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 此补充申请是为了回应特别关注通知而提交的 （NOSI）标识为NOT-CA-22-057，“加强全球癌症的行政补充 健康差异”。这是对Robert Jenkins博士的父项目R 01的补充： 了解生殖系和体细胞改变在乳腺癌发病机制中的相互作用 神经胶质瘤（CA 230712），这是在回答挑衅性问题#3，“做遗传 生殖系变异和体细胞突变之间的相互作用有助于肿瘤的差异 进化？”在2016年之前，中枢神经系统（CNS）肿瘤的诊断是基于 组织学特征2016年，世界卫生组织（WHO）通过了一项诊断 将组织学表现与获得性分子改变相结合的方法。在2021年， 这些标准更新了与各种脑组织相关的更多分子标记物， 肿瘤亚型非洲，进而包括尼日利亚，由于各种原因在这一领域落后， 包括分子方法方面的技术知识有限和缺乏资源 以及对神经肿瘤病例进行分子分析的设备。该补充旨在 为了与过去九年中诊断的胶质瘤病例的组织学特征相匹配， 拉各斯大学教学医院，拉各斯尼日利亚，分子签名。本研究将 这是尼日利亚神经胶质瘤的第一次分子研究，因此将深入了解神经胶质瘤的分子机制。 尼日利亚CNS肿瘤的特征（包括获得性和生殖系分子改变）。 补充特异性Aim 1将进行靶向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受试者。补充 具体目标2将建立一个全球非洲网站的合作联盟，以进一步研究 神经胶质瘤的获得性和生殖系遗传学父NCI激发性问题R 01授权（R 01 CA 230712）旨在评估生殖系和获得性遗传之间的相互作用 成人弥漫性胶质瘤的改变与生殖系变异相互作用的潜在假设 体细胞改变以加速IDH突变体和IDH野生型的发育 神经胶质瘤母体R 01的具体目的是：母体具体目的1：识别新的 与临床定义的胶质瘤分子亚型相关的生殖系风险变异。 亲本特异性目标2：评价生殖系和体细胞联合的临床相关性 与IDH突变型胶质瘤相关的改变。母公司具体目标3： 已知和新鉴定的胶质瘤种系变异体在背景中的功能意义 IDH突变型神经胶质瘤因此，拟议的补充目标是对 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