Genetic characterization of KLRC2 deletion in racially diverse prostate cancer patients

Natural Killer (NK) cells are key mediators of anti-tumor immunity through direct tumor cell lysis. Emerging evidence suggests significant immune microenvironment differences in prostate tumors between African American (AA) and Caucasian American (CA) men; however, the contribution of NK cell-associated genes to these disparities remains incompletely understood. The NK cell receptor gene KLRC2 is of particular interest because prior research within our patient cohort demonstrated significantly lower KLRC2 expression in AA prostate tumors compared to CA tumors. Given that germline KLRC2 deletion polymorphisms differ across global populations, including those with East and West African ancestry, investigating its deletion status may provide insight into downstream expression differences and associated immune variation. This study aims to gain a deeper understanding of immunobiological differences between AA and CA men with prostate cancer (PCa) by evaluating an NK cell-relevant gene, KLRC2 , in racially diverse genomic datasets. We hypothesized that germline deletion may contribute to its variability in downstream expression in tumor tissues and ultimately contribute to observed racial disparities in PCa. Understanding germline deletion variations may provide insight into mechanisms driving tumor immune microenvironment differences and strategies to reduce these disparities in PCa outcomes. We analyzed germline, whole genome sequencing data from a large Center for Prostate Disease Research (CPDR) cohort including African American (AA, n=259) and Caucasian American (CA, n=272) men. Bioinformatics workflows were applied to accurately infer KLRC2 deletion status, including copy-number calling and quality control filtering. We identified a significant difference in the heterozygous deletion status of KLRC2 between AA and CA men in this robust CPDR cohort. These findings suggest population-level variation in KLRC2 copy number that may account for reduced KLRC2 expression previously observed in AA prostate tumors. Germline KLRC2 deletions may influence NK cell-mediated activity within the prostate tumor microenvironment, particularly among African America men. Our findings provide foundational evidence that KLRC2 status may play a role in racial immune disparities. These findings place KLRC2 as a promising biomarker and potential candidate for NK cell-based immunotherapeutic strategies. The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of War (DoW) or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.