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Synergistic Interaction of HOXB13 and CIP2A Predisposes to Aggressive Prostate Cancer.

ABSTRACT: PURPOSE:Distinguishing aggressive prostate cancer from indolent disease improves personalized treatment. Although only few genetic variants are known to predispose to aggressive prostate cancer, synergistic interactions of HOXB13 G84E high-risk prostate cancer susceptibility mutation with other genetic loci remain unknown. The purpose of this study was to examine the interplay of HOXB13 rs138213197 (G84E) and CIP2A rs2278911 (R229Q) germline variants on prostate cancer risk. EXPERIMENTAL DESIGN:Genotyping was done in Finnish discovery cohort (n = 2,738) and validated in Swedish (n = 3,132) and independent Finnish (n = 1,155) prostate cancer cohorts. Expression pattern analysis was followed by functional studies in prostate cancer cell models. RESULTS:Interplay of HOXB13 (G84E) and CIP2A (R229Q) variants results in highest observed inherited prostate cancer risk (OR, 21.1; P = 0.000024). In addition, this synergism indicates a significant association of HOXB13 T and CIP2A T dual carriers with elevated risk for high Gleason score (OR, 2.3; P = 0.025) and worse prostate cancer-specific life expectancy (HR, 3.9; P = 0.048), and it is linked with high PSA at diagnosis (OR, 3.30; P = 0.028). Furthermore, combined high expression of HOXB13-CIP2A correlates with earlier biochemical recurrence. Finally, functional experiments showed that ectopic expression of variants stimulates prostate cancer cell growth and migration. In addition, we observed strong chromatin binding of HOXB13 at CIP2A locus and revealed that HOXB13 functionally promotes CIP2A transcription. The study is limited to retrospective Nordic cohorts. CONCLUSIONS:Simultaneous presence of HOXB13 T and CIP2A T alleles confers for high prostate cancer risk and aggressiveness of disease, earlier biochemical relapse, and lower disease-specific life expectancy. HOXB13 protein binds to CIP2A gene and functionally promotes CIP2A transcription.

SUBMITTER: Sipeky C

PROVIDER: S-EPMC6719560 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Synergistic Interaction of HOXB13 and CIP2A Predisposes to Aggressive Prostate Cancer.

Sipeky Csilla C Gao Ping P Zhang Qin Q Wang Liang L Ettala Otto O Talala Kirsi M KM Tammela Teuvo L J TLJ Auvinen Anssi A Wiklund Fredrik F Wei Gong-Hong GH Schleutker Johanna J

Clinical cancer research : an official journal of the American Association for Cancer Research 20180904 24

<h4>Purpose</h4>Distinguishing aggressive prostate cancer from indolent disease improves personalized treatment. Although only few genetic variants are known to predispose to aggressive prostate cancer, synergistic interactions of HOXB13 G84E high-risk prostate cancer susceptibility mutation with other genetic loci remain unknown. The purpose of this study was to examine the interplay of HOXB13 rs138213197 (G84E) and CIP2A rs2278911 (R229Q) germline variants on prostate canc ...[more]

PMID: 30181389

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Project description:BackgroundMajority of prostate cancer (PCa) deaths are attributed to localized high-grade aggressive tumours which progress rapidly to metastatic disease. A critical unmet need in clinical management of PCa is discovery and characterization of the molecular drivers of aggressive tumours. The development and progression of aggressive PCa involve genetic and epigenetic alterations occurring in the germline, somatic (tumour), and epigenomes. To date, interactions between genes containing germline, somatic, and epigenetic mutations in aggressive PCa have not been characterized. The objective of this investigation was to elucidate the genomic-epigenomic interaction landscape in aggressive PCa to identify potential drivers aggressive PCa and the pathways they control. We hypothesized that aggressive PCa originates from a complex interplay between genomic (both germline and somatic mutations) and epigenomic alterations. We further hypothesized that these complex arrays of interacting genomic and epigenomic factors affect gene expression, molecular networks, and signaling pathways which in turn drive aggressive PCa.MethodsWe addressed these hypotheses by performing integrative data analysis combining information on germline mutations from genome-wide association studies with somatic and epigenetic mutations from The Cancer Genome Atlas using gene expression as the intermediate phenotype.ResultsThe investigation revealed signatures of genes containing germline, somatic, and epigenetic mutations associated with aggressive PCa. Aberrant DNA methylation had effect on gene expression. In addition, the investigation revealed molecular networks and signalling pathways enriched for germline, somatic, and epigenetic mutations including the STAT3, PTEN, PCa, ATM, AR, and P53 signalling pathways implicated in aggressive PCa.ConclusionsThe study demonstrated that integrative analysis combining diverse omics data is a powerful approach for the discovery of potential clinically actionable biomarkers, therapeutic targets, and elucidation of oncogenic interactions between genomic and epigenomic alterations in aggressive PCa.

Project description: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.

Dataset Information

Synergistic Interaction of HOXB13 and CIP2A Predisposes to Aggressive Prostate Cancer.

Publications

Synergistic Interaction of <i>HOXB13</i> and <i>CIP2A</i> Predisposes to Aggressive Prostate Cancer.

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