HLA-E gene polymorphism and expression in colorectal cancer patients

HLA-E has been proposed as an immunomodulatory molecule in various physiological and pathological contexts. However, few data are available on its involvement in bowel oncogenesis. Our aim was to investigate whether HLA-E gene polymorphism and its expression as soluble molecules (sHLA-E) contribute to colorectal cancer (CRC) pathology in the Tunisian population. A total of 240 CRC patients and 254 age/gender-matched healthy controls (CTRLs) were genotyped for HLA-E*01:01/01:03 polymorphism (rs1264457) using sequence-specific-primers (PCR-SSP). sHLA-E levels in plasma samples (50 CRC patients and 97 CTRLs) were measured by Enzyme linked ImmunoSorbent assay (ELISA). Our results revealed lower frequencies of the HLA-E*01:01 allele (OR = 0.70, 95 %CI = [0.55-0.90], p = 0.005) and HLA-E*01:01/01:01 homozygous genotype (OR = 0.55, 95 %CI = [0.36-0.85], p = 0.005) in CRC patients compared to CTRLs. Furthermore, individuals with HLA-E*01:01 are less likely to develop CRC before the age of 50. After stratifying the patients and CTRLs by gender, it became evident that frequencies of HLA-E*01:03 allele (p = 0.001) and HLA-E*01:03/01:03 genotype (p = 0.004) were significantly higher in female patients compared to female CTRLs. However, Kaplan-Meier survival analysis showed that female patients carrying the HLA-E*01:01 (N = 82) displayed a significant shorter 3-year overall survival (HR = 2.37; 95 % CI = [1.15-4.85], p = 0.01) than non-carriers (N = 37). Additionally, sHLA-E levels in patients were significantly (p = 0.006) reduced in females (1.8 ng/ml) compared to males (2.6 ng/ml). No relationship between sHLA-E levels and HLA-E polymorphism was found. Further, there was no significant association between sHLA-E levels and CRC outcome although enriched sHLA-E molecules were able to downregulated T cells mediated IFN-γ production in a dose-independent manner. Overall, these data suggest that in the Tunisian population, HLA-E*01:01/01:03 gene polymorphism and circulating sHLA-E molecules in female CRC patients may be important factors enabling gender-specific strategies for the diagnosis and treatment of this cancer.