ERAP1 Haplotypes Linked to Poorer Survival in Cervical Cancer Patients

Two inherited combinations of variants in the ERAP1 gene were associated with markedly worse survival in patients with cervical cancer, according to a study that combined genomic data from The Cancer Genome Atlas with sequencing of tumor samples from Brazilian patients. In the TCGA-CESC cohort of 173 women with cervical squamous cell carcinoma and endocervical adenocarcinoma, homozygosity for the haplotype the researchers labeled H005 was associated with a more than nine-fold higher risk of death from any cause, and the presence of a second haplotype, H023, was linked to a roughly ten-fold increased risk of overall mortality in multivariate Cox regression analysis.

ERAP1 encodes endoplasmic reticulum aminopeptidase 1, an enzyme that trims the N-termini of peptides inside the endoplasmic reticulum so they reach the eight-to-nine amino acid length required for binding to human leukocyte antigen class I (HLA-I) molecules. These HLA-peptide complexes are displayed on the cell surface, where cytotoxic CD8+ T lymphocytes recognize them. When trimming is inefficient or excessive, the repertoire of tumor epitopes presented to the immune system can be reshaped, a process the study’s authors describe as a potential route to immune evasion in tumors driven by human papillomavirus, the primary risk factor for cervical cancer.

The ERAP1 gene, located on chromosome 5q15, is highly polymorphic, and genome-wide association studies have linked its variants to autoimmune diseases and to several cancers. The researchers analyzed missense variants in coding exons, assembling phased haplotypes from whole-exome sequencing data of both tumor and blood samples from the TCGA-CESC cohort. They identified 52 different haplotypes in 81 unique combinations, with H018, composed of the rs26653, rs30187, and rs27044 variants, the most frequently detected, followed by the wild-type haplotype H001.

At the level of individual variants, the rs2287987 (p.Met349Val) variant showed the strongest adverse signal in the TCGA cohort. In multivariate analysis, homozygosity for this variant was associated with a hazard ratio of 11.04 for overall survival (95% confidence interval 2.18 to 56.05, p = 0.00376) and 13.83 for disease-specific survival (95% CI 2.51 to 76.20, p = 0.00255). The variant lies near the catalytic site of the enzyme, and previous work has suggested it impairs peptide trimming, which could reduce antigen presentation and weaken immune responses. Kaplan-Meier curves showed reduced overall and disease-specific survival among individuals homozygous for the variant.

In contrast, the rs30187 (p.Lys528Arg) variant, located at the interface between domains II and III of the protein, was associated with a reduced risk of mortality in the TCGA cohort, with hazard ratios of 0.374 for heterozygotes and 0.346 for homozygotes in overall survival analysis. The authors note that this variant has previously been reported as protective against Behçet’s disease and has been linked to higher ERAP1 mRNA expression and lower risk of death in non-small cell lung cancer. When evaluated within the haplotype context, however, the protective effect of rs30187 appeared to be attenuated, which the researchers interpret as reflecting complex interactions among variants that collectively alter enzymatic activity and immune modulation.

The H005 haplotype comprises the rs26653 (p.Arg127Pro), rs2287987 (p.Met349Val), rs30187 (p.Lys528Arg), rs17482078 (p.Arg725Gln), and rs27044 (p.Gln730Glu) variants, overlapping substantially with a functionally impaired haplotype described in earlier work that encodes a nonfunctional protein. Homozygosity for H005 was associated with a hazard ratio of 9.59 for overall survival (95% CI 2.07 to 44.41, p = 0.00384) and 12.85 for disease-specific survival (95% CI 2.63 to 62.85, p = 0.00162). The H023 haplotype, which includes rs26653, rs27895 (p.Gly346Asp), rs30187, and rs27044, was associated with a hazard ratio of 10.18 for overall survival (95% CI 1.27 to 81.37, p = 0.02862) and 15.18 for disease-specific survival (95% CI 1.82 to 126.49, p = 0.01191). No individuals were homozygous for H023, so a single copy was sufficient for the observed association in the heterozygous state.

