From an Evolutionary Model to the Unified Paradigm of Cancer Causation (UPCC)

Three essential events launched the field of cancer epidemiology during the 18th century. First, is Bernardino Ramazzini’s study on cervical cancer in 1713, the research of Percival Pott in 1775 that led the way on occupational carcinogenic exposure studies, and Thomas Venner on the danger of tobacco use in his Via Recta, published in London in 1620 (American Cancer Society, 2014). After two centuries when John Hill wrote a book entitled “Cautions Against the Immoderate Use of Snuff” in 1761; Krain (1970), along with other studies in the 1970s, Wynder, Mabuchi, Maruchi and Fortner (1973) explored the causality of tobacco use in the development of PC. Jones et al. (2008) found that PCs have an average of 63 genetic alterations that can explain the major features of pancreatic tumorigenesis. The intensive genetic studies described by Jones et al. (2008) gave way to the better understanding of the core set of pathways and processes, embracing the idea of Owens, Coffey, and Baylin (1982) that tumor heterogeneity is a fundamental facet of all solid tumors. While pancreatic cancer (PC) has few viable treatment options, Jones et al. (2008) suggested that the best hope for therapeutic development may lie in the discovery of agents that target the physiologic effects of the altered pathways and processes rather than their gene components. Above all, the significance that could not have been appreciated in the absence of global analysis is the identification of the precise genetic alterations that may be responsible for tumor pathway dysregulation (Jones et al., 2008).

The pathogenic theory of medicine or the germ theory of disease was highly controversial when first proposed as a concept that microorganisms are the cause of many diseases. After validation in the 19th century, germ theory revolutionized both medical thought and the art of surgery, becoming a fundamental part of modern medicine and clinical microbiology. My metatheory, the “Unified Paradigm of Cancer Causation (UPCC)” is as a composite of germ theory and Darwinian evolutionary system (Greaves & Maley, 2012) along with other theories will provide clarity on the narrative of the initiation of PC. Albeit the acceptance of the somatic mutation theory of carcinogenesis (SMT) as the mainstream narrative of how neoplasms develop (Soto & Sonnenschein, 2004), SMT included in the UPCC’s cocktail of theories will build on the arguments of the core principle of genetic variation and pattern of mutations (environmental and genetics) that are sufficient probable causes of the disease. UPCC could explain the behavior of PC cell in rationalizing the complex array of the possible interaction of smoking and inherited genes.

Pancreatic cancer is the fourth most prevalent cause of cancer death in Western societies and is projected to be the second leading cause within a decade (Waddell et al., 2015). While using the Darwinian methods that link human sociocultural progress to genetic evolution (Richerson & Boyd, 2000); Lynch and Rebbeck (2013) used a “Multi-level Biologic and Social Integrative Construct” (MBASIC) to integrate macro environment and individual factors with biology. Considering the limitation and information generated by single-level studies have reached a saturation point (Lynch & Rebbeck, 2013), I highlighted the significance of individual level (behaviors, carcinogenic exposures); and biologic level (inherited susceptibility variants in my dissertation “Pathopoiesis Mechanism of Smoking and Shared Genes in Pancreatic Cancer.” Germline changes associated with PC could range from slightly increased risk (low penetrance genes) to high lifetime risk (high penetrance genes). Given that PC is the antecedent of inherited (germline), and acquired (somatic) mutations in cancer-causing genes, adding the probable correlation between gender and age, modifiable risk factors to the equation that could trigger or wake up a sleeping germline mutation could position the result of a study for improved public health intervention, translation, and implementation in clinical settings to alter the expression of the disease.

References

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Greaves, M., & Maley, C. C. (2012). Clonal evolution in cancer. Nature, 481(7381), 306-313. doi: 10.1038/nature10762

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Labilles, U. (2015b, September 27). A Promise to a Dying Brother [Web log post]. Retrieved from https://onenationsecho.com/2015/09/27/a-promised-to-a-dying-brother/.

Labilles, U. (2015c). Prospectus: Tobacco Use and Family Cancer History in the Pathopoiesis of Pancreatic Cancer. Unpublished manuscript, College of Health Sciences, Public Health, Epidemiology, Walden University, Minneapolis.

Labilles, U. (2016). The New Public Health: Beyond Genetics and Social Inequalities. Unpublished manuscript, College of Health Sciences, Public Health, Epidemiology, Walden University, Minneapolis.

Labilles, U. (2017). Pathopoiesis Mechanism of Smoking and Shared Genes in Pancreatic Cancer. ProQuest-CSA, LLC. Library of Congress, Copyright R# TX 8-490-984, Washington DC. doi: 10.13140/RG.2.2.30721.35681

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