Biology subjects

Aygun, N.

Publications and source records attributed to Aygun, N..

3 recordsLinked to original sources

bioRxiv2026

Genomic classification and immune profiling define mucosal melanoma

Mucosal melanoma is a rare, lethal melanoma subtype with distinct genetics and limited benefit from immunotherapy. To define features associated with mucosal melanoma clinical outcomes, we assembled a large, multimodally profiled cohort spanning primary and metastatic disease. Compared with cutaneous melanoma, primary mucosal melanoma showed greater genomic heterogeneity, ploidy and aneuploidy, and a more dedifferentiated, proliferative transcriptional state. Analysis of genomic sequencing of 339 patients with mucosal melanoma identified four mutually exclusive genomic subtypes: CDK4/MDM2/CCND1, SF3B1-mutated, TP53/ATRX, and mucosal melanoma Triple WT, associated with distinct anatomic sites but similar outcomes. In the tumor microenvironment, we observed reduced T cell infiltration and increased CD163+ tumor-associated macrophages in mucosal melanoma relative to cutaneous melanoma. In matched longitudinal samples, CD163+ tumor-associated macrophages increased with disease progression and immunotherapy resistance. CD163+ tumor-associated macrophages engaged non-regulatory T cells through GAL9-TIM-3 interactions, nominating TIM-3 blockade as a therapeutic strategy for mucosal melanoma. These findings define the distinct aggressive biology of mucosal melanoma and highlight potential therapeutic targets and mechanisms of immune resistance.

cancer biology↗

bioRxiv2023

WNT activity reveals context-specific genetic effects on gene regulation in neural progenitors

Gene regulatory effects in bulk-post mortem brain tissues are undetected at many non-coding brain trait-associated loci. We hypothesized that context-specific genetic variant function during stimulation of a developmental signaling pathway would explain additional regulatory mechanisms. We measured chromatin accessibility and gene expression following activation of the canonical Wnt pathway in primary human neural progenitors from 82 donors. TCF/LEF motifs, brain structure-, and neuropsychiatric disorder-associated variants were enriched within Wnt-responsive regulatory elements (REs). Genetically influenced REs were enriched in genomic regions under positive selection along the human lineage. Stimulation of the Wnt pathway increased the detection of genetically influenced REs/genes by 66.2%/52.7%, and led to the identification of 397 REs primed for effects on gene expression. Context-specific molecular quantitative trait loci increased brain-trait colocalizations by up to 70%, suggesting that genetic variant effects during early neurodevelopmental patterning lead to differences in adult brain and behavioral traits.

genetics↗

bioRxiv2022

Cellular genome wide association study identifies common genetic variation influencing lithium induced neural progenitor proliferation

Lithium is used in the treatment of bipolar disorder (BD) and is known to increase neural progenitor cell (NPC) proliferation. Though the mechanism of lithiums therapeutic effect is not understood, evidence suggests that genetic variation influences response to treatment. Here, we used a library of genetically diverse human NPCs to identify common genetic variants that modulate lithium induced proliferation. We identified a locus on chr3p21.1 associated with lithium induced proliferation that colocalizes with BD risk. One lithium responsive gene, GNL3, was detected within the locus. The allele associated with increased baseline and lithium-induced GNL3 expression was also associated with increased lithium-induced NPC proliferation. Experimental manipulation of GNL3 expression using CRISPRa/i in NPCs showed that GNL3 was necessary for lithiums full proliferative effects, and sufficient to induce proliferation without lithium treatment. In all, our data suggest that GNL3 expression sensitizes NPCs for a stronger proliferative response to lithium.

genetics↗