NFE2L2 ‐mutated urothelial carcinomas frequently show concomitant myxoid and squamous features and have high PD ‐ L1 expression

AIMS: NFE2L2 encodes the transcription factor, NRF2, which is a regulator of cellular oxidative stress responses and metabolic homeostasis. NFE2L2 alterations are implicated in multiple cancers, with significant study in thoracic oncology, with an adverse prognosis, aggressive behaviour, metabolic reprogramming and diminished responses to chemotherapy and immunotherapy and increased PD-L1 expression. However, the clinicopathological significance of NFE2L2 mutations in urothelial carcinoma is not well understood. METHODS AND RESULTS: To address this, we identified six urothelial carcinomas harbouring NFE2L2 mutations from a cohort of 156 muscle-invasive cases that underwent next-generation sequencing (NGS). Histological review of the five in-house cases showed concomitant squamous and myxoid features. Immunohistochemical analysis revealed high PD-L1 expression, with three of the five cases showing strong, membranous staining in >90% of tumour cells. NGS showed frequent mutations in other genes in addition to the NFE2L2 mutation, most commonly in CDKN2A and TERT promoter. Clinically, all patients presented with or developed metastatic disease and all patients who were not lost to follow up died from the disease (median overall survival: 12 months). CONCLUSIONS: These findings suggest that NFE2L2-mutated urothelial carcinomas frequently have concomitant squamous and myxoid features, aggressive behaviour and high PD-L1 expression. Recognition of the NFE2L2-mutated urothelial carcinomas may have diagnostic and prognostic utility, particularly with immunotherapy and possible targeted therapy against the NRF2 signalling pathway. Further investigation with larger cohorts is warranted to expand the data surrounding NFE2L2 mutations in urothelial carcinoma.