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Molecular pathological epidemiology gives clues to paradoxical findings

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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.

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Abbreviations

CIMP:

CpG island methylator phenotype

MPE:

Molecular pathological epidemiology

MSI:

Microsatellite instability

RCC:

Renal cell carcinoma

SNP:

Single nucleotide polymorphism

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Acknowledgments

This work was supported by U.S. National Institutes of Health (NIH) Grants [R01 CA151993 to S.O.; R35 CA197735 to S.O., and K07 CA190673 to R.N.]. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Correspondence to Reiko Nishihara or Shuji Ogino.

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Use of standardized official symbols: We use HUGO (Human Genome Organisation)-approved official symbols for genes and gene products, including BRAF, FASN, KRAS, MGMT, and SMAD7; all of which are described at www.genenames.org.

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Nishihara, R., VanderWeele, T.J., Shibuya, K. et al. Molecular pathological epidemiology gives clues to paradoxical findings. Eur J Epidemiol 30, 1129–1135 (2015). https://doi.org/10.1007/s10654-015-0088-4

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