HLA

Prognostic significance of high circulating sHLA‐G in ovarian carcinoma

HLA‐G is a non‐classical major histocompatibility complex class Ib molecule. Its expression has been described in various cancer types, including ovarian cancer. HLA‐G molecule has been implicated in immune escape and in progression of ovarian tumor cells. Our goal was to assess if total soluble (s)HLA‐G molecules or HLA‐G5 and sHLA‐G1 isoforms could be considered as circulating ovarian tumor biomarkers, we measured the concentration of these molecules in ovarian carcinoma patients stratified according with their clinicopathological parameters. sHLA‐G, sHLA‐G1 and HLA‐G5 concentrations were dosed in plasma samples by sandwich‐ELISA. The sHLA‐G dimerization was analyzed after immunoprecipitation and SDS‐PAGE migration. Total sHLA‐G and sHLA‐G1 levels were significantly represented in plasma of ovarian carcinoma patients compared to healthy controls. sHLA‐G1 isoform concentration was highly represented in ovarian carcinoma compared to HLA‐G5 isoforms. Additionally, high sHLA‐G molecules have been found in aged patients, as well as in patients with advanced stages, and those with metastatic lymph nodes and those with distant metastasis. Elsewhere, sHLA‐G monomers were highly represented in ovarian carcinoma patients compared to controls. sHLA‐G plasmatic protein was highly represented in ovarian carcinoma. In effect, HLA‐G might be considered as a new checkpoint molecule that could be used to assess progression and recurrence of the disease, thus placing it as a potential biomarker for advanced and complicated ovarian carcinoma.

Polymorphisms in transporter associated with antigen presenting are associated with cervical intraepithelial neoplasia and cervical cancer in a Chinese Han population

The host immune system plays an important role in infectious diseases and cancers. The heterodimer formed by transporter associated with antigen presenting (TAP)1 and TAP2 is responsible for intracellular peptide loading onto MHC‐I molecules. Studies have shown that single‐nucleotide polymorphisms (SNPs) in TAP genes might affect the expression and function of TAP and be associated with cancer risk. We aimed to investigate the association of SNPs in the TAP1 and TAP2 genes with cervical intraepithelial neoplasia (CIN) and cervical cancer (CC) in a Chinese Han population. Six SNPs in the TAP1 gene and seven in the TAP2 gene were selected. The 13 SNPs were genotyped in 1255 healthy individuals, 575 patients with CIN and 1034 patients with CC using the SNaPshot assay. The association between these SNPs and CIN and CC risk was analysed. The allelic and genotypic distributions of rs41549617 and rs1135216 showed significant differences between the control and CC groups (P < 0.0038). The T allele of rs41549617 was associated with a decreased risk of CC (OR = 0.476, 95%CI: 0.286–0.791). Moreover, the G allele of rs1135216 appears to be associated with a decreased risk of CC (OR = 0.746; 95%CI: 0.632–0.881). The allele and genotype distribution of rs241441 showed a significant difference between the control and CC groups (P < 0.0038), and the rs241441 G allele was associated with an increased risk of CC (OR = 1.232, 95%CI: 1.092–1.398). In addition, the results of the association between TAP alleles and CC showed that TAP1*020101 and TAP1*0301 have an association with CC (P = 0.001 and P = 0.002, respectively). Our results demonstrate that the TAP1 and TAP2 genes are associated with CC in the Chinese Han population.

HLA‐B*38:165N and HLA‐B*51:309 alleles identified in two Chinese cervical intraepithelial neoplasia patients

The new HLA‐B*38:165N and HLA‐B*51:309 alleles in two Chinese cervical intraepithelial neoplasia patients.

