Hodgkin disease risk: Role of genetic polymorphisms and gene–gene interactions in inflammation pathway genes

Abstract

Inflammation is a critical component of cancer development. The clinical and pathological features of Hodgkin disease (HD) reflect an abnormal immunity that results from cytokines secreted by Reed-Sternberg cells and the surrounding tumor. Numerous studies have reported the association between genetic polymorphisms in cytokine genes and the susceptibility to different hematologic cancers. However, the effects of such SNPs on modulating HD risk have not yet been investigated. We hypothesized that gene-gene interactions between candidate genes in the anti- and pro-inflammatory pathways carrying suspicious polymorphisms may contribute to susceptibility to HD. To test this hypothesis, we conducted a study on 200 HD cases and 220 controls to assess associations between HD risk and 38 functional SNPs in inflammatory genes. We evaluated potential gene-gene interactions using a multi-analytic strategy combining logistic regression, multi-factor dimensionality reduction, and classification and regression tree (CART) approaches. We observed that, in combination, allelic variants in the COX2, IL18, ILR4, and IL10 genes modify the risk for developing HD. Moreover, the cumulative genetic risk score (CGRS) revealed a significant trend where the risk for developing HD increases as the number of adverse alleles in the cytokine genes increase. These findings support the notion that epigenetic-interactions between these cytokines may influence pathogenesis of HD modulating the proliferation of regulatory T cells. In this way, the innate and adaptative immune responses may be altered and defy their usual functions in the host anti-tumor response. Our study is the first to report the association between polymorphisms in inflammation genes and HD susceptibility risk.

Resiquimod as an Immunologic Adjuvant for NY-ESO-1 Protein Vaccination in Patients with High-Risk Melanoma

“…In our study, no association was observed between vaccine-induced immune responses and the presence of SNP rs3764880. The TLR7 SNP rs179008 has been associated with accelerated HIV-1 disease progression (33) and decreased risk for Hodgkin's disease (34). SNP rs179008 was detected in the 3 patients in Arm B who had detectable NY-ESO-1—specific CD8 + T-cell responses and in 1 patient in Arm A who did not have a detectable NY-ESO-1—specific CD8 + T-cell response (Table 3).…”

Lack of Association of Three Common Polymorphisms in Toll-like receptors (TLRs), TLR2+597T>C, +1350C>T and Arg753Gln with Cancer Risk: a Meta-analysis

“…Recently, many studies have investigated the association between TLRs polymorphisms and cancer risk (Zhou et al, 2006;He et al, 2007;Purdue et al, 2009;Ng et al, 2010;Monroy et al, 2011), but the results were inconclusive. Different from the similar meta-analysis in Neoplasma (Wang et al, 2013), the Delta22 polymorphism (-196 to 174 del) was not analyzed in our manuscript.…”

Association of polymorphisms in TLR genes and in genes of the Toll-like receptor signaling pathway with cancer risk

“…The role of the polymorphisms of these TLR genes in cancer etiology is almost completely unknown. However, there has been no association of the TLR3 polymorphisms with breast cancer (Etokebe et al [195]), cervical cancer (Pandey et al [197]), or HL (Monroy et al [201]). Similar results were obtained for nasopharyngeal carcinoma (He et al [202]), excluding the 829A/C polymorphism, heterozygous genotype, which correlates with increased risk of this malignancy.…”

“…The rs3775290 polymorphism is not associated with the risk of either breast or cervical cancer and possibly is not important for oncogenomics. Polymorphisms of TLR5 and TLR8 genes do not correlate with altered lymphoma risk, but the rs179008 polymorphism of the TLR7 gene was associated with a lower risk of HL [201].…”