Defining the Mutational Landscape That Affects the Histone Demethylase KDM6A/UTX in Human Cancer.

We are developing, standardizing, and implementing advanced methods for genomics interpretation of disease-associated mutations, as a fundamental step toward the discovery of mechanisms of diseases. A key example is the epigenetic regulator, KDM6A/UTX, whose gene and encoded product have elicited significant investigation. When mutated in the germline, KDM6A/UTX gives rise to a developmental disease (Kabuki syndrome), while in somatic cells it mediates cancer development, as a tumor suppressor. However, the full extent of the mutational landscape that affects this gene and the underlying mechanisms of dysfunction remain to be fully explored. Here, we report the results from a multi-tiered approach evaluating the impact of 197 KDM6A/UTX somatic mutations, using information derived from combining conventional genomics bioinformatics with computational biophysics. Our approach incorporates multiple scores derived from alterations in protein sequence, structure, and molecular dynamics to classify the KDM6A/UTX mutations. We identified 136 (69%) as damaging variants, consisting of 15 Structural Variants (SV), 88 Dynamic Variants (DV), and 33 Structural and Dynamic Variants (SDV). Another 32 variants appear to be tolerated by KDM6A/UTX, while 29 still remain as genomic Variants of Uncertain Significance (VUS). Comparative analyses of these results with those obtained by classic genetic diagnostic pipelines demonstrated that our approach provides a more comprehensive evaluation of damaging potential and, more importantly, reveals possible mechanisms underlying dysfunctions of distinct genomic variants. Thus, these results should be taken into consideration for clinical classifications of genomic variation, as well as provide critical insights for experimental validation and the development of mutant-specific drugs to fight diseases caused by KDM6A dysfunctions.