Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis (LCH)

Histiocytosis, Langerhans-Cell Clinical Trial

Official title:

Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis (LCH)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04100408
• Other study ID #: AEPI17N1
• Status: Recruiting
• Start date: June 1, 2020
• Est. completion date: September 30, 2024

Study information

• Verified date: December 2023
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 647
• Est. completion date: September 30, 2024
• Est. primary completion date: September 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 25 Years

Eligibility

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.

Related Conditions & MeSH terms

• Genetic Predisposition to Disease
• Histiocytosis
• Histiocytosis, Langerhans-Cell

Intervention

Other:
• Biospecimen Collection
Undergo saliva or buccal mucosa collection
• Laboratory Biomarker Analysis
Correlative studies
• Questionnaire Administration
Ancillary studies

Locations

Country	Name	City	State
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The role of genetic ancestry on LCH-related somatic mutations	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.	Up to 4 years
Primary	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
Primary	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
Primary	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