Molecular Epidemiology of Langerhans Cell Histiocytosis: Evaluating the Impact of SMAD6 and Genetic Ancestry on Disease Risk

朗格汉斯细胞组织细胞增多症的分子流行病学：评估 SMAD6 和遗传祖先对疾病风险的影响

• 批准号: 10473516
• 负责人: CARL E ALLEN
• 金额: $ 59.04万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10473516
• 关键词: 15 year old; Activins; African ancestry; Age; Alternative Splicing; BRAF gene; Black Populations; Blood; Bone Morphogenetic Proteins; Cancer Research Network; Candidate Disease Gene; Cell Differentiation process; Chemoprevention; Child; Data; Dendritic Cells; Diagnosis; Disease; Disease Management; Disease Progression; Eosinophilic Granuloma; Epidemiology; Ethnic Origin; Ethnic group; Etiology; Event; Failure; Family; GTP-Binding Protein alpha Subunits, Gs; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genome; Genomic Segment; Genotype; Goals; Hispanic Populations; Human; Immunoblot Analysis; Incidence; Inflammatory; Inflammatory Infiltrate; Inherited; Inhibin-beta Subunits; Langerhans cell; Late Effects; Lesion; Life; MADH6 gene; MAP Kinase Gene; MAP2K1 gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Messenger RNA; Modeling; Molecular Epidemiology; Morbidity - disease rate; Mutate; Mutation; Myelogenous; Native American Ancestry; Native Americans; Neoplasms; Not Hispanic or Latino; Organ; Parents; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pediatric Oncology Group; Population; Predisposition; Prevalence; Prevention therapy; Protocols documentation; Race; Recurrence; Registries; Relapse; Reporter; Reporting; Risk; Risk Factors; Role; Scanning; Signal Transduction; Signaling Protein; Smad6 Protein; Somatic Mutation; Susceptibility Gene; Symptoms; Testing; Transforming Growth Factor beta; Variant; Work; admixture mapping; anticancer research; biobank; black patient; cancer genetics; chemotherapy; cohort; disorder risk; experience; gene discovery; genetic risk factor; genetic testing; genetic variant; genome wide association study; genome-wide; high risk; improved; long-term sequelae; multi-ethnic; new therapeutic target; novel; protein expression; recruit; risk variant; tumor

PROJECT SUMMARY/ABSTRACT Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by lesions including pathogenic CD207+ dendritic cells among an inflammatory infiltrate. The median age at diagnosis is 30 months, and up-front chemotherapy fails in ~50% of patients resulting in multiple relapse events for 40-50% of cases, and long-term sequelae. Sequencing studies have found recurrent, mutually exclusive somatic activat- ing mutations in MAPK pathway genes in ~85% of LCH lesions, including BRAF V600E in 50-65%. There is a “Misguided Myelomonocytic Dendritic Cell Precursor Model” in which specific somatic MAPK mutations at criti- cal stages of myeloid differentiation determine extent of disease. However, this model fails to explain the signif- icant differences in LCH risk across ethnicities. Despite advances to elucidate the somatic mutational land- scape underlying LCH pathogenesis, germline risk factors remain largely unknown. Therefore, we conducted the first genome-wide association study of LCH and identified a SMAD6 variant associated with increased risk. SMAD6 inhibits bone morphogenetic protein and transforming growth factor-beta/activin signaling, which are determinants of Langerhans cell differentiation. This variant appears to suppress SMAD6 protein expression without a decrease in SMAD6 messenger RNA expression in patients carrying the risk allele. This risk allele is also more common in Hispanics who are at the highest risk of LCH, and absent in blacks who experience the lowest LCH incidence. Our preliminary data also support the emerging observation that LCH somatic activating mutations vary by race/ethnicity. Specifically, sequencing of tumors from black patients indicated that only 25% were BRAF V600E+ (compared to >60% in other populations), whereas 50% had mutations in MAP2K1 (com- pared to <10% in other populations). Therefore, the objectives of the current study are to characterize the role of SMAD6 on LCH susceptibility and identify germline genomic regions associated with LCH somatic mu- tations. The central hypotheses are: (1) causal genetic variant(s) in SMAD6 underlie susceptibility to LCH, and (2) differences in LCH somatic activating mutations by race/ethnicity are related to Native American ge- netic ancestry. We will utilize the Childhood Cancer Research Network (CCRN) and the newly opened registra- tion and biobanking protocol, Project:EveryChild, to recruit 600 LCH case-parent trios through the Children’s Oncology Group (COG). We will also work with our collaborators worldwide to assemble a cohort of an addi- tional 400 LCH cases. The specific aims are to: 1) systematically evaluate inherited and de novo SMAD6 ge- netic variation and identify novel loci for LCH susceptibility using 600 case-parent trios; 2) characterize the function of germline variation in SMAD6 on LCH pathogenesis; and 3) identify the role of the germline genome on LCH somatic mutations using admixture mapping in a multi-ethnic cohort of 1,000 cases. Successful com- pletion of the proposed aims may (1) improve genetic testing and counseling strategies in LCH patients and families; (2) advance surveillance and chemoprevention protocols; and (3) identify novel therapeutic targets.

