Molecular stratification useful for fine prognostication of adult gliomas

A study conducted by the Chinese University of Hong Kong (CUHK), Fudan University in Shanghai, China, and Zhengzhou University in Zhengzhou, China, has found that a molecular stratification system based on single-gene alterations aids fine prognostication of adult gliomas.

“While most pathology departments in the more [economically] advanced societies will have the capacity for single-gene studies and molecular tests, such as Sanger sequencing, a majority of general pathology laboratories in the world are not in a position to carry out next-generation sequencing or genome-wide methylation profiling routinely on all their neurosurgical specimens, as these tests remain expensive and demand considerable expertise for interpretation. We therefore believe that there is a need to develop a relatively simple molecular grading algorithm based on single-gene testing derived from current literature on molecular pathology of gliomas,” wrote the researchers. [N Engl J Med 2015;372:2499-2508; BMC Cancer 2019;19:968]

In the study, molecular diagnostic data of 1,275 adult diffuse glioma cases from three hospitals were evaluated for IDH1/2 mutation, TERTp mutation, 1p19q codeletion, EGFR amplification, 10q deletion, BRAF^V600E, and H3 mutations. All of these tests were routinely performed as part of regular diagnostic work-up at the three institutions. [Front Oncol 2022;doi:10.3389/fonc.2022.839302]

“We hypothesized that combinations of IDH1/2, TERTp, 1p19q, EGFR, 10q, BRAF, and H3 gene status can stratify gliomas for risk and may even be superior to conventional histological grading for prognostication,” explained the researchers.

IDH genotype has been shown to be a major classifier and prognostic factor for gliomas, while combining IDH genotype with TERTp mutation status aids precise prognostication of low-grade gliomas. Furthermore, combination of IDH genotype and 1p19q status predicts survival in low-grade gliomas. While rare in low-grade gliomas, EGFR amplification is more common in grade II–IV astrocytomas and correlates with histological malignancy grade and lower overall survival (OS). Similarly, loss of 10q predicts a survival disadvantage. BRAF mutation is associated with good survival in younger adults, while mutations of the chromatin genes, H3.3 and H3.1, are associated with poor prognosis.

Glioma cases were stratified into six molecular grades, according to genetic alterations: 1) IDH mutant (mut), 1p19q codeleted; 2) IDHmut, 1p19q non-codeleted, TERTpmut; 3) IDHmut, 1p19q non-codeleted, TERTp wild-type (wt); 4) IDHwt, BRAFmut; 5) IDHwt, BRAFwt, TERTpwt, EGFR^-, no 10q loss, H3wt; 6) IDHwt, TERTpmut, EGFR amplification, 10q loss, or H3 mutations.

This molecular grading was found to be significantly associated with histological grade (p<0.001). “Molecular group 1 was enriched for WHO grade II tumours [76.3 percent] and absent in WHO grade IV tumours, while nearly 70 percent of tumours in group 6 were WHO grade IV,” pointed out the researchers.

Univariate analyses showed that all molecular grades were significantly associated with OS. After adjusting for age, gender, histological grades, tumour resection, radiotherapy, and chemotherapy in the multivariable analysis, molecular groups were found to have independent prognostic value (p<0.001) across the cohort. Notably, tumours in groups 3, 5, and 6 demonstrated significantly worse prognosis, and group 2 and 4 tumours showed trends of unfavourable prognosis vs reference group (group 1).

The WHO 2016 classification introduced molecular criteria in the diagnosis of some brain tumours. However, grading of adult diffuse gliomas remains entirely histological depending mainly on mitoses, cellular anaplasia, necrosis, and microvascular proliferation. [Acta Neuropathol;131:803-820] “The present study showed that a simple molecular grading scheme can satisfactorily fine-grade adult gliomas, and these tests can be performed relatively quickly in practically all pathology laboratories. Our molecular grading scheme should provide critical and timely information for immediate clinical management of glioma patients,” concluded the researchers.