Tumors of the Glia: Recent Advances

Abstract

Gliomas are the most common primary malignant central nervous system (CNS) tumors and are associated with significant morbidity and mortality. They can be either diffuse or circumscribed. Diffuse gliomas occur at all ages, though more common among adults. Morphologically they are classified as astrocytomas and oligodendrogliomas, and their grade of malignancy is represented across WHO grades 2–4. Circumscribed gliomas are more frequent in children, the most common type being pilocytic astrocytoma. Recent research has elucidated molecular heterogeneity among glial tumors, which have led to identification of various important genetic and epigenetic pathways that drive glioma initiation and proliferation. Thus astrocytomas are characterized by IDH1/2 mutations, while oligodendrogliomas have 1p/19q co-deletion in addition to IDH1/2 mutations. These molecular alterations also serve as diagnostic and prognostic markers, while MGMT promoter methylation is a predictive biomarker. Pediatric-type diffuse gliomas (low grade and high grade) share similar histology with their adult counterparts; however, they harbor distinct genetic alterations. Low-grade diffuse gliomas and circumscribed gliomas are characterized by alterations in the RAS/MAPK pathway and high-grade diffuse gliomas by histone H3 gene mutations (H3K27M and H3G34V/R mutations). Numerous clinical trials are ongoing using these markers for targeted therapy in pediatric gliomas. Thus the latest Fifth edition of WHO CNS tumor classification emphasizes on significance of combining histologic and molecular parameters for the integrated diagnosis of brain tumors that would provide valuable diagnostic, prognostic, and predictive information and for some entities, suggest targeted therapies.

Annexure I: Contributions from Neuropathology Unit, Department of Pathology, AIIMS, New Delhi

Significant research contributions have been made in pediatric and adult neuro-oncology. The knowledge of medical science has been combined with insight into molecular biology and genetics to obtain novel insights into the biology of gliomas. Some of the work has been taken from bench to bedside, and the role of various immunohistochemical, proliferation, and molecular markers has been established for more accurate objectivized diagnosis, prognostication, and predicting treatment response of gliomas. Many of these biomarkers are now used in routine neuropathology practice to supplement histopathological classification and grading for better patient management.

• 1. Initial studies have established the light microscopic and ultrastructural morphological diversity and histogenesis of various glial tumors with documentation of several novel and rare phenotypes/variants. Studies on expression of immunohistochemical tumor markers have established their role as diagnostic biomarkers (Sarkar et al. 1988, 1997, 2005; Roy et al. 1988; Dinda et al. 1990, 1992; Sharma et al. 1996, 2004, 2006; Karak et al. 2000; Srivastava et al. 2004; Deb et al. 2005, 2006; Malik et al. 2006; Agarwal et al. 2012; Khanna et al. 2018).

• 2. Studies related to in vivo and in vitro cell proliferation kinetics, apoptosis, and angiogenesis have contributed significantly to understanding the biological aggressiveness of gliomas and their role as prognostic biomarkers (Kharbanda et al. 1993, 1995; Dinda et al. 1993a, b; Banerjee et al. 1996; Rathore et al. 1999; Ralte et al. 2001; Sharma et al. 2004, 2006; Sarkar et al. 2005; Avninder et al. 2006; Das et al. 2011).

• 3. Studies in molecular neuro-oncology have given novel insights into the genetic and epigenetic events fundamental to glioma initiation and progression. Studies also identified specific molecular alterations that serve as diagnostic, prognostic, and predictive biomarkers (Banerjee et al. 1996; Chattopadhyay et al. 1997; Rathore et al. 1999; Misra et al. 2000; Sarkar et al. 2000, 2002, 2003, 2004; Sharma et al. 2004, 2006; Nayak et al. 2004; Srivastava et al. 2004; Avninder et al. 2006; Shukla et al. 2009; Jha et al. 2010a, b, 2011a, c, 2015; Kakkar et al. 2011, 2016a, b; Das et al. 2011; Agarwal et al. 2013; Purkait et al. 2013, 2015, 2016a, b).

