Abstract 2711: Mechanism of natural progression from low grade glioma to glioblastoma: A case report

Abstract

Abstract Introduction: Current studies about the progression mechanisms of gliomas mainly focus on the progression under treatment selection. Little is known about how low grade gliomas (LGG) progress to glioblastoma (GBM) under natural pressure, which remains to be elucidated. Methods: We reported a 67-years-old woman, whose intracranial lesion was diagnosed first in 2010 but without treatment. An enhanced peripheral lesion was detected around the primary lesion in 2018. Both the primary and secondary lesions were resected and diagnosed as diffuse astrocytoma(LGG) and glioblastoma (GBM), respectively. Both samples were subjected to whole exome sequencing, RNA sequencing, methylation array and TCR sequencing. Results: The results showed that both samples were IDH1 mutant, 1p/19q non-codel, TERT promoter wild-type, G-CIMP High and MGMT methylated. About 50% of the mutant genes were identical in both samples, suggesting that both samples had the same origin. Comparing with the primary glioma (LGG), the mutant allele fractions (MAFs) of these shared genes were increased in the secondary lesion (GBM). Furthermore, the MAFs of a novel mutation (p.N219K) in the gene NAF1 increased from 44% to 75%, and the ratio of the corresponding RNA reads increased from 37.5% to 75%, which indicating NAF1(p.N219K) maybe a novel driver mutation promoting tumor progression in LGG. The unique genes in the secondary lesion (GBM) with MAFs>15% were CIC, HMCN1, RPA4 and BRAC2. As it is well known, RPA4 and BRCA2 are involved in homologous recombination repair system. The ssGSEA analysis revealed that KRAS pathway and NF-kB pathway was activated in the secondary lesion (GBM). Mast cells were increased in the GBM, whereas CD4+ memory T cells and CD8+ T cells decreased, which suggesting potentiation of innate immune response and suppression of adaptive immune response. Surprisingly, although only 2.13% (n=14) of TCR sequences detected in the blood were shared in the LGG or the GBM, their reads accounted for 44% of all TCR sequences reads in blood, 71.10% in the LGG and 46.40% in the GBM, suggesting these T cells may play vital functions in the process of glioma progression. Conclusion: Here, we reported an IDHmut-1p/19q-noncodel glioma case with natural evolution. Several biological processes were identified in this progression including deficiency of DNA damage repair, activation of KRAS pathway and NF-kB pathway, excitation of innate immune response and suppression of adaptive immune response. We uncovered a novel driver mutation (NAF1, p.N219K), further analyses of its role in the natural progression of glioma are expected. We also found several significantly proliferated T cell clones in the development of gliomas, which suggesting the promise of T cells in clinical diagnosis and treatment of glioma. Citation Format: Long Wang, Xuegang Li, Tunan Chen, Feilong Zhao, Tonghui Ma, Hua Feng, Fei Li. Mechanism of natural progression from low grade glioma to glioblastoma: A case report [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2711.