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
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.