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Potentially Prognostic Lower-Grade Glioma Markers Described in Chinese Population

NEW YORK (GenomeWeb) – New research suggests mutations in the TP53 gene or H3.3 histone might serve as markers to help classify some lower-grade gliomas in Chinese cases that lack other known molecular biomarkers.

As they reported in a correspondence article to the New England Journal of Medicine, researchers from the Chinese University of Hong Kong and Fudan University focused on tumor samples from more than 450 individuals with grade II or grade III diffuse gliomas. In the 17.4 percent of tumors — the so-called 'triple-negative lower-grade gliomas' that were negative for three established glioma biomarkers — they saw an over-representation of TP53 mutations or histone H3.3-K27M mutations.

The team noted that both of those seemed to portend poorer survival times in the Chinese population tested, suggesting there may be a benefit to applying the alterations to guide or design treatments for patients with triple-negative lower-grade glioma.

"The prognostic implications of TP53 and H3.3-K27M mutations in the triple-negative subgroup suggest a need to examine these biomarkers for more precise prognostication and to assign patients to more aggressive or potential subgroup-specific therapeutic protocols in the future," Ho-Keung Ng, chair of the anatomical and cellular pathology department at the Chinese University of Hong Kong, and his co-authors wrote.

Prior studies of lower-grade glioma have identified five molecular subtypes marked by alterations such as chromosome 1p/19q co-deletion, mutations affecting the promoter of telomerase enzyme-coding gene TERT, or IDH gene mutations.

For their analysis, Ng and his colleagues focused on lower-grade glioma cases that did not involve any of these alterations. They identified all three markers in more than 30 percent of the 459 adult lower-grade glioma patients tested for the study. Another 28.1 percent had IDH mutations, almost 6 percent had TERT mutations, and just over 9 percent of the tumors contained mutations affecting both IDH and TERT.

But despite detecting these and other genetic alterations, the team noted that some 17.4 percent of the lower-grade glioma cases it evaluated were triple-negative for chromosome 1p/19q co-deletion, TERT promoter mutation, or IDH mutations — a larger proportion than has been described in other populations.

When the researchers did targeted sequencing on TP53 on samples from 21 of the triple-negative cases with sufficient tissue available — including 20 cases with corresponding survival information — they identified TP53 mutations in 43 percent of the tumors, particularly those from patients with shorter overall survival times.

Survival times also appeared to be abbreviated in the four triple-negative lower-grade glioma cases with H3.3-K27M mutations, the team reported. It noted that TP53 mutations turned up in all four of the triple-negative tumors with H3.3-K27M mutations — changes that almost always affected the same mutation hotspot in TP53. 

"Our clinicopathological study extends the clinical relevance of the principal groups defined according to 1p/19q co-deletion and IDH and TERT mutations in a large cohort of lower-grade gliomas in Chinese patients and shows a higher prevalence of triple-negative gliomas among these patients than in previous studies involving white patients," the authors noted.