Davies, Olivia M. T.

The PI3K enzymes modify phospholipids to regulate cell growth and differentiation. Somatic variants in PI3K are recurrent in cancer and drive a proliferative phenotype. Somatic mosaicism of PIK3R1 and PIK3CA are associated with vascular anomalies and overgrowth syndromes. Germline PIK3R1 variants are associated with varying phenotypes, including immunodeficiency or facial dysmorphism with growth delay, lipoatrophy, and insulin resistance associated with SHORT syndrome. There has been limited study of the molecular mechanism to unify our understanding of how variants in PIK3R1 drive both undergrowth and overgrowth phenotypes. Thus, we compiled genomic variants from cancer and rare vascular anomalies and sought to interpret their effects using an unbiased physics-based simulation approach for the protein complex. We applied molecular dynamics simulations to mechanistically understand how genetic variants affect PIK3R1 and its interactions with PIK3CA. Notably, iSH2 genetic variants associated with undergrowth destabilize molecular interactions with the PIK3CA receptor binding domain in simulations, which is expected to decrease activity. On the other hand, overgrowth and cancer variants lead to loss of inhibitory interactions in simulations, which is expected to increase activity. We find that all disease variants display dysfunctions on either structural characteristics or intermolecular interaction energy. Thus, this comprehensive characterization of novel mosaic somatic variants associated with two opposing phenotypes has mechanistic importance and biomedical relevance and may aid in future therapeutic developments.

AbstractBackgroundSpitzoid neoplasms in pediatric patients pose an interesting challenge for clinicians. More data on the clinical, histologic, and molecular characteristics of these lesions are necessary to distinguish features that may portend recurrence or malignant behavior to help determine future treatment guidelines in pediatric patients.MethodsInstitutional Review Board approval was obtained from Children's Hospital of Wisconsin to conduct a retrospective analysis of spitzoid neoplasms. Patients with biopsied or excised spitzoid neoplasms between 01/01/2000 and 08/01/2016 were included. Pertinent clinical and histologic data were collected. Atypical, unusual, or diagnostically uncertain lesions were selected for re‐review.Results266 lesions from 264 patients were included. 243 were classified as benign (91.35%), 22 as atypical (8.27%), and 1 as spitzoid melanoma (0.38%). No clinical or histologic variables were found to be statistically significant between the benign Spitz, atypical Spitz, and spitzoid melanoma cohorts. No known deaths occurred.ConclusionOur findings highlight the extreme variability of spitzoid neoplasms clinically and histologically. Importantly, this study demonstrates that the vast majority of spitzoid neoplasms in pediatric populations are benign and supports conservative management of spitzoid lesions in children.