RECQL4 alterations in gliomas and nerve sheath tumors: Expression patterns and therapeutic implications

RECQL4 plays an important role in maintaining the integrity of the genome and regulating DNA replication. However, the role of RECQL4 in CNS tumors remains unknown. Sequencing data were reviewed and immunohistochemistry was performed on a variety of glial and nerve sheath tumors. Functional studies were performed in glioma (U251) and malignant peripheral nerve sheath tumors (MPNSTs) (NF90-8, ST88-14) cell lines following RECQL4 knockdown and treatment with ATR-inhibitors. Across 1580 CNS tumors, RECQL4 gene variants were identified in 71 cases (4.5%), with 21 (29.6%) of probable pathogenic significance. RECQL4 expression differed significantly across glioma subgroups (P=0.012). Low-grade gliomas (diffuse: median H-score 57.5; circumscribed: median 130) showed lower expression than high-grade gliomas (median 145, P<0.05). Neurofibromas displayed higher RECQL4 expression (median 160) compared with MPNSTs (median 97.5, P<0.001). Among MPNSTs, NF1-associated cases (n=24, median 95) expressed significantly less RECQL4 than sporadic cases (n=8, median 162.5, P<0.001). RECQL4 knockdown in glioma and MPNST cell lines resulted in increased apoptosis and susceptibility to ATR-inhibitors. Our findings show that RECQL4 expression has divergent patterns across tumor types and that targeting RECQL4 may dampen tumor survival and enhance susceptibility to ATR inhibitor therapy in CNS tumors.