Inside the pocket: Critical elements ofHLA‐mediated susceptibility to cervical precancerous lesions

Human papillomavirus (HPV) infection is a necessary cause for cervical cancer (CC), but it also depends on genetic factors, such as HLA polymorphism. However, few reports addressed the role of amino acids residues at the HLA peptide‐binding cleft in HPV‐related cervical disease. Therefore, we aimed to investigate the association betweenHLA‐B, HLA‐C,andHLA‐DRB1polymorphism and amino acid residues composing the pockets of the peptide‐binding cleft of the respective polypeptide chains with cervical intraepithelial neoplasia (CIN II/III). HLA typing was performed by PCR‐SSOP in 184 women with CIN II/III and 174 controls from South Brazil. Associations were estimated by multivariate logistic regression. FDR test was performed to correct thep‐value for multiple comparisons.HLA‐DRB1*13:01was associated with protection against CIN II/III, whileHLA‐C*03:04was associated with susceptibility. The amino acid residues isoleucine, tyrosine, and leucine at positions 95, 116, and 163 of HLA‐C, respectively, were associated with CIN II/III susceptibility. In contrast, serine at positions 11 and 13 of HLA‐DRB1 was associated with protection against the disease. Our results confirm previously reported associations between HLA and cervical diseases caused by HPV and suggest a role for amino acid residues at different positions of HLA‐C and HLA‐DRB1 in CIN II/III. This finding may be further explored to better understand the genetic risk and the influence of immune response to CC development.

Validation and functional follow‐up of cervical cancer risk variants at the HLA locus

Cervical cancer is the fourth most common cancer in females. Genome‐wide association studies (GWASs) have proposed cervical cancer susceptibility variants at the HLA locus on chromosome 6p21. To corroborate these findings and investigate their functional impact in cervical tissues and cell lines, we genotyped nine variants from cervical cancer GWASs (rs17190106, rs535777, rs1056429, rs2763979, rs143954678, rs113937848, rs3117027, rs3130214, and rs9477610) in a German hospital‐based series of 1122 invasive cervical cancers, 1408 dysplasias, and 1196 healthy controls. rs17190106, rs1056429 and rs143954678/rs113937848 associated with cervical malignancies overall, while rs17190106 and rs535777 associated specifically with invasive cancer (OR = 0.69, 95% CI = 0.55–0.86, p = 0.001) or adenocarcinomas (OR = 1.63, 95%CI = 1.17–2.27, p = 0.004), respectively. We tested these and one previously genotyped GWAS variant, rs9272117, for potential eQTL effects on 36 gene transcripts at the HLA locus in 280 cervical epithelial tissues. The strongest eQTL pairs were rs9272117 and HLA‐DRB6 (p = 1.9x10E‐5), rs1056429 and HLA‐DRB5 (p = 2.5x10E‐4), and rs535777 and HLA‐DRB1 (p = 2.7x10E‐4). We also identified transcripts that were specifically upregulated (DDX39B, HCP5, HLA‐B, LTB, NFKBIL1) or downregulated (HLA‐C, HLA‐DPB2) in HPV+ or HPV16+ samples. In comparison, treating cervical epithelial cells with proinflammatory cytokine γ‐IFN led to a dose‐dependent induction of HCP5, HLA‐B, HLA‐C, HLA‐DQB1, HLA‐DRB1, HLA‐DRB6, and repression of HSPA1L. Taken together, these results identify relevant genes from both the MHC class I and II regions that are inflammation‐responsive in cervical epithelium and associate with HPV (HCP5, HLA‐B, HLA‐C) and/or with genomic cervical cancer risk variants (HLA‐DRB1, HLA‐DRB6). They may thus constitute important contributors to the immune escape of precancerous cells after HPV‐infection.

