GRWD1 is a novel oncoprotein that downregulates p53 through multiple mechanisms. Analysis of the TCGA database revealed that high GRWD1 expression is associated with poor prognosis in lower-grade glioma (LGG), skin cutaneous melanoma (SKCM), and kidney renal clear cell carcinoma (KIRC) with wild-type p53 (upper panel). Further investigation indicated that copy number alterations in the GRWD1 gene are one determinant of its expression levels (lower left panel). Notably, even in patients with a diploid GRWD1 gene, high GRWD1 expression remained associated with poor prognosis in LGG, SKCM, and KIRC with wild-type p53. Additional analyses suggest that certain transcription factors may regulate GRWD1 expression in cancers with a diploid GRWD1 gene, for example as indicated by their binding to the GRWD1 promoter region (lower right panel). Collectively, these fi ndings suggest that high GRWD1 expression may contribute to malignant progression and serve as a predictor of poor clinical outcomes in LGG, SKCM, and KIRC with wild-type p53. Kayama, K., Ooga, A., Hasetsu, K., Kokubo, R., Sugimoto, N. and Fujita, M. (2025) High GRWD1 expression may predict clinically aggressive lower grade glioma, skin cutaneous melanoma, and kidney renal clear cell carcinoma carrying wild-type p53: a systematic study based on TCGA data analysis. J. Biochem. 177, 351-361