👤 Mohammed Shahin

Pilocytic astrocytoma (PA) is a circumscribed low-grade glioma, typically defined by biphasic architecture, Rosenthal fibres, eosinophilic granular bodies, and MAPK pathway activation. However, PAs may sometimes display atypical morphologies, creating diagnostic dilemmas. DNA methylation profiling has emerged as a robust adjunct for resolving such ambiguity. We retrospectively analysed 68 gliomas with ambiguous histopathology. All underwent integrated work-up, including detailed histology, immunohistochemistry, fluorescence in situ hybridisation (FISH) for BRAF::KIAA Fusion, next-generation sequencing, transcriptomic profiling, and genome-wide DNA methylation profiling. Clinical and radiological data were reviewed with follow-up documentation. Out of 68 gliomas with ambiguous histopathological features, six cases were classified as pilocytic astrocytoma (PA) based on DNA methylation profiling. Ancillary molecular analyses revealed MAPK pathway alterations in all cases. The tumours occurred across cortical, midline, and infratentorial locations, exhibiting varied histomorphological appearances. Clinico-radiological correlation supported an indolent biological behavior, with all patients remaining alive and progression-free at 11-38 months of follow-up. Our findings emphasise the limitations of morphology-based diagnosis in histologically heterogeneous gliomas and demonstrate the critical role of DNA methylation profiling in establishing accurate classification. Adoption of integrated histological and molecular approaches is essential to avoid misclassification, prevent overtreatment, and improve prognostic assessment. Not applicable. Show less

VKORC1 and CYP2C9 genotypes explain less variability in warfarin dose requirements in African Americans compared with Europeans. Variants in BCKDK and GATA-4 gene regions, purported to regulate VKORC1 and CYP2C9 expression, have been shown to play an important role in warfarin dose requirements in Europeans and Asians, respectively. We sought to determine whether rs56314408 near BCKDK or GATA-4 rs2645400 influence warfarin dose requirements in 200 African Americans. Unlike the strong linkage disequilibrium (LD) between rs56314408 and VKORC1 rs9923231 in Europeans, they were not in LD in African Americans. No associations were found on univariate analysis. On multivariable analysis, rs56314408 was associated (P = 0.027) with dose in a regression model excluding VKORC1 rs9923231, and GATA-4 rs2645400 was associated (P = 0.032) with dose in a model excluding CYP2C (CYP2C9*2, *3, *5, *6, *8, and *11, CYP2C rs12777823) variants. Neither variant contributed to dose in the model that included both VKORC1 rs9923231 and CYP2C variants. Our results do not support contributions of the studied variants to warfarin dose requirements in African Americans. However, they illustrate the value of studies in African descent populations, who have low LD in their genome, in teasing out genetic variation underlying drug response associations. They also emphasize the importance of confirming associations in persons of African ancestry. Show less