Authors:

Tooba Rizwan

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About Paper:

Skin cancer is one of the most aggressive types of cancer while being the 17th most common cancer in the world with high incidence rates in North America and Europe and high mortality rates in Asia. It can be a result of both genetic and environmental factors. Previous genome-wide association studies (GWAS) have identified susceptibility loci, however, the functional impact of these variants across tissues and specific cell types remains poorly understood. To address this gap, we analyzed data from the Million Veteran Program (MVP; n = 635,969) to identify genome-wide significant SNPs associated with skin cancer and evaluated their predicted gene expression in skin tissues and single-cell immune models to understand genetic contributions to melanogenesis pathways and metastatic progression of skin cancer. Multiple significant gene-level associations were identified. Replication analyses using single-cell PrediXcan (Sc-PrediXcan) in the All of Us (AoU) cohort confirmed several single-cell-associated signals. DBNDD1 (p = 3.96 x 10), ARNT (p = 1.42 x 107°), MINDY1 (p = 2.76 x 10°"), and many other genes demonstrated strong replicated associations across cohorts in different immune cell types. To further investigate whether these associations reflect cell-type-specific or cell-type-enriched regulatory effects, we applied the Aggregated Cauchy Association Test (ACAT) to immune cell PrediXcan results from the AoU cohort. Four genes were cell-type enriched: MYH7B in dendritic cells (p = 3.47 x 10°'), TXNDC9 in CD4* af T cells (p = 2.36 x 10°), IRF4 in transitional-stage B cells (p = 1.56 x 107°), and ENSA in platelets (p = 1.38 x 10°'). ACAT p-values suggest that the observed associations are driven by cell-type-enriched regulatory mechanisms that contribute to skin cancer susceptibility. Although ENSA appears cell-type-enriched, it is expressed in a limited number of immune cell types. OO SOOM OHOS OH SOO OOOH CSS OSC OSHS SOS OHOHOSES TC OOOH OOOO HELE OEH DIDIDIFIFHIDDIFISIOS©DDIDIIDIDGHHIDDIHIIHHIIIIIOVO

Source:

Loyola University Chicago

Topics:

No topics listed

Co-authors:

Tooba Rizwan