A team led by Professors Li Gang and Xue Hao from the Department of Neurosurgery at Qilu Hospitalof Shandong University, has recently published their groundbreaking research findings in Neuro-Oncology, the official journal of the Society for Neuro-Oncology. Their paper, titled "Copy number gain of FAM131B-AS2 promotes the progression of glioblastoma by mitigating replication stress," reveals a novel mechanism underlying the malignant progression of glioblastoma. This research sheds light on the characteristic copy number alterations in glioblastoma and elucidates how the non-coding gene FAM131B-AS2 enhances tumour cells' tolerance to replication stress, thereby driving tumour progression and resistance to treatment. Professors Li Gang and Xue Hao are the corresponding authors of the paper, with Dr. Wang Shaobo and Dr. Qi Yanhua from the Department of Neurosurgery at Qilu Hospital of Shandong University serving as co-first authors.

In 2021, the World Health Organization (WHO) incorporated copy number gain of chromosome 7 (chr7) and loss of chromosome 10 (+7/-10) into the molecular diagnostic criteria for glioblastoma (GBM), underscoring the significance of specific chromosomal copy number alterations (CNAs) in assessing the malignancy of GBM and its diagnosis. The team's earlier work involved comparing transcriptome data between GBM samples with chr7 CNG and normal brain tissue samples. Through low-expression gene filtering, genomic localization, and literature review, they identified a significantly elevated copy number of the long non-coding RNA "FAM131B-AS2" in the 7q34 region of the GBM genome, correlating with poor prognosis in GBM patients.

Further investigation revealed that FAM131B-AS2 enhances the binding of the deubiquitinase USP7 to the DNA damage checkpoint protein RPA1, thereby reducing the ubiquitination level of RPA1 and maintaining its stability. Elevated RPA1 protein activates the ATR-CHEK1 signalling pathway in GBM cells, thereby enhancing their tolerance to replication stress and conferring resistance to therapies such as radiotherapy and chemotherapy. Conversely, inhibiting FAM131B-AS2 increases DNA damage in tumour cells, activates the cGAS-STING signalling pathway, promotes type I interferon secretion, enhances lymphocyte infiltration and improves the therapeutic efficacy of PD-1 antibodies. Thus, the key pathogenic gene FAM131B-AS2 amplified in the 7q34 region is implicated in enhancing GBM replication stress tolerance, thereby facilitating tumour malignant progression. This discovery provides a crucial theoretical basis for enhancing the efficacy of radiotherapy and chemotherapy for GBM.

Professor Li Gang and his team have long been dedicated to researching the pathogenesis of gliomas, identifying precise molecular targets for diagnosis and treatment, translating research into clinical practice, and engaging in interdisciplinary approaches to diagnose and treat brain tumours. They have achieved numerous high-level research outcomes, publishing multiple papers in prestigious academic journals including Advanced Science, Autophagy, Theranostics, Clinical Cancer Research, Cancer Research and Molecular Cancer. This research has been supported by grants from the National Natural Science Foundation of China, the Taishan Scholar Climbing Program and the Taishan Scholar Young Expert Program, as well as by platforms such as the Shandong Key Laboratory of Brain Function Remodeling and theInstitute of Brain and Brain-Inspired Sciences of Shandong University.

Article Link:https://doi.org/10.1093/neuonc/noae014