Allelic loss of HLA class I facilitates evasion from immune surveillance in cervical intraepithelial neoplasia

Loss of heterozygosity (LOH) has been reported to occur in HLA regions in cervical intraepithelial neoplasia (CIN) and cervical cancer. However, the details of how this is related to the progression of CIN have been unclear. In this study, we examined the human papillomavirus (HPV) antigen‐presenting capacity of people with CIN and the significance of LOH of HLA class I in the progression of CIN. It was shown that differences in antigen‐presenting capacity among each case depended on HLA types, not HPV genotypes. Focusing on the HLA type, there was a positive correlation between antigen‐presenting capacity against HPV and the frequency of allelic loss. Furthermore, the lost HLA‐B alleles had a higher HPV antigen‐presenting capacity than intact alleles. In addition, frequency of LOH of HLA class I was significantly higher in advanced CIN (CIN2–3) than in cervicitis or early‐stage CIN (CIN1): around half of CIN2–3 had LOH of any HLA class I. Moreover, the antigen‐presenting capacity against E5, which is the HPV proteins that facilitate viral escape from this immune surveillance by suppressing HLA class I expression, had the most significant impact on the LOH in HLA‐B. This study suggests that HPV evades immune surveillance mechanisms when host cells lose the capacity for antigen presentation by HLA class I molecules, resulting in long‐term infection and progression to advanced lesions.

Association of HLA class I and II genes with cervical cancer susceptibility in a Han Chinese population

Cervical cancer (CC) is one of the leading causes of cancer‐related death in females worldwide. Genome‐wide association studies (GWASs) have identified CC‐related susceptibility loci in HLA regions. To investigate the associations between HLA genes and cervical intraepithelial neoplasia (CIN) or cervical cancer (CC), six loci of HLA class I (HLA‐A, ‐B, and ‐C) and II (HLA‐DRB1, ‐DPB1, and ‐DQB1) were selected for genotyping, and the associations between these alleles or their haplotypes with CIN or CC risk or protection from disease were evaluated. In total, 2193 participants, including 909 healthy individuals in the control group, 769 patients with CC, and 515 patients with CIN2+ (CIN II and III), were enrolled in the current study. HLA genes were genotyped using the NGSgo Illumina MiSeq workflow, and the associations between these loci and CIN2+ or CC at the allele and haplotype levels were analyzed. The allele frequencies of HLA‐A*33:03, B*58:01, C*03:02, DPB1*05:01, and DRB1*12:01 were lower in both the CC and CIN2+ groups than in the control group, whereas those of B*55:02, C*04:03, and DPB1*03:01 were higher in the CC group than in the control group. In the histologic CC type analysis, the differences in the frequencies of these alleles in squamous cell carcinoma (SCC) of the cervix and stage I CC showed a consistent trend. In the haplotype analysis, the frequency of A*33:03‐C*03:02‐B*58:01 was lower in the CC and CIN2+ groups than in the control group, and that of A*24:02‐C*04:03‐B*15:25 was higher in the CC group than in both the control and CIN2+ groups. These three different haplotype frequencies were also identified in the FIGO CC stage analysis. In addition, in human papilloma virus (HPV) genotype analyses, the frequencies of HLA‐C*03:02 and DPB1*05:01 were significantly lower in the CC and CIN2+ groups than in the control group, and in SCC subgroup, the frequencies of HLA‐DQB1*04:01 and DRB1*04:05 were higher in the HPV other genotype infection group than in the HPV16 infection group. In both HPV16 single infection and coinfection with other HPVs, the frequency of haplotype A*33:03‐C*03:02‐B*58:01 was lower in both CC and CIN2+ than in the control group, while the frequencies of A*11:01‐C*14:02‐B*51:01 and A*24:02‐C*03:04‐B*13:01 were higher in the CIN2+ than in CC and the control group. In the HPV16 and other HPV infection comparisons, the frequencies of DRB1*04:05‐DQB1*04:01‐DPB1*02:01 and DRB1*11:01‐DQB1*03:01‐DPB1*05:01 were lower in the HPV16 infection group than in the other HPV infection group. Our results suggest that the HLA class I and II genes may affect the risk of CIN and CC as well as the histologic CC types and FIGO stages of CC in the Han Chinese population. In addition, HLA genes were associated with HPV16 infection at both the allelic and haplotype levels.