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.

Study Overview

• Status: Recruiting
• Conditions: Histiocytosis, Langerhans-Cell
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Questionnaire Administration; Other: Biospecimen Collection

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 Type: Observational
• Enrollment (Estimated): 647

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
      • Contact: Michael Scheurer, PhD; Phone Number: 713-798-5547; Email: Scheurer@bcm.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Michael Scheurer, PhD, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2020
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): September 30, 2024

Study Registration Dates

• First Submitted: September 20, 2019
• First Submitted That Met QC Criteria: September 20, 2019
• First Posted (Actual): September 24, 2019

Study Record Updates

• Last Update Posted (Estimated): December 6, 2023
• Last Update Submitted That Met QC Criteria: December 5, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lymphatic Diseases; Lung Diseases; Disease Attributes; Lung Diseases, Interstitial; Disease Susceptibility; Histiocytosis, Langerhans-Cell; Histiocytosis; Genetic Predisposition to Disease
• Other Study ID Numbers: AEPI17N1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No