Next Generation Sequencing of Normal Tissues Prospectively in Pediatric Oncology Patients

NCT02530658 | Recruiting

• 1 other identifier: G4K
• Study Type: observational
• Target: 2,500
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (2)

• Overall success rate

  Success is defined by the combined successes of (1) quality interpretable genomic data are generated from sequencing tumor and germline tissues, and (2) communicating genomic test results to the primary SJCRH oncologist and the patient and his/her parents. The Binomial proportion of successful performance will be estimated by the sample proportion and the 99% confidence interval based on the normal approximation. Sample size is 400.

  Approximately 3 months after study enrollment

• Number and type of somatic genetic variants and germline genetic variants

  WGS, WES and RNA sequence data will be used to identify and characterize somatic genetic variants of pathological significance and germline genetic variants associated with increased cancer risk. Descriptive statistics, such as counts and proportions of variants associated with increased cancer risk will be computed within each patient and in each disease type.

  Approximately 3-4 months after the germline sample is obtained

Other Outcomes (3)

• Proportion of parents/participants by perception of genomic testing

  At study end (up to 13 months after last participant enrollment)

• Number of participants/parents by level of understanding

  At study end (up to 13 months after last participant enrollment)

• Proportion of successful sequences of formalin-fixed, paraffin-embedded (FFPE) samples

  Approximately 3 months after enrollment

Study Arms (1)

Participants

St. Jude patients with a diagnosed solid or liquid tumor (benign or malignant) and their biological parents or legally authorized representative. Interventions: Study Introduction Visit, Informed Consent Visit, Informed Consent Follow-Up Visit, Return of Results Conversation, two Return of Results Follow-Up Visits, Tissue Sample (when available), Blood Sample or Skin Biopsy.

Other: Study Introduction Visit; Other: Informed Consent Visit; Other: Informed Consent Follow-Up Visit; Other: Return of Results Conversation; Other: Return of Results Follow-Up Visits; Procedure: Blood Sample; Procedure: Skin Biopsy

Interventions

Study Introduction Visit OTHER

Within 5±3 weeks following arrival at SJCRH, or at the participant/family's convenience, participants will meet with a genetic counselor and clinician, provide information for a family pedigree, undergo a physical and discuss germline testing options. Study introduction materials will be provided. Families interested in the G4K study will be referred to the study nurse or other G4K member and an Informed consent visit will be scheduled.

Participants

Informed Consent Visit OTHER

Within 1±3 weeks following the Study Introduction Visit, or at the participant/family's convenience, the research nurse or other study team member will consent the family and collect demographic and medical information. Participants will complete assessment questionnaires.

Also known as: Demographic and Medical forms, Questionnaires

Participants

Informed Consent Follow-Up Visit OTHER

At or after enrollment but before the release of the gerline results, or at the participant/family's convenience, a subset of participants (30-40) will participate in semi-structured interviews.

Also known as: Interviews

Participants

Return of Results Conversation OTHER

Participants will complete the assessment questionnaires.

Also known as: Questionnaires, Interviews

Participants

Return of Results Follow-Up Visits OTHER

Return of Results Follow-Up Visits will be conducted twice: the first within 8±4 weeks of the Return of Results Conversation, or at the participant/family's convenience, and the second within 28 ± 4 weeks of the Return of Results Conversation or at the participant/family's convenience. At each visit, participants will complete assessment questionnaires. Semi-structured interviews with parents and adolescents will be conducted.

Also known as: Questionnaires, Interviews

Participants

Blood Sample PROCEDURE

For patients who have not previously provided a blood sample, a sample of blood will be obtained as a source of germline DNA.

Also known as: Phlebotomy

Participants

Skin Biopsy PROCEDURE

After consent, for participants with a diagnosis where peripheral blood is likely to be contaminated by tumor cells, skin biopsies may be done as a source of germline DNA.

Also known as: Biopsy

Participants

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

RECRUITING

Related Publications (2)

• 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.

  PMID: 35471132 DERIVED

• 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.

  PMID: 31604778 DERIVED

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

Biospecimen

Retention: SAMPLES WITH DNA

Normal tissue (germline) will be analyzed.

MeSH Terms

Conditions

Central Nervous System Neoplasms; Genetic Predisposition to Disease

Interventions

Demography; Surveys and Questionnaires; Interviews as Topic; Blood Specimen Collection; Phlebotomy; Biopsy

Condition Hierarchy (Ancestors)

Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Nervous System Diseases; Disease Susceptibility; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Population Characteristics; Epidemiologic Measurements; Public Health; Environment and Public Health; Data Collection; Epidemiologic Methods; Investigative Techniques; Health Care Evaluation Mechanisms; Quality of Health Care; Health Care Quality, Access, and Evaluation; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Therapeutics; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical

Study Officials

• Kim E. Nichols, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kim E. Nichols, MD

CONTACT

888-226-4343; referralinfo@stjude.org

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 19, 2015
• First Posted: August 21, 2015
• Study Start: August 28, 2015
• Primary Completion (Estimated): December 31, 2033
• Study Completion (Estimated): December 31, 2038
• Last Updated: April 29, 2026

Record last verified: 2026-04

Locations

US (1)