UNDERSTANDING THE INTERACTIONS BETWEEN GERMLINE AND SOMATIC ALTERATIONS in the PATHOGENESIS OF GLIOMAS

了解胶质瘤发病机制中种系和体细胞改变之间的相互作用

• 批准号: 10625788
• 负责人: ROBERT B. JENKINS
• 金额: $ 20万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-04 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625788
• 关键词: Address; Administrative Supplement; Adopted; Adult; Africa; Africa South of the Sahara; African; Appearance; Biological Assay; Brain Neoplasms; Central Nervous System Neoplasms; Characteristics; Clinic; Clinical; Development; Diagnosis; Diffuse; Equipment; European; Evolution; Funding; Gene Fusion; Genetic; Genetic study; Glioma; Grant; Healthcare; Histologic; Institution; Malignant Neoplasms; Methods; Methylation; Modernization; Molecular; Molecular Analysis; Molecular Profiling; Mutation; Nigeria; Parents; Pathogenesis; Patients; Population; Research Personnel; Resources; Schedule; Site; Societies; Somatic Mutation; Specimen; Teaching Hospitals; Testing; Tumor Subtype; Universities; Update; Variant; Work; World Health Organization; base; cancer health disparity; clinical diagnostics; clinical sequencing; clinically relevant; diagnostic strategy; insight; interest; meetings; molecular marker; molecular subtypes; mutant; neuro-oncology; novel; response; risk variant; tumor

Provocative Question 3: Supplemental Application Summary/Abstract This supplement application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-22-057, “Administrative Supplements to Strengthen Global Cancer Health Disparities.” This is a supplement to the parent R01 project of Dr. Robert Jenkins: Understanding the interactions between germline and somatic alterations in the pathogenesis of gliomas (CA230712), which was funded in response to Provocative Question #3, “Do genetic interactions between germline variants and somatic mutations contribute to differences in tumor evolution?” Prior to 2016, the diagnosis of central nervous system (CNS) tumors was based on histologic features. In 2016, the World Health Organization (WHO) adopted a diagnostic approach that integrates histologic appearance with acquired molecular alterations. In 2021, these criteria were updated with many more molecular markers associated with various brain tumor subtypes. Africa, and by extension Nigeria, lags behind in this field for various reasons, including limited technical know-how in terms of molecular methods and the lack of resources and equipment to perform molecular analyses for neuro-oncology cases. This supplement aims to match the histologic characteristics of cases of gliomas diagnosed over the last nine years in Lagos University Teaching Hospital, Lagos Nigeria, with molecular signatures. This study will be the first molecular study of glioma in Nigeria, and therefore will give insight into the molecular features (including both acquired and germline molecular alterations) of CNS tumors in Nigeria. Supplement Specific Aim1 will perform targeted clinical sequencing and copy number profiling on 60 global African glioma subjects from Lagos University Teaching Hospital. Supplement Specific Aim 2 will build a collaborative consortium of global African sites to further study the acquired and germline genetics of glioma. The parent NCI Provocative Question R01 grant (R01 CA230712) is aimed at evaluating the interaction between germline and acquired genetic alterations in adult diffuse glioma with the underlying hypothesis that germline variants interact with somatic alterations to accelerate the development of IDH-mutant and IDH wild-type gliomas. The specific aims of the parent R01 are: Parent Specific Aim 1: To identify novel germline risk variants that are associated with clinically-defined glioma molecular subtypes. Parent Specific Aim 2: To evaluate the clinical relevance of combined germline and somatic alterations associated with IDH-mutant glioma. Parent Specific Aim 3: To characterize the functional implication of the known and newly identified glioma germline variants in the context of IDH-mutant glioma. Thus, the proposed supplement aims are a natural extension to the parent R01 by extending studies to patients with glioma in sub-Saharan Africa.

