Gene-gene interactions in gastrointestinal cancer susceptibility

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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-beta 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.
Publisher
IMPACT JOURNALS LLC
Issue Date
2016-10
Language
English
Article Type
Review
Keywords

GENOME-WIDE ASSOCIATION; SINGLE NUCLEOTIDE POLYMORPHISM; SQUAMOUS-CELL CARCINOMA; S-TRANSFERASE GENOTYPES; BETA SIGNALING PATHWAY; LYMPH-NODE METASTASIS; GASTRIC-CARDIA-CANCER; BASE EXCISION-REPAIR; DNA-DAMAGE REPAIR; COLORECTAL-CANCER

Citation

ONCOTARGET, v.7, no.41, pp.67612 - 67625

ISSN
1949-2553
DOI
10.18632/oncotarget.11701
URI
http://hdl.handle.net/10203/214843
Appears in Collection
BS-Journal Papers(저널논문)
Files in This Item
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