Molecular pathological epidemiology gives clues to paradoxical findings

Abstract

A number of epidemiologic studies have described what appear to be paradoxical associations, where an incongruous relationship is observed between a certain well-established risk factor for disease incidence and favorable clinical outcome among patients with that disease. For example, the "obesity paradox" represents the association between obesity and better survival among patients with a certain disease such as coronary heart disease. Paradoxical observations cause vexing clinical and public health problems as they raise questions on causal relationships and hinder the development of effective interventions. Compelling evidence indicates that pathogenic processes encompass molecular alterations within cells and the microenvironment, influenced by various exogenous and endogenous exposures, and that interpersonal heterogeneity in molecular pathology and pathophysiology exists among patients with any given disease. In this article, we introduce methods of the emerging integrative interdisciplinary field of molecular pathological epidemiology (MPE), which is founded on the unique disease principle and disease continuum theory. We analyze and decipher apparent paradoxical findings, utilizing the MPE approach and available literature data on tumor somatic genetic and epigenetic characteristics. Through our analyses in colorectal cancer, renal cell carcinoma, and glioblastoma (malignant brain tumor), we can readily explain paradoxical associations between disease risk factors and better prognosis among disease patients. The MPE paradigm and approach can be applied to not only neoplasms but also various non-neoplastic diseases where there exists indisputable ubiquitous heterogeneity of pathogenesis and molecular pathology. The MPE paradigm including consideration of disease heterogeneity plays an essential role in advancements of precision medicine and public health.

Keywords: Bias; Cardiovascular disease; Molecular diagnostics; Multifactorial diseases; Personalized medicine.

Fig. 1

The apparent paradoxical associations in colorectal cancer, renal cell carcinoma, and glioblastoma (malignant brain tumor), utilizing molecular pathological epidemiology (MPE) approach and literature data. a. Lynch syndrome is associated with incidence of colorectal cancer with high levels of microsatellite instability (MSI-high), and MSI-high cancer is associated with better prognosis among patients with colorectal cancer. Hence, the carrier status of Lynch syndrome mutation is associated with higher colorectal cancer risk, but with better prognosis among colorectal cancer patients. b. The major G allele of the rs4939827 SMAD7 polymorphism is associated with colorectal cancer with earlier stage, and earlier cancer stage is associated with better prognosis among patients with colorectal cancer. The major G allele of the rs4939827 SMAD7 polymorphism is associated with higher colorectal cancer risk, but with better prognosis among colorectal cancer patients. c. Obesity is associated with a subtype of renal cell carcinoma (RCC) characterized by low-stage, low-grade, and FASN non-upregulation, and all of these features are associated with better prognosis among RCC patients. Hence, obesity is associated with higher RCC risk, but with better prognosis among RCC patients. d. The minor T allele of the rs16906252 polymorphism in the MGMT promoter region is associated with loss of MGMT expression in glioblastoma, and loss of MGMT expression is associated with better prognosis among patients with glioblastoma. Hence, the minor T allele of rs16906252 polymorphism contributes to pathogenesis of glioblastoma, but is associated with better prognosis among glioblastoma patients. MSI, microsatellite instability.