Interaction among apoptosis-associated sequence variants and joint effects on aggressive prostate cancer

Abstract

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.

AKT3 rSNPs, Transcriptional Factor Binding Sites and Human Disease

“…PCA risk factors include older age, ethnic race and family history while other potential contributors include lifestyle, genetic factors and imbalances in biological pathways [5]. GWAS has resulted in the detection of numerous PCA susceptibility loci [37] from which three AKT3 SNPs that have been previously associated with PCA [5] have been found to be also associated with changes in TFBS within intron one. Perhaps the most interesting TFBS change occurs with the rs10157763 SNP whose minor allele AKT3-T creates the chromatin insulator-binding factor (CTCF) TFBS that is found only once in the gene ( Table 1 and Supplement).…”

“…The AKT3 SNPs (rs10157763, rs10927067 and rs-2125230) are significantly associated with PCA [5]. The rs10157763 AKT3-C allele creates six unique TFBS for the ELF5, ELK1, Mycn, SPIB, SPI1 and TFAP2A TFs whose function are described in the Supplement.…”

“…The AKT3 single nucleotide polymorphism (SNP, rs4590656) from intron one was recently found to be significantly associated with three physiological parameters (hemoglobin, hematocrit and red blood cell count) in chronic mountain sickness patients indicating the strong association of this gene with angiogenesis [4]. Other intron one AKT3 SNPS (rs10157763, rs10927067 and rs2125230) have been significantly associated with aggressive prostate cancer (PCA) [5] in addition to the SNPs (rs4132509, rs-12031994, rs2345994) which have been recently found to be significantly associated with renal cell carcinoma risk (RCC) [6]. This suggests that intron one maybe a regulatory region for the AKT3 gene.…”

Regulatory SNPs and transcriptional factor binding sites in ADRBK1, AKT3, ATF3, DIO2, TBXA2R and VEGFA

“…16 Other AKT3 rSNPs in intron 1 (rs10157763, rs10927067, and rs2125230) have been significantly associated with aggressive prostate cancer (PCa). 47 These rSNPs also alter the TFBS for TFs that regulate the AKT3 gene, 16 where the rs2125230 rSNP minor AKT3-A allele (0.26) creates a unique TFBS for the IRF1 TF. 16 The IRF1 (interferon regulatory factor 1) TF is a member of the interferon regulatory transcription factor (IRF) family.…”

Toward the automated analysis of complex diseases in genome-wide association studies using genetic programming

“…Men were included in the current analysis if they had a baseline PSA measurement before October 1, 2003, completed a baseline questionnaire, returned at least one Annual Study Update (ASU), and had available SNP profile data through the CGEMS data portal 1 . Prior to this study, the CGEMS dataset was filtered to the 219 SNPs associated with biological pathways relevant to aggressive prostate cancer [20]. We call this dataset the "CGEMS Prostate Cancer GWAS dataset.…”