Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis (LCH)
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 647
- 试验地点
- 1
- 主要终点
- The frequency of de novo mutations and systematic assessment of the underlying genetic makeup of LCH
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Observational
- 观察模型
- Family Based
- 时间视角
- Prospective
入排标准
- 年龄范围
- — 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •≤ 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,
- •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.
排除标准
- 未提供
研究组 & 干预措施
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.
干预措施: Biospecimen Collection (Other)
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.
干预措施: Laboratory Biomarker Analysis (Other)
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.
干预措施: Questionnaire Administration (Other)
结局指标
主要结局
The frequency of de novo mutations and systematic assessment of the underlying genetic makeup of LCH
时间窗: 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.
The difference in LCH-related somatic mutations by race/ethnicity due to underlying genetic ancestry
时间窗: 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.
Characterized germline variants in SMAD6 and their association with Langerhans Cell Histiocytosis (LCH)
时间窗: 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.
次要结局
未报告次要终点