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Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology

Abstract

Regular use of aspirin reduces incidence and mortality of various cancers, including colorectal cancer. Anticancer effect of aspirin represents one of the ‘Provocative Questions’ in cancer research. Experimental and clinical studies support a carcinogenic role for PTGS2 (cyclooxygenase-2), which is an important enzymatic mediator of inflammation, and a target of aspirin. Recent ‘molecular pathological epidemiology’ (MPE) research has shown that aspirin use is associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic PIK3CA mutation as a molecular biomarker that predicts response to aspirin therapy. The PI3K (phosphatidylinositol-4,5-bisphosphonate 3-kinase) enzyme has a pivotal role in the PI3K-AKT signaling pathway. Activating PIK3CA oncogene mutations are observed in various malignancies including breast cancer, ovarian cancer, brain tumor, hepatocellular carcinoma, lung cancer and colon cancer. The prevalence of PIK3CA mutations increases continuously from rectal to cecal cancers, supporting the ‘colorectal continuum’ paradigm, and an important interplay of gut microbiota and host immune/inflammatory reaction. MPE represents an interdisciplinary integrative science, conceptually defined as ‘epidemiology of molecular heterogeneity of disease’. As exposome and interactome vary from person to person and influence disease process, each disease process is unique (the unique disease principle). Therefore, MPE concept and paradigm can extend to non-neoplastic diseases including diabetes mellitus, cardiovascular diseases, metabolic diseases, and so on. MPE research opportunities are currently limited by paucity of tumor molecular data in the existing large-scale population-based studies. However, genomic, epigenomic and molecular pathology testings (for example, analyses for microsatellite instability, MLH1 promoter CpG island methylation, and KRAS and BRAF mutations in colorectal tumors) are becoming routine clinical practices. In order for integrative molecular and population science to be routine practice, we must first reform education curricula by integrating both population and molecular biological sciences. As consequences, next-generation hybrid molecular biological and population scientists can advance science, moving closer to personalized precision medicine and health care.

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Acknowledgements

This work was supported by grants from the USA National Institute of Health (NIH) (R01 CA151993 (to SO), R01 CA137178 (to ATC), P50 CA127003 (to CSF), R01 CA124908 (to CSF), P01 CA87969 (to SEH) and UM1 CA167552 to WCW). ATC is a Damon Runyon Clinical Investigator.

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The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. Funding agencies did not have any role in the decision to submit the manuscript for publication, or the writing of the manuscript. This work was not funded by Bayer Healthcare, Millennium Pharmaceuticals or Pfizer Inc.

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ATC was a consultant of Bayer Healthcare, Millennium Pharmaceuticals and Pfizer Inc. The remaining authors declare no conflict of interest.

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Ogino, S., Lochhead, P., Giovannucci, E. et al. Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology. Oncogene 33, 2949–2955 (2014). https://doi.org/10.1038/onc.2013.244

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