BACKGROUNDRecent advances demonstrate a relationship between chronic/recurrent inflammation and prostate cancer (PCA). Among inflammatory regulators, toll-like receptors (TLRs) play a critical role in innate immune responses. However, it remains unclear whether variant TLR genes influence PCA risk among men of African descent. Therefore, we evaluated the impact of 32 TLR-associated single nucleotide polymorphisms (SNPs) on PCA risk among African-Americans and Jamaicans.METHODSSNP profiles of 814 subjects were evaluated using Illumina’s Veracode genotyping platform. Single and combined effects of SNPs in relation to PCA risk were assessed using age-adjusted logistic regression and entropy-based multifactor dimensionality reduction (MDR) models.RESULTSSeven sequence variants detected in TLR6, TOLLIP, IRAK4, IRF3 were marginally related to PCA. However, none of these effects remained significant after adjusting for multiple hypothesis testing. Nevertheless, MDR modeling revealed a complex interaction between IRAK4 rs4251545 and TLR2 rs1898830 as a significant predictor of PCA risk among U.S. men (permutation testing p-value = 0.001).CONCLUSIONSMDR identified an interaction between IRAK4 and TLR2 as the best two factor model for predicting PCA risk among men of African descent. However, these findings require further assessment and validation.

BackgroundChemokine and chemokine receptors play an essential role in tumorigenesis. Although chemokine-associated single nucleotide polymorphisms (SNPs) are associated with various cancers, their impact on prostate cancer (PCA) among men of African descent is unknown. Consequently, this study evaluated 43 chemokine-associated SNPs in relation to PCA risk. We hypothesized inheritance of variant chemokine-associated alleles may lead to alterations in PCA susceptibility, presumably due to variations in antitumor immune responses.MethodsSequence variants were evaluated in germ-line DNA samples from 814 African-American and Jamaican men (279 PCA cases and 535 controls) using Illumina’s Goldengate genotyping system.ResultsInheritance of CCL5 rs2107538 (AA, GA+AA) and rs3817655 (AA, AG, AG+AA) genotypes were linked with a 34-48% reduction in PCA risk. Additionally, the recessive and dominant models for CCR5 rs1799988 and CCR7 rs3136685 were associated with a 1.52-1.73 fold increase in PCA risk. Upon stratification, only CCL5 rs3817655 and CCR7 rs3136685 remained significant for the Jamaican and U.S. subgroups, respectively.ConclusionsIn summary, CCL5 (rs2107538, rs3817655) and CCR5 (rs1799988) sequence variants significantly modified PCA susceptibility among men of African descent, even after adjusting for age and multiple comparisons. Our findings are only suggestive and require further evaluation and validation in relation to prostate cancer risk and ultimately disease progression, biochemical/disease recurrence and mortality in larger high-risk subgroups. Such efforts will help to identify genetic markers capable of explaining disproportionately high prostate cancer incidence, mortality, and morbidity rates among men of African descent.

Mounting evidence indicates that anomalies in the inflammatory and immune response pathways are essential to tumorigenesis. However, tumor-based innate immunity initiated by transformed breast epithelia tissues has received much less attention. This review summarizes published reports on the role of the toll-like receptor signaling pathway on breast cancer risk, disease progression, survival, and disease recurrence. Specifically, we discuss the underlying biological mechanisms that contribute to the tumorigenic and/or anti-tumorigenic properties of toll-like receptors and their associated agonists in relation to breast tumorigenesis and cancer treatment. Further, we use results from preclinical, clinical, and population-based studies as prompts for the exploration of new and more effective breast cancer therapies. As the knowledge base of innate immunity's involvement in breast cancer progression increases, current and new immune-modifying strategies will be refined to effectively treat breast cancer.

BackgroundMolecular and epidemiological evidence demonstrate that altered gene expression and single nucleotide polymorphisms in the apoptotic pathway are linked to many cancers. Yet, few studies emphasize the interaction of variant apoptotic genes and their joint modifying effects on prostate cancer (PCA) outcomes. An exhaustive assessment of all the possible two-, three- and four-way gene-gene interactions is computationally burdensome. This statistical conundrum stems from the prohibitive amount of data needed to account for multiple hypothesis testing.MethodsTo address this issue, we systematically prioritized and evaluated individual effects and complex interactions among 172 apoptotic SNPs in relation to PCA risk and aggressive disease (i.e., Gleason score ≥ 7 and tumor stages III/IV). Single and joint modifying effects on PCA outcomes among European-American men were analyzed using statistical epistasis networks coupled with multi-factor dimensionality reduction (SEN-guided MDR). The case-control study design included 1,175 incident PCA cases and 1,111 controls from the prostate, lung, colo-rectal, and ovarian (PLCO) cancer screening trial. Moreover, a subset analysis of PCA cases consisted of 688 aggressive and 488 non-aggressive PCA cases. SNP profiles were obtained using the NCI Cancer Genetic Markers of Susceptibility (CGEMS) data portal. Main effects were assessed using logistic regression (LR) models. Prior to modeling interactions, SEN was used to pre-process our genetic data. SEN used network science to reduce our analysis from > 36 million to < 13,000 SNP interactions. Interactions were visualized, evaluated, and validated using entropy-based MDR. All parametric and non-parametric models were adjusted for age, family history of PCA, and multiple hypothesis testing.ResultsFollowing LR modeling, eleven and thirteen sequence variants were associated with PCA risk and aggressive disease, respectively. However, none of these markers remained significant after we adjusted for multiple comparisons. Nevertheless, we detected a modest synergistic interaction between AKT3 rs2125230-PRKCQ rs571715 and disease aggressiveness using SEN-guided MDR (p = 0.011).ConclusionsIn summary, entropy-based SEN-guided MDR facilitated the logical prioritization and evaluation of apoptotic SNPs in relation to aggressive PCA. The suggestive interaction between AKT3-PRKCQ and aggressive PCA requires further validation using independent observational studies.

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