Genetic Epidemiology of Glioblastoma Multiforme: Confirmatory and New Findings from Analyses of Human Leukocyte Antigen Alleles and Motifs

Abstract

BackgroundHuman leukocyte antigen (HLA) class I genes mediate cytotoxic T-lymphocyte responses and natural killer cell function. In a previous study, several HLA-B and HLA-C alleles and haplotypes were positively or negatively associated with the occurrence and prognosis of glioblastoma multiforme (GBM).Methodology/Principal FindingsAs an extension of the Upper Midwest Health Study, we have performed HLA genotyping for 149 GBM patients and 149 healthy control subjects from a non-metropolitan population consisting almost exclusively of European Americans. Conditional logistic regression models did not reproduce the association of HLA-B*07 or the B*07-Cw*07 haplotype with GBM. Nonetheless, HLA-A*32, which has previously been shown to predispose GBM patients to a favorable prognosis, was negatively associated with occurrence of GBM (odds ratio = 0.41, p = 0.04 by univariate analysis). Other alleles (A*29, A*30, A*31 and A*33) within the A19 serology group to which A*32 belongs showed inconsistent trends. Sequencing-based HLA-A genotyping established that A*3201 was the single A*32 allele underlying the observed association. Additional evaluation of HLA-A promoter and exon 1 sequences did not detect any unexpected single nucleotide polymorphisms that could suggest differential allelic expression. Further analyses restricted to female GBM cases and controls revealed a second association with a specific HLA-B sequence motif corresponding to Bw4-80Ile (odds ratio = 2.71, p = 0.02).Conclusions/SignificanceHLA-A allelic product encoded by A*3201 is likely to be functionally important to GBM. The novel, sex-specific association will require further confirmation in other representative study populations.

Non-additive and epistatic effects of HLA polymorphisms contributing to risk of adult glioma

“…Namely, our finding that HLA-B*4001 and HLA-DRB1*1302 were protective against glioma was consistent with prior observations that HLA-B*40 and HLA-DRB1*13 were enriched among the control group[17,18,21], although the association was not significant in those prior studies and the opposite direction of effect was observed in another study[22]. Although a previous GWAS found that rosacea (recently linked to glioma risk in a large Danish cohort[5]) is associated with three HLA alleles found to be in high linkage disequilibrium in our study (DRB1*0301, DQA1*0501, and DQB1*0201)[8], we did not observe these alleles to be associated with glioma risk, suggesting that the glioma-rosacea link is not likely due to shared HLA risk variants with pleiotropic effects.…”

Selected human leukocyte antigen class II polymorphisms and risk of adult glioma

“…Another small Italian study confirmed an elevated frequency of the DRB1*14 allele and, in addition, found elevated frequencies of the DQB1*06 and DRB3*01 alleles in 56 cases with high-grade gliomas (La Torre et al, 2009). Other larger studies (155 and 149 GBM patients, respectively), however, have observed no association between DRB1 alleles and glioma ([Tang et al, 2005] and [Song et al, 2009]). Class I genes involving the HLA-A, -B , and -Cw loci have similarly been found to have both positive and negative associations with glioma ([Machulla et al, 2001], [La Torre et al, 2009], [Tang et al, 2005], [Song et al, 2009], and [Nitta et al, 1994]).…”

“…Other larger studies (155 and 149 GBM patients, respectively), however, have observed no association between DRB1 alleles and glioma ([Tang et al, 2005] and [Song et al, 2009]). Class I genes involving the HLA-A, -B , and -Cw loci have similarly been found to have both positive and negative associations with glioma ([Machulla et al, 2001], [La Torre et al, 2009], [Tang et al, 2005], [Song et al, 2009], and [Nitta et al, 1994]). The largest HLA study to date with 155 GBM cases conducted in the United States found the risk of GBM to be positively associated with the class I B*13 allele, and negatively associated with the Cw*01 allele (Tang et al, 2005).…”

“…With regard to glioma, evidence has been limited and inconsistent, with only a few small studies that have examined polymorphisms in HLA genes as a potential susceptibility factor ([Guerini et al, 2006], [Machulla et al, 2001], [La Torre et al, 2009], [Tang et al, 2005], [Song et al, 2009] and [Nitta et al, 1994]). Each, however, has suggested an association between glioma and specific class I or class II HLA alleles or haplotypes.…”

Epidemiology and Outcome of Glioblastoma

“…According to the 2016 WHO classification of GBM multiforme, this tumor has been separated from the classical identity and is currently classified into three groups: GBM IDH-wild type (including giant cell GBM, gliosarcoma, and epithelioid GBM), GBM IDH-mutant, and GBM NOS (1). The average annual age-adjusted incidence rate (IR) of GBM is 3.19 per 100,000 persons in the United States (11), with the age-adjusted GBM rates being 2.5 times higher in European Americans than in African Americans (12).…”