is a non-therapeutic study examining the feasibility, acceptance and impact of clinical
WGS, WES and RNA sequencing in a pediatric oncology setting. Investigators anticipate a
sample size of approximately 400 patients and 400-800 biological parents.
- To perform clinical next generation whole genome (WGS), exome (WES), and RNA sequencing
on SJCRH pediatric oncology patients prospectively over a 24-month period.
- To use WGS, WES and RNA sequence data to identify and characterize somatic genetic
variants of pathological significance and germline genetic variants associated with
increased cancer risk.
OTHER PRESPECIFIED OBJECTIVES:
- To generate and analyze data describing the informed consent process and patient/parent
perceptions of genomic investigations and research.
- To generate and analyze data surrounding the return of genomic sequencing results,
examine patient/parent understanding of these results and assess the impact of results
on patients and families.
- To determine the feasibility and reliability of performing WES and RNA sequencing on
derivatives from formalin-fixed, paraffin-embedded (FFPE) tumor samples alongside the
analysis of matched frozen tumor and germline samples.
For participants who give consent, a tumor and/or normal tissue sample will be obtained and
used for WGS, WES and RNA sequence analysis. Once the results of these analyses are
available, they will be disclosed to physicians, patients and parents. Mixed measures
approaches will be used to assess understanding, acceptance and impact of genomic results on
patients and parents.
All tumor samples analyzed via the clinical genomics pipeline will undergo routine clinical
pathology testing, which will be run in parallel with this study. Genetic variants deemed
reportable by the Clinical Genomics Committee will be considered for return to physicians,
patients and parents after several validation steps. Genes from the tumor tissue will be
analyzed and those with biological and/or clinical relevance will be reported. A defined list
of 63 genes will be analyzed for reporting using normal (germline) tissue. During the course
of the study, the investigators anticipate the list of genes to be reported using normal
tissue to change due to advances in the literature or other evidence linking additional genes
to tumor formation and cancer risk, and new lists may be defined.
To assess provider, patient and family understanding and describe the impacts of genomic
testing and return of results, this study will also incorporate administration of surveys and
semi-structured interviews. Surveys and interviews are optional, but will be offered to all
primary SJCRH providers, as well as all eligible participants and parents, regardless of
whether or not they consent to pursue the genomic testing.
A sample of blood or a skin biopsy will be obtained as a source of germline DNA. This sample
is necessary as it is the comparator against which tumor samples are evaluated. Skin biopsies
may be done on patients who have a diagnosis where peripheral blood is likely to be
contaminated by tumor cells.
- New St. Jude patients prospectively identified at the time of study activation with:
- Newly diagnosed solid or liquid tumor (benign or malignant),
- Relapsed solid or liquid tumor (benign or malignant), or
- Refractory solid or liquid tumor (benign or malignant)
- Current St. Jude patients who develop a new mass and undergo a surgical procedure to
establish the diagnosis of recurrent disease or a new primary tumor.
- Current St. Jude patients who, while on therapy, develop refractory disease and
undergo a surgical procedure to palliate symptoms.
- Adequate tissue must be available (e.g. sufficient germline and/or tumor tissue, from
which >1 µg DNA and >0.1 µg RNA must be isolated). Patients with retinoblastoma,
diffuse intrinsic pontine glioma, craniopharyngioma, or optic pathway tumors who have
no tumor tissue available may enroll using only a germline sample.
- Past history of hematopoietic stem cell transplantation (or other condition that would
result in hematopoietic cell DNA failing to match host tissue DNA).
- Tumor or germline tissue not meeting the criteria listed above.
- Inability or unwillingness of research participant or legal guardian/representative to
give written informed consent.
- Participants who are unable to read, write or converse fluently in English will be
excluded from Prespecified Objectives 3 and 4.