Sex-Specific miRNA Differences in Liquid Biopsies from Subjects with Solid Tumors and Healthy Controls

Dysregulation of epigenetic mechanisms has been recognized to play a crucial role in cancer development, but these mechanisms vary between sexes. Therefore, we focused on sex-specific differences in the context of cancer-based data from a recent study. A total of 12 cell-free DNA methylation targets in CpG-rich promoter regions and 48 miRNAs were analyzed by qPCR in plasma samples from 8 female and 7 male healthy controls as well as 48 female and 80 male subjects with solid tumors of the bladder, brain, colorectal region (CRC), lung, stomach, pancreas, and liver. Due to the small sample size in some groups and/or the non-balanced distribution of men and women, sex-specific differences were evaluated statistically only in healthy subjects, CRC, stomach or pancreas cancer patients, and all cancer subjects combined (n female/male-8/7, 14/14, 8/15, 6/6, 48/80, respectively). Several miRNAs with opposing expressions between the sexes were observed for healthy subjects (miR-17-5p, miR-26b-5p); CRC patients (miR-186-5p, miR-22-3p, miR-22-5p, miR-25-3p, miR-92a-3p, miR-16-5p); stomach cancer patients (miR-133a-3p, miR-22-5p); and all cancer patients combined (miR-126-3p, miR-21-5p, miR-92a-3p, miR-183-5p). Moreover, sex-specific correlations that were dependent on cancer stage were observed in women (miR-27a-3p) and men (miR-17-5p, miR-20a-5p). Our results indicate the complex and distinct role of epigenetic regulation, particularly miRNAs, depending not only on the health status but also on the sex of the patient. The same miRNAs could have diverse effects in different tissues and opposing effects between the biological sexes, which should be considered in biomarker research.