Distinctive Genomic Features of Hydroa Vacciniforme Lymphoproliferative Disorder in Latin American Patients: A Multicenter Multi-Omics Study

This study was used to determine clinicopathological features and molecular profiles of HV-LPD patients from Latin America and Mexico. We performed a clinicopathologic review of 43 HV-LPD cases from Latin America and Mexico. We also executed the first comprehensive multi-omics study of 28 Hispanic and Latin American HV-LPD patients, incorporating whole-exome and RNA sequencing, and copy number variation profiling. Analysis revealed somatic mutations, with epigenetic regulator KMT2D being the most frequently mutated gene (28%), followed by CREBBP (21.4%), and BCOR (14.3%). Inactivation of tumor suppressor genes (TSG), including ATM (14.3%), MLH1 (10.7%) and BARD1 (10.7%) were observed. Copy number analysis revealed deletions involving TSGs, MAP2K4 (50%), SMARCB1 (36%), FANCA (36%) and PRDM1 (14.2%) . Differential gene expression analysis identified significant gene overexpression in cytokine signaling, NK/T-cell activity, and JAK signaling. Analysis of serial biopsies at two different time points in three patients with HV-LPD revealed increased EBV RNA and progressive accumulation of mutations, particularly in epigenetic regulator genes including KMT2D alterations. Our findings suggest that disruption of KMT2D and other epigenetic regulators, with subsequent inactivation of tumor suppressor genes, is key in HV-LPD development in this Latin American cohort.