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: 10688298
• 负责人: CARL E ALLEN
• 金额: $ 58.68万
• 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/10688298
• 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 Population; Etiology; Event; Family; Genes; Genetic; Genetic Counseling; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genome; Genomic Segment; Genotype; Goals; Growth Factor; Hispanic Populations; Human; Immunoblot Analysis; Incidence; Inflammatory; Inflammatory Infiltrate; Inherited; 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; Neoplasms; Not Hispanic or Latino; Organ; Parents; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pediatric Oncology Group; Population; Predisposition; Prevalence; Prevention; Prevention Protocols; 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; Treatment Failure; 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.

项目总结/摘要 朗格汉斯细胞组织细胞增生症（LCH）是一种炎性骨髓瘤，其特征是病变包括 炎性浸润物中的致病性CD 207+树突状细胞。诊断时的平均年龄为30岁 约50%的患者前期化疗失败，导致40-50%的患者发生多次复发事件。 病例和长期后遗症。测序研究发现了反复出现的，相互排斥的体细胞激活因子， 在约85%的LCH病变中发现MAPK通路基因突变，包括50- 65%的BRAF V600 E。有一个 “误导的骨髓单核细胞树突状细胞前体细胞模型”，其中特异性体细胞MAPK突变在criti- 骨髓分化的最后阶段决定了疾病的程度。然而，这一模式并不能解释这一现象。 不同种族间LCH风险的显著差异。尽管在阐明体细胞突变方面取得了进展- 作为LCH发病机制的基础，生殖系风险因素仍然在很大程度上未知。因此，我们进行了 LCH的第一个全基因组关联研究，并确定了与风险增加相关的SMAD 6变体。 SMAD 6抑制骨形态发生蛋白和转化生长因子-β/激活素信号传导，它们是 朗格汉斯细胞分化的决定因素。该变体似乎抑制SMAD 6蛋白表达 携带危险等位基因的患者中SMAD 6信使RNA表达没有降低。这个风险等位基因是 在LCH风险最高的西班牙裔中也更常见，而在经历LCH的黑人中则不存在。 LCH发病率最低。我们的初步数据也支持LCH体细胞激活 突变因种族/民族而异。具体来说，对黑人患者的肿瘤进行测序表明，只有25%的肿瘤细胞是由一种基因型引起的。 BRAF V600 E+（与其他人群中>60%相比），而50%的人在MAP 2K 1（com-）中有突变。 在其他人群中，约为10%）。因此，本研究的目的是表征 SMAD 6在LCH易感性中的作用，并鉴定与LCH体细胞mu. 站。中心假设是：（1）SMAD 6中的因果遗传变异是LCH易感性的基础， 和（2）不同种族/民族的LCH体细胞激活突变的差异与美洲原住民基因相关， 遗传祖先我们将利用儿童癌症研究网络（CCRN）和新开设的登记处， 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）。我们还将与世界各地的合作者合作，组建一个addi- LCH 400例。具体目标是：1）系统评估遗传性和从头SMAD 6基因- 遗传变异，并确定新的基因位点的LCH易感性使用600例父母三人组; 2）表征 SMAD 6的生殖系变异在LCH发病机制中的作用;以及3）鉴定生殖系基因组的作用 在1,000例病例的多种族队列中，使用混合物图谱对LCH体细胞突变进行研究。成功的com- 所提出的目标的一部分可能（1）改善LCH患者的遗传检测和咨询策略， 家庭;（2）先进的监测和化学预防方案;（3）确定新的治疗靶点。