项目摘要/摘要 朗格汉斯细胞组织细胞增生症(LCH)是一种炎症性髓系肿瘤，其特征包括 炎性浸润物中致病的CD207+树突状细胞。确诊时的中位年龄为30岁 几个月后，约50%的患者前期化疗失败，导致40%-50%的患者多次复发 病例和长期后遗症。测序研究发现，反复的、相互排斥的体细胞活动- 约85%的LCH病变中存在MAPK通路基因的ING突变，包括50-65%的BRAF V600E。有一个 误导的骨髓单核细胞树突状细胞前体模型，在该模型中，特定的体细胞MAPK突变是关键的。 髓系分化的CAL分期决定了疾病的程度。然而，这一模型不能解释信号-- LCH风险在不同种族之间存在显著差异。尽管在阐明体细胞突变土地方面取得了进展- 在LCH的发病机制下，生殖系危险因素仍然很大程度上未知。因此，我们进行了 首次对LCH进行全基因组关联研究，发现了一种与风险增加相关的SMAD6变异。 Smad6抑制骨形态发生蛋白和转化生长因子-β/激活素信号转导，它们是 朗格汉斯细胞分化的决定因素。该变体似乎抑制了Smad6蛋白的表达 携带危险等位基因的患者中SMAD6信使RNA的表达没有下降。这个风险等位基因是 在西班牙裔中也更常见，他们患LCH的风险最高，而在经历LCH的黑人中缺失 LCH发生率最低。我们的初步数据也支持新的观察结果，即LCH躯体激活 突变因种族/民族而异。具体地说，对黑人患者的肿瘤测序表明，只有25% BRAF V600E+(在其他人群中为60%)，而MAP2K1(COM- 与其他人群的10%相比)。因此，当前研究的目标是描述 Smad6在LCH易感性中的作用及与LCH体细胞突变相关的种系基因组区域的确定 注解。中心假设是：(1)Smad6基因的因果遗传变异(S)是LCH易感性的基础， (2)不同种族的Lch体细胞激活突变的差异与美洲原住民的Ge-Ge有关。 有磁性的祖先。我们将利用儿童癌症研究网络(CCRN)和新开放的登记- 教育和生物库协议，项目：EveryChild，通过儿童基金会招募600名LCH病例-父母三人组 肿瘤组(COG)。我们还将与我们在世界各地的合作者合作，组装一批ADDI- 传统性LCH 400例。其具体目标是：1)系统地评估遗传的和从新的SMAD6基因。 利用600个病例-亲本三联体，确定LCH易感性的新基因座；2)表征 Smad6基因的生殖系变异在LCH发病机制中的作用；以及3)确定生殖系基因组的作用 混合作图在1000例多民族队列中对LCH体细胞突变的研究成功的COM- 完成拟议的目标可以(1)改善LCH患者的基因检测和咨询策略，并 (2)先进的监测和化学预防方案；(3)确定新的治疗目标。