挑衅性问题3：补充申请摘要/摘要 该支持申请正在响应特殊利益通知提交 （NOSI）被确定为非CA-22-057，“加强全球癌症的行政补充剂 健康差异。 了解胚芽和躯体改变在发病机理中的相互作用 Gliomas（CA230712），是根据挑衅性问题3资助的：“遗传 种系变异与体细胞突变之间的相互作用导致肿瘤的差异 进化？ 组织学特征在2016年，世界卫生组织（WHO）采用了诊断 将组织学外观与获得的分子变化的方法。 这些标准用与各种大脑相关的摩尔分子更新 肿瘤亚型。 在分子方法和缺乏资源方面包括有限的技术知识 以及对神经肿瘤学疾病进行分子分析的设备。 在过去的九年中，诊断出的神经胶质瘤的组织学特征与 拉各斯大学教学医院，尼日利亚拉各斯，分子签名。 尼日利亚神经胶质瘤的首次分子研究，因此将深入了解分子 尼日利亚的中枢神经系统肿瘤的特征（包括获得的生殖线分子改变）。 补充特定的AIM1将执行针对性的临床测序和拷贝数分析 来自拉各斯大学教学医院的60名全球非洲神经胶质瘤学科。 特定目标2将建立全球非洲网站的协作合作协作，以进一步研究 胶质瘤的获得和种系遗传学。 CA230712）旨在评估种系与获得的遗传之间的相互作用 成人弥漫性神经胶质瘤的改变，其基本假设是种系变体相互作用 随着躯体变化以加速IDH突变和IDH野生型的发展 神经胶质瘤。 与临床定义的胶质瘤分子亚型相关的种系风险变异。 父母特定目标2：评估联合种系和体细胞的临床相关性 与Mutant神经胶质瘤相关的变化。 在上下文中已知和新鉴定的神经胶质瘤种系的功能含义 IDH突变神经瘤。 父母R01通过将研究扩展到撒哈拉以南非洲的神经胶质瘤患者。

项目成果

Concomitant 1p/19q co-deletion and IDH1/2, ATRX, and TP53 mutations within a single clone of "dual-genotype" IDH-mutant infiltrating gliomas.

• DOI: 10.1007/s00401-020-02141-x
• 发表时间: 2020-06
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Zepeda-Mendoza CJ;Vaubel RA;Zarei S;Ida CM;Matthews M;Acree S;Raghunathan A;Giannini C;Jenkins RB
• 通讯作者: Jenkins RB

Searching for causal relationships of glioma: a phenome-wide Mendelian randomisation study.

• DOI: 10.1038/s41416-020-01083-1
• 发表时间: 2021-01
• 期刊: British journal of cancer
• 影响因子: 8.8
• 作者: Saunders CN;Cornish AJ;Kinnersley B;Law PJ;Houlston RS;Collaborators
• 通讯作者: Collaborators

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations.

• DOI: 10.1007/s00401-021-02291-6
• 发表时间: 2021-06
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Tesileanu CMS;Vallentgoed WR;Sanson M;Taal W;Clement PM;Wick W;Brandes AA;Baurain JF;Chinot OL;Wheeler H;Gill S;Griffin M;Rogers L;Rudà R;Weller M;McBain C;Reijneveld J;Enting RH;Caparrotti F;Lesimple T;Clenton S;Gijtenbeek A;Lim E;de Vos F;Mulholland PJ;Taphoorn MJB;de Heer I;Hoogstrate Y;de Wit M;Boggiani L;Venneker S;Oosting J;Bovée JVMG;Erridge S;Vogelbaum MA;Nowak AK;Mason WP;Kros JM;Wesseling P;Aldape K;Jenkins RB;Dubbink HJ;Baumert B;Golfinopoulos V;Gorlia T;van den Bent M;French PJ
• 通讯作者: French PJ

Molecular Biomarker Testing for the Diagnosis of Diffuse Gliomas.

• DOI: 10.5858/arpa.2021-0295-cp
• 发表时间: 2022-05-01
• 期刊: ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE
• 影响因子: 4.6
• 作者: Brat, Daniel J.;Aldape, Kenneth;Bridge, Julia A.;Canoll, Peter;Colman, Howard;Hameed, Meera R.;Harris, Brent T.;Hattab, Eyas M.;Huse, Jason T.;Jenkins, Robert B.;Lopez-Terrada, Dolores H.;McDonald, William C.;Rodriguez, Fausto J.;Souter, Lesley H.;Colasacco, Carol;Thomas, Nicole E.;Yount, Michelle Hawks;van den Bent, Martin J.;Perry, Arie
• 通讯作者: Perry, Arie