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Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis (LCH)

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ClinicalTrials.gov Identifier: NCT04100408
Recruitment Status : Recruiting
First Posted : September 24, 2019
Last Update Posted : December 6, 2023
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Tracking Information
First Submitted Date September 20, 2019
First Posted Date September 24, 2019
Last Update Posted Date December 6, 2023
Actual Study Start Date June 1, 2020
Estimated Primary Completion Date September 30, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: September 20, 2019)
  • Characterized germline variants in SMAD6 and their association with Langerhans Cell Histiocytosis (LCH) [ Time Frame: Up to 4 years ]
    Will re-sequence SMAD6 among LCH case-parent trios to characterize the association between SMAD6 inherited genetic effects and LCH susceptibility using targeted next-generation sequencing. We will also analyze de novo single-nucleotide variants (SNVs), copy-number variants (CNVs), and insertions/deletions(INDELs) obtained through SMAD6 sequence data generated from the biologic samples of the CCRN/PEC LCH case-parent trios.
  • The frequency of de novo mutations and systematic assessment of the underlying genetic makeup of LCH [ Time Frame: Up to 4 years ]
    Will use the maximum number of LCH case-parent trios enrolled utilizing the CCRN/PEC with viable biologic samples to conduct genome-wide SNP genotyping. This methodology will identify new genes and pathways associated with LCH susceptibility. We will also determine the prevalence of novel de novo mutations associated with LCH in these case-parent trios. This will provide a systematic assessment of the underlying genetic makeup of LCH in a large sample of families.
  • The difference in LCH-related somatic mutations by race/ethnicity due to underlying genetic ancestry [ Time Frame: Up to 4 years ]
    Genetic ancestry will be determined using germline genome-wide SNP array data generated from CCRN/PEC LCH cases in Aim 2. In parallel, we will determine patient somatic mutational profiles using a custom, targeted 91-gene panel. We will then conduct a genome-wide admixture-mapping scan to identify LCH-related loci that are associated with specific LCH somatic mutational profiles.
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: September 20, 2019)		 The role of genetic ancestry on LCH-related somatic mutations [ Time Frame: Up to 4 years ]
The analysis of data generated in this outcome measure will be primarily descriptive in nature. the objective will be to characterize LCH case-parent trios based on demographic, epidemiologic, and clinical characteristics. Findings from primary outcome measures findings will be validated and will assess if the frequency of validated inherited genetic variants differs by these characteristics.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis (LCH)
Official Title Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis (LCH)
Brief Summary The long-term goal is to define the mechanisms of pathogenesis underlying Langerhans cell histiocytosis (LCH). The overall objectives of the current study are to characterize the role of SMAD6 inherited genetic variation on LCH susceptibility and identify germline genomic regions associated with LCH somatic mutations. Building from preliminary data, the central hypotheses are: (1) causal genetic variants in SMAD6 underlie susceptibility to LCH, and (2) differences in LCH-related somatic activating mutations by race/ethnicity are related to Amerindian (i.e., Native American) genetic ancestry. The Central hypothesis will be tested by pursuing the specific aims.
Detailed Description

PRIMARY OBJECTIVES:

I. To comprehensively characterize germline variants in SMAD6 and their association with LCH.

II. To identify novel germline variants associated with LCH.

III.To determine the role of genetic ancestry on LCH-related somatic mutations.

EXPLORATORY OBJECTIVES:

I. To integrate clinical and epidemiologic questionnaire data with genetic risk factor data from the Primary Aims to more comprehensively elucidate LCH susceptibility.

OUTLINE:

Case identification and recruitment followed by questionnaires and specimen processing.
Study Type Observational
Study Design Observational Model: Family-Based
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Saliva
Sampling Method Non-Probability Sample
Study Population Patients diagnosed with Langerhans cell histiocytosis (LCH) on or after January 1, 2008.
Condition Histiocytosis, Langerhans-Cell
Intervention
  • Other: Biospecimen Collection
    Undergo saliva or buccal mucosa collection
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Questionnaire Administration
    Ancillary studies
Study Groups/Cohorts Ancillary-Correlative (biospecimen collection)
LCH patients and their parents undergo collection of saliva or buccal mucosa samples for genetic mutational analysis. Germline DNA from saliva or buccal brushing will be sequenced, genotyped, and analyzed.
Interventions:
  • Other: Biospecimen Collection
  • Other: Laboratory Biomarker Analysis
  • Other: Questionnaire Administration
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: September 20, 2019)		 647
Original Estimated Enrollment Same as current
Estimated Study Completion Date September 30, 2024
Estimated Primary Completion Date September 30, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • ≤ 25 years old at the time of original LCH diagnosis
  • The patient must be enrolled on ACCRN07 and/or APEC14B1 and registered with COG by a North American member institution
  • The patient must have a diagnosis of LCH (ICD Codes/Morphology: 9751/1; 9752/1; 9753/1; or 9754/3).
  • The patient must be diagnosed with LCH on or after January 1, 2008.
  • All questionnaire respondents must understand English or Spanish.
  • All patients and/or their parents or legal guardians must provide informed consent.
  • All institutional, FDA, and NCI requirements for human studies must be met.
Sex/Gender
Sexes Eligible for Study: All
Ages up to 25 Years   (Child, Adult)
Accepts Healthy Volunteers No
Contacts
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT04100408
Other Study ID Numbers AEPI17N1
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement Not Provided
Current Responsible Party Children's Oncology Group
Original Responsible Party Same as current
Current Study Sponsor Children's Oncology Group
Original Study Sponsor Same as current
Collaborators National Cancer Institute (NCI)
Investigators
Principal Investigator: Michael Scheurer, PhD Children's Oncology Group
PRS Account Children's Oncology Group
Verification Date December 2023