Molecular landscape of IDH-mutant astrocytoma and oligodendroglioma grade 2 indicate tumor purity as an underlying genomic factor

Abstract

Background IDH-mutant astrocytoma and oligodendroglioma have an indolent natural history and are recognized as distinct entities of neoplasms. There is little knowledge on the molecular differences between IDH-mutant astrocytoma and oligodendroglioma grade 2. Therefore, we investigated the multiomics and clinical data regarding these two types of tumors. Method In silico analyses were performed around mRNA, somatic mutations, copy number alternations (CNAs), DNA methylation, microRNA (miRNA), epigenetics, immune microenvironment characterization and clinical features of the two types of gliomas. A diagnostic model incorporating tumor purity was further established using machine learning algorithms, and the predictive value was evaluated by receiver operative characteristic curves. Results Both types of gliomas shared chromosomal instability, and astrocytomas exhibited increased total CNAs compared to oligodendrogliomas. Oligodendrogliomas displayed distinct chromosome 4 (chr 4) loss, and subtyping of chr 7 gain/chr 4 loss (+ 7/− 4) presented the worst survival (P = 0.004) and progression-free interval (PFI) (P < 0.001). In DNA damage signatures, oligodendroglioma had a higher subclonal genome fraction (P < 0.001) and tumor purity (P = 0.001), and astrocytoma had a higher aneuploidy score (P < 0.001). Furthermore, astrocytomas exhibited inflamed immune cell infiltration, activated T cells and a potential response to immune checkpoint inhibitors (ICIs), while oligodendrogliomas were more homogeneous with increased tumor purity and decreased aggression. The tumor purity-involved diagnostic model exhibited great accuracy in identifying astrocytoma and oligodendroglioma. Conclusion This study addresses the similarities and differences between IDH-mutant astrocytoma and oligodendroglioma grade 2 and facilitates a deeper understanding of their molecular features, immune microenvironment, tumor purity and prognosis. The diagnostic tool developed using machine learning may offer support for clinical decisions.

Advances in Immune Microenvironment and Immunotherapy of Isocitrate Dehydrogenase Mutated Glioma

“…IDH-As are more heavily infiltrated by monocytic-lineage cells derived from circulation, they upregulate myeloid-cell chemotaxis genes (CSF1, FLT3LG) and upstream transcription factors (NFKB1), compared to IDH-Os ( 5 ). Moreover, immune cell (including M0, M1, and M2 macrophages) infiltration in WHO II IDH-As was generally higher than in WHO II IDH-Os, whereas T cells (CD3+, CD4+, and CD8+), cytotoxic cells, and T helper cells infiltrated in IDH-Os were significantly higher than those in IDH-As ( 14 , 15 ). Reduced tumor purity (i.e., increased invasion of glioma by non-tumor cells such as immune and stromal cells) was linked to higher malignancy and shorter survival ( 16 ).…”

“…In gliomas, IDH mutant has been linked to reduced immunological checkpoint(PD-1, CTLA-4, LAG3, and IDO1) expression and immunosuppressive cell infiltration ( 72 , 73 ). Compared with IDH-Os, IDH-As appear to be more responsive to checkpoint immunotherapy, one reason for the relatively poor anti-checkpoint immunotherapy of IDH-Os is its reduced expression of PD-L1 and other checkpoint molecules, another reason is higher levels of T cell rejection, promoting T cell dysfunction and immunotherapy resistance ( 15 , 74 , 75 ). Berghoff et al.…”

New insights into the Immune TME of adult-type diffuse gliomas

“…Differences in the TME of astrocytomas and oligodendriogliomas suggested by bulk RNA-seq studies [ 36 , 42 , 68 , 69 ] may be linked to their distinct prognosis and need to be ascertained using scRNA-seq. IDH-mutant tumors are infiltrated by a low number of immune cells.…”

“…Although, the IDH-mutated status was suggested to shape the TME, IDH-mutant astrocytomas and oligodendrogliomas differ in some genetic alterations, and exhibit different prognoses. In this regard, evaluation of TCGA and CGGA data indicated that immune infiltration is higher in astrocytomas than oligodendriogliomas [ 42 ]. Further analysis of bulk tumors using a combination of scRNA-seq and scATAC-seq approaches revealed a significant overexpression of chemotaxis factors CSF1 and FLT3LG in ATRX-mutated astrocytomas, and upregulation of CD163, a marker of immunosuppressive myeloid cells [ 43 ▪▪ ].…”

Intraindividual Tumor Heterogeneity of Mismatch Repair Status in Metastatic Colorectal Cancer

“… 27 The mode of metastasis may be associated with heterogeneous MMR status. Thus, metastasis diverges before the development of MSI, 28 because the progenitors of malignant cells do not harbor all mutations present in the primary tumor before metastatic seeding, and the tumor mutation burden of these discordant metastases is reduced. 6 However, the reason underlying MMR status heterogeneity is unknown.…”