Total copy number variation as a prognostic factor in adult astrocytoma subtypes

Abstract

Since the discovery that IDH1/2 mutations confer a significantly better prognosis in astrocytomas, much work has been done to identify other molecular signatures to help further stratify lower-grade astrocytomas and glioblastomas, with the goal of accurately predicting clinical outcome and identifying potentially targetable mutations. In the present study, we subclassify 135 astrocytomas (67 IDH -wildtype and 68 IDH -mutant) from The Cancer Genome Atlas dataset (TCGA) on the basis of grade, IDH -status, and the previously established prognostic factors, CDK4 amplification and CDKN2A/B deletion, within the IDH -mutant groups. We analyzed these groups for total copy number variation (CNV), total mutation burden, chromothripsis, specific mutations, and amplifications/deletions of specific genes/chromosomal regions. Herein, we demonstrate that across all of these tumor groups, total CNV level is a relatively consistent prognostic factor. We also identified a trend towards increased levels of chromothripsis in tumors with lower progression-free survival (PFS) and overall survival (OS) intervals. While no significant differences were identified in overall mutation load, we did identify a significantly higher number of cases with mutations in genes with functions related to maintaining genomic stability in groups with higher mean CNV and worse PFS and OS intervals, particularly in the IDH -mutant groups. Our data further support the case for total CNV level as a potential prognostic factor in astrocytomas, and suggest mutations in genes responsible for overall genomic instability as a possible underlying mechanism for some astrocytomas with poor clinical outcome. Electronic supplementary material The online version of this article (10.1186/s40478-019-0746-y) contains supplementary material, which is available to authorized users.

Comparative molecular profiling of distant metastatic and non-distant metastatic lung adenocarcinoma.

“…The presence of DM is a poor prognostic factor in various cancer types. Concordant with our observations, several studies have reported that the high level of copy number alteration is significantly associated with poor survival and outcomes in various cancer types, including primary prostate, breast, endometrial, pancreatic, and colorectal cancer [31][32][33].…”

An immune relevant signature for predicting prognoses and immunotherapeutic responses in patients with muscle‐invasive bladder cancer (MIBC)

“…But the frequencies of mutations in MIBC patients are overall high, it is not surprising that the differences were not obvious among patients with different infiltrating TMEs. CNVs are duplications or deletions of continuous base pairs of genes, and several studies have found that higher frequencies of CNVs always predict a worse prognosis in tumor patients . CNVs were also found to be associated with resistance to ICIs such as anti‐CTLA‐4 therapy in melanoma .…”

Beyond IDH-Mutation: Emerging Molecular Diagnostic and Prognostic Features in Adult Diffuse Gliomas

“…Our analysis of a subset of astrocytoma cases within The Cancer Genome Atlas (TCGA) glioma dataset showed similar results with mutual exclusivity between CDK4 and CDKN2A alterations in all except one case. IDH-mutant astrocytomas with either CDK4 amplifications or CDKN2A deletions had significantly shorter survival (median PFS of 32 months; median OS of 36 months) compared to IDH-mutant astrocytomas without these alterations (median PFS of 95 months, p = 0.02; median OS of >172 months, p = 0.02) [52]. The association of mutation or homozygous deletion of RB1 with shorter survival is not as well defined.…”

“…Higher overall CNV correlated with worse prognosis within the IDH-mutant astrocytomas, irrespective of other histologic or genetic alterations. Cases with CDK4 amplification or CDKN2A deletion and poor outcomes tend to have elevated CNV [52], although a significant portion of cases with high CNV and poor outcome did not have evidence of CDK4 amplification or CDKN2A deletion [41,42], suggesting that these two measures may not be inextricably linked to one another. Measuring overall CNV appears to be a consistent and reproducible method for stratifying IDH-mutant astrocytomas.…”

“…Measuring overall CNV appears to be a consistent and reproducible method for stratifying IDH-mutant astrocytomas. In addition, cohorts with high CNV (and poor clinical outcomes) also had an increased fraction of cases with chromothripsis [52] and mutations in genes with functions relating to maintenance of overall genome stability [41,52], suggesting a possible mechanism underlying both the elevated CNV and the poor clinical outcomes identified in these patients [71]. In addition, IDH-mutant astrocytomas with low G-CIMP methylation patterns (reduced global DNA methylation) have been associated with shorter overall survival [43,72].…”