Pathways to hypermutation in high-grade gliomas: Mechanisms, syndromes, and opportunities for immunotherapy

Abstract

Despite rapid advances in the field of immunotherapy, including the success of immune checkpoint inhibition in treating multiple cancer types, clinical response in high-grade gliomas (HGGs) has been disappointing. This has been in part attributed to the low tumor mutational burden (TMB) of the majority of HGGs. Hypermutation is a recently characterized glioma signature that occurs in a small subset of cases, which may open an avenue to immunotherapy. The substantially elevated TMB of these tumors most commonly results from alterations in the DNA mismatch repair pathway in the setting of extensive exposure to temozolomide or, less frequently, from inherited cancer predisposition syndromes. In this review, we discuss the genetics and etiology of hypermutation in HGGs, with an emphasis on the resulting genomic signatures, and the state and future directions of immuno-oncology research in these patient populations.

Keywords: DNA mismatch repair; glioma; hypermutation; immune checkpoint inhibitor (ICI); temozolomide.

Figure 1.

Function of the mismatch repair pathway in DNA replication fidelity. A mispairing is recognized by the Mut-S complex, which binds to the site of the error, along with the Mut-L heterodimer. Mut-L undergoes an ATP-dependent conformational change and recruits further MMR components, including EXO1, which excises the surrounding bases, and RPA, which binds to and preserves the resulting single-stranded gap. PCNA is thought to serve several roles in MMR, including facilitating the recruitment of Mut-S and Mut-L and re-synthesis by DNA pol.

Figure 2.

Mechanism of post-TMZ exposure hypermutation in gliomas. Newly diagnosed non-hypermutated gliomas treated with TMZ heterogeneously accumulate somatic mutations. Loss of MMR function is an evolutionarily favorable alteration, conferring TMZ resistance. Therefore, if an MMR gene is mutated, the MMR-D cell population likely expands to a clonal level, bringing with additional TMZ-driven mutations, as well as continuing to accumulate further alterations due to the ablation of replication repair machinery. This results in a hypermutated recurrent tumor.

Figure 3.

Mechanisms of tumor development in patients with CMMRD. Patients with inherited biallelic mutation in 1 of the 4 major MMR genes lack a functional DNA repair system. This results in heterogeneous accumulation of somatic mutations in healthy tissue, especially frameshift and microsatellite mutations. Eventually, this leads to emergence of MSI-H, hypermutated cancers. However, research suggests a separate pathway to tumorigenesis may be triggered if a secondary DNA polymerase mutation is acquired. In this case, SNVs account for the majority of genetic changes, and the resulting malignancies tend to be MSS and ultra-hypermutated. Tumors following this secondary mechanism are more likely to occur in the central nervous system and develop at a younger age.

Figure 4.

From publicly available MSK-IMPACT Clinical Sequencing Cohort. (A) Gliomas with mutations in at least 1 MMR gene have a significantly higher median tumor mutational burden (TMB) than those with an intact MMR system. PMS2 mutations are excluded due to an insufficient number of cases. (B) Gliomas with mutations in both the MMR system (MSH2, MLH1, MSH6, or PMS2) and DNA pol (POLE or POLD1) have a significantly higher TMB compared to either type of mutation alone.