Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis (LCH)

Active, not recruiting

• Conditions: Histiocytosis, Langerhans-Cell
• Interventions: Other: Biospecimen Collection; Other: Laboratory Biomarker Analysis; Other: Questionnaire Administration

• Registration Number: NCT04100408
• Lead Sponsor: Children's Oncology Group

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 Timeline

• Study First Submitted: 2019-09-20
• Study First Submitted QC: 2019-09-20
• Study First Posted: 2019-09-24
• Study Start: 2020-06-01
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-20
• Last Update Posted: 2025-03-21
• Primary Completion: 2025-09-30
• Study Completion: 2025-09-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 647

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.

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Ancillary-Correlative (biospecimen collection)	Questionnaire Administration	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.
Ancillary-Correlative (biospecimen collection)	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.
Ancillary-Correlative (biospecimen collection)	Laboratory Biomarker Analysis	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.

Primary Outcome Measures

Name	Time	Method
The frequency of de novo mutations and systematic assessment of the underlying genetic makeup of LCH	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	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.
Characterized germline variants in SMAD6 and their association with Langerhans Cell Histiocytosis (LCH)	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.

Trial Locations

Locations (1)

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center; 🇺🇸 Houston, Texas, United States