EPCO-25 - Heterogeneity of insertion/deletion and single nucleotide variation in drivers of lower grade gliomas

Single nucleotide variation (SNV) and copy number variation (CNV) have been extensively studied across tumor types. Their impact on tumor evolution has been a primary research focus. However, insertion/deletion (indels) have received less attention due to their high false positive and false negative rate and the absence of hotspot indel sites. We examine adult IDH wildtype/mutant gliomas, and utilize spatially mapped samples within the same tumors (84 tumors, averaging 8 to 9 samples/tumor), as well as primary/recurrent paired samples (n=37), to investigate the heterogeneity and progression of indels and SNVs. We used two indel-detecting algorithms, Pindel and Muect2, and discovered and validated several indels, which had not been previously emphasized, including in TCHH. We report on two frequently mutated driver genes, CIC and ATRX, in IDHmut-Codel and IDHmut-noncodel gliomas, respectively. CIC SNVs and indels are observed as complementary occurrences. For example, among 9 samples of the tumor recurrence of one patient, 6 showed CIC SNVs, with only two sharing the same mutation. In contrast, 8 of 9 samples exhibited CIC indels, representing 4 different types. Notably, all samples displayed either CIC SNVs or indels. In IDHmut-noncodel tumors, a similar pattern was observed with ATRX. Nonetheless, all samples displayed either ATRX SNVs or indels. This study highlights the tremendous intratumor heterogeneity and evolution in drivers of LGG, emphasizing their complex role in tumorigenesis. Prior studies may have underestimated the frequency and heterogeneity due to calling accuracy and limitations in tumor sampling. By focusing on indels and other genetic variations within gliomas, this study sheds light on their significance in understanding tumor progression, the essential nature of CIC and ATRX inactivation over whole tumors, and the potential implications for therapeutic interventions.