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Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis (LCH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04100408
Recruitment Status : Recruiting
First Posted : September 24, 2019
Last Update Posted : December 16, 2019
National Cancer Institute (NCI)
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment
Histiocytosis, Langerhans-Cell Other: Biospecimen Collection Other: Laboratory Biomarker Analysis Other: Questionnaire Administration

Detailed Description:


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.


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


Case identification and recruitment followed by questionnaires and specimen processing.

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Study Type : Observational
Estimated Enrollment : 647 participants
Observational Model: Family-Based
Time Perspective: Prospective
Official Title: Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis (LCH)
Actual Study Start Date : August 30, 2019
Estimated Primary Completion Date : September 30, 2024
Estimated Study Completion Date : September 30, 2024

Group/Cohort Intervention/treatment
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.
Other: Biospecimen Collection
Undergo saliva or buccal mucosa collection

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Questionnaire Administration
Ancillary studies

Primary Outcome Measures :
  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 Outcome Measures:
  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.

Biospecimen Retention:   Samples With DNA

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients diagnosed with Langerhans cell histiocytosis (LCH) on or after January 1, 2008.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04100408

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United States, Texas
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Michael Scheurer, PhD    713-798-5547   
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
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Principal Investigator: Michael Scheurer, PhD Children's Oncology Group
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Responsible Party: Children's Oncology Group Identifier: NCT04100408    
Other Study ID Numbers: AEPI17N1
First Posted: September 24, 2019    Key Record Dates
Last Update Posted: December 16, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Histiocytosis, Langerhans-Cell
Genetic Predisposition to Disease
Disease Susceptibility
Disease Attributes
Pathologic Processes
Lymphatic Diseases
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases