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Open Access Research article

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

Nicole A Lavender1, Erica N Rogers1, Susan Yeyeodu2, James Rudd2, Ting Hu5, Jie Zhang4, Guy N Brock4, Kevin S Kimbro2, Jason H Moore3, David W Hein1 and La Creis R Kidd15*

Author Affiliations

1 Department of Pharmacology & Toxicology, School of Medicine, University of Louisville (UofL), Louisville, KY, USA

2 Department of Biology, The Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA

3 Departments of Genetics and Community and Family Medicine, Institute for Quantitative Biomedical Sciences, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH, USA

4 Department of Bioinformatics & Biostatistics, School of Public Health and Information Sciences, UofL, Louisville, KY, USA

5 505 South Hancock Street, Clinical & Translational Research Building, Room 306, Louisville, KY 40202, USA

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BMC Medical Genomics 2012, 5:11  doi:10.1186/1755-8794-5-11

Published: 30 April 2012

Abstract

Background

Molecular 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.

Methods

To 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.

Results

Following 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).

Conclusions

In 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.

Keywords:
Prostate cancer; Apoptosis; Single nucleotide polymorphisms; Gene-gene interactions; Multifactor dimensionality reduction (MDR); Statistical epistasis networks (SEN)