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Genetic variants in the HLA class II region associated with risk of cutaneous squamous cell carcinoma.

ABSTRACT: BACKGROUND:The immune system has been implicated in the pathophysiology of cutaneous squamous cell carcinoma (cSCC) as evidenced by the substantially increased risk of cSCC in immunosuppressed individuals. Associations between cSCC risk and single nucleotide polymorphisms (SNPs) in the HLA region have been identified by genome-wide association studies (GWAS). The translation of the associated HLA SNPs to structural amino acids changes in HLA molecules has not been previously elucidated. METHODS:Using data from a GWAS that included 7238 cSCC cases and 56,961 controls of non-Hispanic white ancestry, we imputed classical alleles and corresponding amino acid changes in HLA genes. Logistic regression models were used to examine associations between cSCC risk and genotyped or imputed SNPs, classical HLA alleles, and amino acid changes. RESULTS:Among the genotyped SNPs, cSCC risk was associated with rs28535317 (OR?=?1.20, p?=?9.88?×?10-?11) corresponding to an amino-acid change from phenylalanine to leucine at codon 26 of HLA-DRB1 (OR?=?1.17, p?=?2.48?×?10-?10). An additional independent association was observed for a threonine to isoleucine change at codon 107 of HLA-DQA1 (OR?=?1.14, p?=?2.34?×?10-?9). Among the classical HLA alleles, cSCC was associated with DRB1*01 (OR?=?1.18, p?=?5.86?×?10-?10). Conditional analyses revealed additional independent cSCC associations with DQA1*05:01 and DQA1*05:05. Extended haplotype analysis was used to complement the imputed haplotypes, which identified three extended haplotypes in the HLA-DR and HLA-DQ regions. CONCLUSIONS:Associations with specific HLA-DR and -DQ alleles are likely to explain previously observed GWAS signals in the HLA region associated with cSCC risk.

SUBMITTER: Wang W

PROVIDER: S-EPMC7081741 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Genetic variants in the HLA class II region associated with risk of cutaneous squamous cell carcinoma.

Wang Wei W Ollila Hanna M HM Whittemore Alice S AS Demehri Shadmehr S Ioannidis Nilah M NM Jorgenson Eric E Mignot Emmanuel E Asgari Maryam M MM

Cancer immunology, immunotherapy : CII 20180512 7

<h4>Background</h4>The immune system has been implicated in the pathophysiology of cutaneous squamous cell carcinoma (cSCC) as evidenced by the substantially increased risk of cSCC in immunosuppressed individuals. Associations between cSCC risk and single nucleotide polymorphisms (SNPs) in the HLA region have been identified by genome-wide association studies (GWAS). The translation of the associated HLA SNPs to structural amino acids changes in HLA molecules has not been previously elucidated.< ...[more]

PMID: 29754218

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Project description:Background: The genetic etiology of osteosarcoma remains poorly understood despite the publication of a genome-wide association study. Association between HLA genetic variants and risk of several cancers has been observed, but HLA variation is not well captured by standard SNP arrays.Methods: We genotyped 207 Californian pediatric osteosarcoma cases and 696 controls of European ancestry using a custom genome-wide array supplemented with approximately 6,000 additional probes across the MHC region. We subsequently imputed 4-digit classical HLA alleles using a reference panel of 5,225 individuals who underwent high-resolution HLA typing via next-generation sequencing. Case-control comparisons were adjusted for ancestry-informative principal components, and top associations from the discovery analysis underwent replication in an independent dataset of 657 cases and 1,183 controls.Results: Three highly correlated HLA class II variants (r 2 = 0.33-0.98) were associated with osteosarcoma risk in discovery analyses, including HLA-DRB1*0301 (OR = 0.52; P = 3.2 × 10-3), HLA-DQA1*0501 (OR = 0.74; P = 0.031), and HLA-DQB1*0201 (OR = 0.51; P = 2.7 × 10-3). Similar associations were observed in the replication data (P range = 0.011-0.037). Meta-analysis of the two datasets identified HLA-DRB1*0301 as the most significantly associated variant (ORmeta = 0.62; P meta = 1.5 × 10-4), reaching Bonferroni-corrected statistical significance. The meta-analysis also revealed a second significant independent signal at HLA-DQA1*01:01 (ORmeta = 1.33, P meta = 1.2 × 10-3), and a third suggestive association at HLA-DQB1*0302 (ORmeta = 0.73, P meta = 6.4 × 10-3).Conclusions: Multiple independent HLA class II alleles may influence osteosarcoma risk.Impact: Additional work is needed to extend our observations to other patient populations and to clarify the potential causal mechanisms underlying these associations. Understanding immunologic contributions to the etiology of osteosarcoma may inform rational therapeutic targets. Cancer Epidemiol Biomarkers Prev; 27(10); 1151-8. ©2018 AACR.

Dataset Information

Genetic variants in the HLA class II region associated with risk of cutaneous squamous cell carcinoma.

Publications

Genetic variants in the HLA class II region associated with risk of cutaneous squamous cell carcinoma.

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