Clinical trial NCT02530658: Next Generation Sequencing of Normal Tissues Prospectively in Pediatric Oncology Patients
Official title: Genomes for Kids (G4K)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Solid, Liquid, Central Nervous System Tumors
Keywords: Genetic Predisposition
Pediatric
Genomic Analysis
Heritable Disease
Cancer Risk
Genetic Counseling
DNA
Clinical Genomics
Clinical Decision-Making
Treatment Planning
Germline
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
First posted: 2015-08-21
Enrollment: 2500
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Participants will be patients at St. Jude Children's Research Hospital (SJCRH) with diagnoses of hematological, solid or central nervous system tumors who agree to participate in this study and their parents or legally authorized representatives who consent to participate.

Brief summary: 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 measures.

This protocol was initially enacted to usher NGS approaches into routine clinical care. During the initial phase of the G4K protocol, 310 participants were recruited and enrolled onto the study. Tumor and/or germline sequencing was completed on all 310 patients, with 253 somatic reports generated (representing 96% of the 263 participants for whom tumor tissue was available and analyzed) and 301 germline reports generated (100% of the 301 participants who agreed to the receipt of germline results). Analyses of the study data are ongoing with plans to prepare initial manuscripts within the next several months. Due to the successful initial execution of the G4K protocol, clinical genomic sequencing of tumor and germline samples is now offered as part of standard clinical care for pediatric oncology patients at St. Jude.

The G4K protocol has now been revised. With the revision, the study team will record, store and analyze germline and tumor genomic information. Through the collection of these data, we will examine how germline mutations in 150 cancer predisposition genes influence clinical presentation, tumor histology, tumor genomic findings, response to therapy and long-term outcomes. The overall goals of this research are to further define the prevalence, spectrum and heritability of germline variants in these genes and to decipher how germline mutations influence the phenotypes of an expanding array of cancer predisposition syndromes. These studies allow us to provide more accurate genetic counseling and management strategies to future children harboring mutations in these genes.

This remains a non-therapeutic study. Investigators anticipate a sample size of approximately 2500 patients who will be recruited over the next 7 years.

Detailed description: PRIMARY OBJECTIVES:

* To use clinical genomic sequencing to define the prevalence and spectrum of germline mutations in cancer predisposition genes in children with cancer.
* For those identified with germline mutations, to correlate germline genomic information with clinical presentation, tumor genomic findings, treatment response, and outcome.

OTHER PRESPECIFIED OBJECTIVES:

* To generate and analyze data describing patient/parent perceptions of genomic investigations and research at various time points throughout the study.
* 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 normal tissue sample will be obtained and used for WGS, WES and RNA sequence analysis. A defined list of 150 genes will be analyzed for reporting using the normal tissue. 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. 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.

Eligibility criteria: Inclusion Criteria:

* St. Jude patients prospectively identified at the time of study activation with a diagnosed solid or liquid tumor (benign or malignant).
* 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 who have no tumor tissue available may enroll using only germline sample.

Exclusion Criteria:

* 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 or Spanish will be excluded from Prespecified Objectives 3 and 4.

Primary outcomes:
measure: Overall success rate
timeFrame: Approximately 3 months after study enrollment
measure: Number and type of somatic genetic variants and germline genetic variants
timeFrame: Approximately 3-4 months after the germline sample is obtained
Secondary outcomes:
Other outcomes:
measure: Proportion of parents/participants by perception of genomic testing
timeFrame: At study end (up to 13 months after last participant enrollment)
measure: Number of participants/parents by level of understanding
timeFrame: At study end (up to 13 months after last participant enrollment)
measure: Proportion of successful sequences of formalin-fixed, paraffin-embedded (FFPE) samples
timeFrame: Approximately 3 months after enrollment
Locations:
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Kim E. Nichols, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Johnson LM, Mandrell BN, Li C, Lu Z, Gattuso J, Harrison LW, Mori M, Ouma AA, Pritchard M, Sharp KMH, Nichols KE. Managing Pandora's Box: Familial Expectations around the Return of (Future) Germline Results. AJOB Empir Bioeth. 2022 Jul-Sep;13(3):152-165. doi: 10.1080/23294515.2022.2063994. Epub 2022 Apr 26.
citation: Maciaszek JL, Oak N, Chen W, Hamilton KV, McGee RB, Nuccio R, Mostafavi R, Hines-Dowell S, Harrison L, Taylor L, Gerhardt EL, Ouma A, Edmonson MN, Patel A, Nakitandwe J, Pappo AS, Azzato EM, Shurtleff SA, Ellison DW, Downing JR, Hudson MM, Robison LL, Santana V, Newman S, Zhang J, Wang Z, Wu G, Nichols KE, Kesserwan CA. Enrichment of heterozygous germline RECQL4 loss-of-function variants in pediatric osteosarcoma. Cold Spring Harb Mol Case Stud. 2019 Oct 23;5(5):a004218. doi: 10.1101/mcs.a004218. Print 2019 Oct.