• 4. Studies have provided better understanding of genetic heterogeneity within tumors of the same histological type and grade, thus explaining varying tumor behavior. Simple, economical, and reliable prognostic signatures/risk stratification systems based on both genetic and epigenetic markers have been developed, which can separate histologically similar tumors of the same grade into prognostically relevant subgroup, thus paving the way for personalized medicine (Purkait et al. 2016a, b, c).

• 5. New insights have been gained into epigenetic regulation in gliomas. Studies on polycomb repressive complexes have highlighted the role of the epigenetic regulator EZH2 (enhancer of zest homologue 2) and its positive correlation with DNA methyl transferases (DNMT1 and DNMT3B) and microRNA network in GBMs (Purkait et al. 2015, 2016b; Sharma et al. 2016). Further, studies on EZH2 and trimethylation of histone H3 on lysine 27 (H3K27me3) using whole-genome ChipSeq analysis highlight the differences in genes and pathways targeted by H3K27me3 in GBMs vs. low-grade gliomas. This work has produced the first high-resolution genome-wide map of H3K27me3 modification in adult human primary glioma samples. Interestingly, SLC25A23, a calcium-dependent mitochondrial solute carrier gene and an important target of H3K27ME3 modification, was identified as a potential new prognostic biomarker in GBMs, which needs further validation (Sharma et al. 2017).

• 6. Recent studies on the role of micro-RNA clusters have demonstrated tumor-suppressive role of C14MC in oligodendrogliomas and glioblastomas (Kumar et al. 2018; Nayak et al. 2018). Further, two specific microRNAs with potential therapeutic values have been identified in GBMs, which may be relevant for development of new therapeutic strategies. Also, for the first time, it has been demonstrated that the calcitonin-calcitonin receptor (CT-CALCR) axis is an important tumor suppressor pathway in gliomas, and mutations in the receptor predict poor prognosis. Thus, the CALCR could be considered as a novel therapeutic target for GBM (Pal et al. 2018).

• 7. Work in pediatric neuro-oncology is indeed novel as it has established that pediatric tumors, though histomorphologically indistinguishable from their adult counterparts, are a distinct molecular entity both genetically and epigenetically. Thus, it has been shown that pediatric GBMs are distinctly different from adult GBMs in terms of genetic alterations, histone methylation, whole-genome DNA methylation profile, and genome-wide small noncoding RNA profile. Similar molecular genetic differences have been demonstrated between pediatric and adult oligodendrogliomas and pilocytic astrocytomas. For the first time, the possible role of reactive oxygen species, altered global histone methylation, and downregulation of snoRNA cluster HbII-52 has been established as novel mechanisms of pediatric GBM pathogenesis. The first genome-wide profiling study of noncoding RNA in pediatric GBMs has highlighted the downregulation of Sno-RNA which have now been shown to be upcoming drivers of cancer. Findings indicate that results from adult cases cannot simply be extrapolated to pediatric patients, thus highlighting the need for identification of separate prognostic markers and molecular targeted therapy tailored for age (Suri et al. 2009, 2011b; Jha et al. 2011d, 2014, 2015, 2019; Purkait et al. 2013; Kumar et al. 2015; Pathak et al. 2015; Kakkar et al. 2016a, 2017; Purkait et al. 2017; Agrawal et al. 2018; Santosh et al. 2019; Manjunath et al. 2021).

• 8. This unit faculty has contributed as coauthors to chapters in successive editions (2000, 2007, 2016 and 2021) of the WHO Classification of CNS Tumors (Becker et al. 2000; McLendon et al. 2007, 2016; Lopes et al. 2007, 2016, 2021; Korshunov et al. 2016; Louis et al. 2020, 2021b; Brat et al. 2020; Brandner et al. 2021; Ellison et al. 2021). About a dozen publications of this unit are cited in the reference list of the WHO fascicles.