Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis (LCH)

NCT04100408 | Active Not Recruiting

• 1 other identifier: AEPI17N1
• Study Type: observational
• Target: 647
• Locations: 1 country
• Sites: 1

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.

Conditions

Histiocytosis, Langerhans-Cell

Outcome Measures

Primary Outcomes (3)

• Characterized germline variants in SMAD6 and their association with Langerhans Cell Histiocytosis (LCH)

  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.

  Up to 4 years

• The frequency of de novo mutations and systematic assessment of the underlying genetic makeup of LCH

  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.

  Up to 4 years

• The difference in LCH-related somatic mutations by race/ethnicity due to underlying genetic ancestry

  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.

  Up to 4 years

Other Outcomes (1)

• The role of genetic ancestry on LCH-related somatic mutations

  Up to 4 years

Study Arms (1)

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; Other: Laboratory Biomarker Analysis; Other: Questionnaire Administration

Interventions

Biospecimen Collection OTHER

Undergo saliva or buccal mucosa collection

Ancillary-Correlative (biospecimen collection)

Laboratory Biomarker Analysis OTHER

Correlative studies

Ancillary-Correlative (biospecimen collection)

Questionnaire Administration OTHER

Ancillary studies

Ancillary-Correlative (biospecimen collection)

Eligibility Criteria

• Age: Up to 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Patients diagnosed with Langerhans cell histiocytosis (LCH) on or after January 1, 2008.

You may qualify if:

• ≤ 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.

Sponsors & Collaborators

• Children's Oncology Group: lead

Study Sites (1)

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

Houston, Texas, 77030, United States

Location

Biospecimen

Retention: SAMPLES WITH DNA

Saliva

MeSH Terms

Conditions

Histiocytosis, Langerhans-Cell

Condition Hierarchy (Ancestors)

Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Michael Scheurer, PhD

  Children's Oncology Group

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: FAMILY BASED
• Time Perspective: PROSPECTIVE
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 20, 2019
• First Posted: September 24, 2019
• Study Start: June 1, 2020
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2026
• Last Updated: January 9, 2026

Record last verified: 2026-01

Locations

US (1)