“De novo replication repair deficient glioblastoma, IDH-wildtype” is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade

Abstract

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant “ultrahypermutation”. The median age at diagnosis was 50 years (range 27–78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as “Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A”. Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that “De novo replication repair deficient glioblastoma, IDH-wildtype” represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

A case report: Gliosarcoma associated with a germline heterozygous mutation in MSH2

“…Accurate identification of at-risk populations will assist in developing early disease surveillance and intervention programs for detecting precancerous lesions or early-stage tumors. Studies have shown that the early stages of LS-related tumors exhibit greater sensitivity to immune checkpoint inhibitors ( 26 ), and patients with GBMs resulting from underlying LS may benefit from these medicines like pembrolizumab ( 27 ). Therefore, keenly identifying patients with suspected LS, confirming the diagnosis with genetic testing, and subsequently developing individualized treatment plans for them are of great significance for improving patients’ quality of life in the future.…”

Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma

“…Interestingly, these tumors were epigenetically distinct from IDH-mutant astrocytomas, with reduced global methylation levels, and were distinguishable with methylation profiling from secondary MMR-deficient tumors, which tended to match better with their MMR-retained IDH-mutant astrocytoma counterparts [ 59 , 200 ]. This may also be true of IDH-wild-type glioblastomas [ 87 ], suggesting that there may be fundamental differences in the biology of tumors with acquired and germline MMR mutations.…”

“…MMR mutations also increase the number of neoantigens (mutant proteins potentially viewed as novel by the immune system) [ 15 , 109 , 112 , 135 ], with some data suggesting that as many as 42% of nonsynonymous mutations in exon regions may result in neoantigen formation [ 17 ]. This property makes immune checkpoint inhibitor therapy an attractive adjuvant treatment option for these tumors [ 24 , 47 , 53 , 83 , 87 , 93 , 101 , 112 , 131 , 180 , 182 , 209 ], although not all hypermutant cancers respond [ 112 , 143 , 180 , 209 ]. Other studies have suggested that immune therapy may only remove MMR-mutant subclones [ 140 , 180 , 220 ], so this therapy may be most effective in patients with germline mutations as the MMR mutations are more uniform in these cases [ 24 , 200 ].…”