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

点击翻译按钮获取中文摘要

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.