Abstract
Background: Uveal melanoma (UVM) is a rare cancer that shows sex difference in incidence and survival, with little previous report for the underlying mechanism. Methods: This study used the SEER data (1974–2016) for an age-dependent analysis on sex difference in UVM, and further used the TCGA-UVM genomics dataset for analyzing the differential gene expression profiles in tumors from men and women. Results: Our results demonstrate a sex difference in older age (≥40 years) but not in younger patients, with men exhibiting a higher incidence rate than women. However, younger women have shown a continuous increasing trend since 1974. Examining the 11 major oncogenes and tumor suppressors in UVM revealed that EIF1AX showed a significant sex difference in mRNA accumulation and copy number variation, with female tumors expressing higher levels of EIF1AX and exhibiting more variations in copy numbers. EIF1AX mRNA levels were significantly inversely correlated with EIF1AX copy numbers in female tumors only, but not in male tumors. Differential gene expression analysis at the whole genomic level identified a set of 92 protein-coding and 16 RNA-coding genes which exhibited differential expression in men and women (fold of change cutoff at 1.7, adjusted p value < 0.05, FDR < 0.05). Network analysis showed significant difference in immune response and in disulfide bond formation, with EGR1/EGR2 and PDIA2 genes as regulators for immune response and disulfide bond formation, respectively. The melanocortin pathway which is linked to both melanin synthesis and obesity seems to be altered with unclear significance, as the sex difference in POMC, DCT/TYRP2, and MRAP2 was observed but with no clear direction. Conclusion: This study reveals possible mechanisms for the sex difference in tumorigenesis of UVM which has potentials for better understanding and prevention of UVM.
Highlights
Uveal melanoma (UVM) is a cancer of the eye, involving three uveal melanocytic cell types: the iris, the ciliary body, and the choroid [1]
The uveal melanoma data was downloaded from SEER 18 registries with SEERStat software (Version 8.3.8), which included all cases from 1975 to 2016
In order to determine where there is major difference in mutation burdens in tumors derived from male and female patients, we examined the mutation rate, copy number variation, and mRNA expression levels of the major oncogenes or tumor suppressors including GNAQ, GNA11, BAP1, PLCB4, SF3B1, SRSF2, EIF1AX, TERT, CNKSR3, CYSLTR2, and YAP1
Summary
Uveal melanoma (UVM) is a cancer of the eye, involving three uveal melanocytic cell types: the iris, the ciliary body, and the choroid (collectively referred to as the uvea) [1]. Some studies included retinoblastoma, while other studies included other cancer types which arise from the orbital structure [6]. Uveal melanoma (UVM) is a rare cancer that shows sex difference in incidence and survival, with little previous report for the underlying mechanism. Methods: This study used the SEER data (1974–2016) for an age-dependent analysis on sex difference in UVM, and further used the TCGA-UVM genomics dataset for analyzing the differential gene expression profiles in tumors from men and women. Examining the 11 major oncogenes and tumor suppressors in UVM revealed that EIF1AX showed a significant sex difference in mRNA accumulation and copy number variation, with female tumors expressing higher levels of EIF1AX and exhibiting more variations in copy numbers.
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