Beyond FIGO stage III/IV disease, which was independently associated with poorer overall and disease-specific survival in the TCGA cohort, the study also examined the tumor immune microenvironment. Using the TIMER tool, the researchers found that ERAP1 expression correlated positively with the infiltration of CD8+ T cells (partial correlation 0.264), CD4+ T cells (0.312), neutrophils (0.483), and dendritic cells (0.342), while correlations with macrophages and B cells were not statistically significant. In a multivariate Cox model, CD8+ T cell infiltration was significantly associated with improved survival (hazard ratio 0.006, p = 0.049), and CD4+ T cell infiltration was significantly associated with improved survival in Kaplan-Meier analysis (p = 0.027). The authors emphasize that these findings should be interpreted as supportive associations rather than evidence of a direct causal relationship.

The picture was different in the Brazilian cohort, in which 52 tumor samples from patients treated at Presidente Dutra University Hospital between August 2022 and March 2023 were sequenced by the Sanger method at six preselected variants. None of the ERAP1 variants analyzed were significantly associated with overall or disease-specific survival in this cohort. The authors attribute this partly to the limited sample size and low number of events, which diminished statistical power, and partly to population-specific differences in genetic background and environmental factors. Minor allele frequencies were broadly consistent between the two cohorts for most variants, although rs30187 showed notable variability, with a frequency of 39.3% in TCGA, 49% in the Brazilian cohort, and 39.6% in the AbraOM database of healthy Brazilian individuals. Haplotype-level analysis was not possible in the Brazilian dataset because haplotype identification was not performed in those samples.

HLA-I typing of the TCGA patients revealed that HLA-A*02:01, HLA-B*07:02, and HLA-C*07:02 were the most frequent alleles at their respective loci, but no statistically significant associations were found between HLA-I alleles and FIGO stage, and no pattern of HLA-I alleles emerged among patients carrying the survival-associated ERAP1 haplotypes. The authors suggest that the extensive polymorphism of HLA genes and the limited sample size may explain the absence of associations, and they call for larger cohorts to investigate these relationships further.

The study’s conclusions are cautious. The authors state that the lack of statistically significant associations in the Brazilian cohort does not exclude a biological role for ERAP1 variants in cervical cancer prognosis, but underscores the need for larger, well-powered validation studies in diverse populations. They recommend that future research validate the prognostic significance of the H005 and H023 haplotypes and CD8+ T cell infiltration levels in independent cohorts, including Brazilian populations, and conduct functional studies to elucidate how these haplotypes influence ERAP1 enzymatic activity, antigen processing, and immune evasion. As an observational analysis of two cohorts with non-uniform age distribution, tumor stage, and treatment modalities, the findings identify candidate prognostic markers rather than established clinical tools, and any use in risk stratification would require prospective validation.

Subject of Research: The association of ERAP1 genetic variants and haplotypes with survival outcomes in cervical cancer patients

Article Title: Prognostic Impact of ERAP1 Genetic Variants and Haplotypes in Cervical Cancer: Insights From TCGA‐CESC and a Brazilian Patient Cohort

Article References: Dian, A. L., Cunha, A. P. A., Melo, C. P. D. S., Nascimento, M. D. D. S. B., Carvalho, M. G. R., & Ruiz, J. C. (2026). Prognostic Impact of ERAP1 Genetic Variants and Haplotypes in Cervical Cancer: Insights From TCGA ‐ CESC and a Brazilian Patient Cohort. Molecular Genetics & Genomic Medicine, 14(10), Article e70170. https://doi.org/10.1002/mgg3.70170

Image Credits: AI Generated

DOI: 10.1002/mgg3.70170

Keywords: ERAP1, cervical cancer, haplotypes, TCGA-CESC, survival, HLA class I, antigen processing, rs2287987, rs30187, CD8+ T cells, Brazilian cohort, genetic variants