IDH mutant lower grade (WHO Grades II/III) astrocytomas can be stratified for risk by CDKN2A, CDK4 and PDGFRA copy number alterations

Abstract

In the 2016, WHO classification of tumors of the central nervous system, isocitrate dehydrogenase (IDH) mutation is a main classifier for lower grade astrocytomas and IDH-mutated astrocytomas is now regarded as a single group with longer survival. However, the molecular and clinical heterogeneity among IDH mutant lower grade (WHO Grades II/III) astrocytomas have only rarely been investigated. In this study, we recruited 160 IDH mutant lower grade (WHO Grades II/III) astrocytomas, and examined PDGFRA amplification, CDKN2A deletion and CDK4 amplification by FISH analysis, TERT promoter mutation by Sanger sequencing and ATRX loss and p53 expression by immunohistochemistry. We identified PDGFRA amplification, CDKN2A homozygous deletion and CDK4 amplification in 18.8%, 15.0% and 18.1% of our cohort respectively, and these alterations occurred in a mutually exclusive fashion. PDGFRA amplification was associated with shorter PFS (P = 0.0003) and OS (P < 0.0001). In tumors without PDGFRA amplification, CDKN2A homozygous deletion or CDK4 amplification was associated with a shorter OS (P = 0.035). Tumors were divided into three risk groups based on the presence of molecular alterations: high risk (PDGFRA amplification), intermediate risk (CDKN2A deletion or CDK4 amplification) and low risk (neither CDKN2A deletion and CDK4 amplification nor PDGFRA amplification). These three risk groups were significantly different in overall survival with mean survivals of 40.5, 62.9 and 71.5 months. The high-risk group also demonstrated a shorter PFS compared to intermediate-(P = 0.036) and low-risk (P < 0.0001) groups. One limitation of this study is the relatively short follow-up period, a common confounding factor for studies on lowgrade tumors. Our data illustrate that IDH mutant lower grade astrocytomas is not a homogeneous group and should be molecularly stratified for risk.

Homozygous deletion of CDKN2A by fluorescence in situ hybridization is prognostic in grade 4, but not grade 2 or 3, IDH-mutant astrocytomas

“…Tumors with mid-level deletion (10-30%) fared somewhat worse than those with low level deletion (< 10%), but this difference was not significant (p = 0.0636, log-rank test). Using the 2007/2016 WHO Classification histologic grading criteria, there was minimal to no separation of grade 2 and grade 3 tumors, as has been previously demonstrated by multiple groups [3,4,11]. Primary histologic grade 4 tumors had significantly decreased survival compared to histologic grades 2/3 (p < 0.0001, log-rank test).…”

“…Additionally, some of the morphologic features used to grade IDHwt tumors do a poor job of stratifying IDHm astrocytoma survival, particularly mitotic activity [2][3][4]. To address these shortcomings, a number of groups have investigated molecular correlates of aggressive behavior in IDHm astrocytomas [5][6][7][8][9][10][11]. Based on these studies, homozygous deletion of the CDKN2A gene, which encodes the cell-cycle regulators p16INK4A and p14ARF, has emerged as a leading candidate molecular marker of high-grade behavior in these tumors [3,7,[10][11][12].…”

Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

“…The latter has been shown to predict the response to temozolomide (TMZ) [48], the standard-of-care chemotherapeutic agent approved for GBM [94]. A separate group of adult diffuse gliomas characterized by activating IDH1 (IDH1mut) or IDH2 (IDH-2mut) mutations comprise 1p/19q intact astrocytomas and 1p/19q co-deleted oligodendrogliomas, with varying grades (II-IV) and survival rates [89], further displaying, e.g., PDG-FRA and CDK4 amplification, CDKN2A/B deletion, ATRX, TP53, or TERT promoter mutations [60,83,116], as well as a glioma CpG Island Methylator Phenotype (G-CIMP) [33,79]. Several studies point towards an evolution of diffuse gliomas upon treatment and recurrence, where IDH1/2mut astrocytomas show most and IDHwt GBMs least changes in relapsed tumors [5,29,38,57].…”

Updating the grading criteria for adult diffuse gliomas: beyond the WHO2016CNS classification

“…They also found that the deletion did not exist in grade II astrocytoma. Although another study by Appay et al confirmed this finding [2], Yang et al identified this homozygous deletion in 12% of grade II tumors [16]. One possible reason for such a discrepancy is that while Shirahata et al [13] used pHH3 antibody, which is sensitive as mentioned above, Yang et al [16] did not; without using pHH3 antibody, they might have identified fewer mitoses, and thus regarded grade III tumors in other studies as grade II ones, resulting in a lower rate of grade III.…”