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NCT Number: NCT04100408

Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis (LCH)

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.

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Key information

Conditions

Histiocytosis, Langerhans-Cell Hemic and Lymphatic Diseases Histiocytosis Lung Diseases Lung Diseases, Interstitial Lymphatic Diseases Respiratory Tract Diseases

Age range

Up to 25 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

Houston, Texas, 77030, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Biospecimen Collection

Other

Undergo saliva or buccal mucosa collection

laboratory biomarker analysis

Other

Correlative studies

Questionnaire Administration

Other

Ancillary studies

Primary outcomes

  1. 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.

  2. 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.

  3. 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.

Other outcomes

  1. 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.

Sponsors and collaborators

Lead sponsor

Children's Oncology Group

Network

Registry information

Important dates

Study start
2020
Primary completion
2026
Study completion
2026
First posted
Sep 24, 2019
Registry last updated
Jan 9, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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