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Review
. 2016 Oct 11;7(41):67612-67625.
doi: 10.18632/onco_target.11701.

Gene-gene interactions in gastrointestinal cancer susceptibility

Affiliations
Review

Gene-gene interactions in gastrointestinal cancer susceptibility

Jineun Kim et al. Onco_target. .

Abstract

Cancer arises from complex, multi-layer interactions between diverse genetic and environmental factors. Genetic studies have identified multiple loci associated with tumor susceptibility. However, little is known about how germline polymorphisms interact with one another and with somatic mutations within a tumor to mediate acquisition of cancer traits. Here, we survey recent studies showing gene-gene interactions, also known as epistases, affecting genetic susceptibility in colorectal, gastric and esophageal cancers. We also catalog epistasis types and cancer hallmarks with respect to the interacting genes. A total of 22 gene variation pairs displayed all levels of statistical epistasis, including synergistic, redundant, suppressive and co-suppressive interactions. Five genes primarily involved in base excision repair formed a linear topology in the interaction network, MUTYH-OGG1-XRCC1-PARP1-MMP2, and three genes in mTOR cell-proliferation pathway formed another linear network, PRKAG2-RPS6KB1-PIK3CA. Discrete pairwise epistasis was also found in nucleotide excision repair, detoxification, proliferation, TP53, TGF-β and other pathways. We propose that three modes of biological interaction underlie the molecular mechanisms for statistical epistasis. The direct binding, linear pathway and convergence modes can exhibit any level of statistical epistasis in susceptibility to gastrointestinal cancers, and this is likely true for other complex diseases as well. This review highlights the link between cancer hallmarks and susceptibility genes.

Keywords: colorectal cancer; epistasis; esophageal cancer; gastric cancer; gene-gene interaction.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Quantitative levels of statistical epistasis
Epistasis can be synergistic or antagonistic, if not null, and antagonistic epistasis can be redundant, suppressive or co-suppressive. OR represents the effect of each gene allele on disease susceptibility. ORcombined is OR observed for a combination of two gene alleles. ORinteraction is deviation of ORcombined from (OR1 × OR2). If ORcombined = (OR1 × OR2), or ORinteraction = 1, the interaction is ‘null,’ as the two individual gene allele effects are each additive to the other, with no interaction between them. Therefore, they act independently of each other. If ORcombined > (OR1×OR2), or ORinteraction > 1, the interaction is considered ‘synergistic,’ as the two individual alleles, when combined, act synergistically. Conversely, if ORcombined < (OR1×OR2), or ORinteraction < 1, two gene alleles have an ‘antagonistic’ effect. Antagonistic interactions can be further subcategorized into redundant, suppressive and co-suppressive interactions depending on the extent to which ORcombined departs from the two individual ORs, OR1 and OR2. If ORcombined ≥ OR1 ≥ OR2, the interaction is considered ‘redundant,’ as one gene allele effect is redundant with the other gene allele effect. If OR1 > ORcombined ≥ OR2, the interaction is considered ‘suppressive’ because one gene allele suppresses the other's effect. Lastly, if ORcombined ≤ OR2 < OR1, the interaction is ‘co-suppressive,’ as both gene alleles suppress each other.
Figure 2
Figure 2. Topology of epistasis networks
A. Five genes, primarily part of the base excision repair system, form a linear or lariat epistasis network. B. Three genes involved in mTOR signaling of cell proliferation form a linear epistasis network.
Figure 3
Figure 3. Three plausible modes of biological interaction between two statistically epistatic gene products
A. In the direct binding mode, two partners physically bind to each other and function together to affect disease susceptibility. B. In the linear pathway mode, two partners work sequentially. C. In the convergence mode, two partner-involving pathways converge to promote disease susceptibility.

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