GE-34 * THE MUTATIONAL LANDSCAPE AND TEMPORAL AND SPATIAL CLONAL EVOLUTION TO PROGRESSION IN 351 LOW-GRADE GLIOMAS

Abstract

Low grade gliomas (LGGs) are common infiltrative brain tumors in adults. Although LGGs typically show slower tumor progression and generally better clinical outcomes than high-grade gliomas, their clinical course is invariably indolent and deadly. In contrast to high-grade tumors, our knowledge about the genetic lesions and clonal evolution in LGG is still incomplete. In this study, we investigated relevant gene mutations and their role in clonal evolution using high-throughput genomics. Analysis of whole exome sequencing (WES) data from 52 LGGs identified significantly mutated genes included not only previously known mutational genes, including IDH1/2, TP53, ATRX, CIC, FUBP1 and NOTCH1, as well as multiple components of the PI3K pathway and the SWI/SNF complex. We further analyzed significant mutated genes in 351 LGGs by targeted deep sequencing. WES of multi-regional/time-point sampling from 14 cases further revealed complexity of intratumor heterogeneity and patterns of clonal evolution. According to the observed variant allele frequencies (VAFs), mutations of IDH1/2 and 1p19q co-deletion were thought to exist in the major clone, representing truncal mutations in most cases. In contrast, mutations in TP53, ATRX, CIC and FUBP1 were more often identified in one or more phylogenic branches in different subclones and involved in parallel evolution, where different mutations of the same genes were found at different time points in different locations. Collectively, our findings revealed two major, mutually exclusive patterns in clonal evolution in IDH-mutated LGGs; in some cases IDH1/2 mutations and 1p19q co-deletions were trunchal events, followed by CIC, FUBP1, NOTCH1 and other mutations in subsequent phylogenic branches. In other cases, the IDH1/2 mutations predated TP53, ATRX and other gene mutations.