Molecular pathological epidemiology gives clues to paradoxical findings
- 633 Downloads
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.
KeywordsBias Cardiovascular disease Molecular diagnostics Multifactorial diseases Personalized medicine
CpG island methylator phenotype
Molecular pathological epidemiology
Renal cell carcinoma
Single nucleotide polymorphism
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.
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflicts of interest.
- 16.Ogino S, Nishihara R, VanderWeele TJ, et al. Molecular pathological epidemiology is essential in studying neoplastic and non-neoplastic diseases in the era of precision medicine. Epidemiology. (in press).Google Scholar
- 26.Bishehsari F, Mahdavinia M, Vacca M, Malekzadeh R, Mariani-Costantini R. Epidemiological transition of colorectal cancer in developing countries: environmental factors, molecular pathways, and opportunities for prevention. World J Gastroenterol. 2014;20(20):6055–72.PubMedCentralCrossRefPubMedGoogle Scholar
- 27.Brandstedt J, Wangefjord S, Nodin B, Eberhard J, Jirstrom K, Manjer J. Associations of hormone replacement therapy and oral contraceptives with risk of colorectal cancer defined by clinicopathological factors, beta-catenin alterations, expression of cyclin D1, p53, and microsatellite-instability. BMC Cancer. 2014;14:371.PubMedCentralCrossRefPubMedGoogle Scholar
- 37.Simons CC, van den Brandt PA, Stehouwer CD, van Engeland M, Weijenberg MP. Body size, physical activity, early-life energy restriction, and associations with methylated insulin-like growth factor-binding protein genes in colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2014;23(9):1852–62.CrossRefPubMedGoogle Scholar
- 48.Epplein M, Bostick RM, Mu L, Ogino S, Braithwaite D, Kanetsky PA. Challenges and opportunities in international molecular cancer prevention research: An ASPO Molecular Epidemiology and the Environment and International Cancer Prevention Interest Groups Report. Cancer Epidemiol Biomarkers Prev. 2014;23(11):2613–7.PubMedCentralCrossRefPubMedGoogle Scholar
- 49.Ogino S. Molecular pathological epidemiology (MPE): overview of its paradigm and wide applicability even without tumor tissue [abstract]. In: Proceedings of the twelfth annual AACR international conference on frontiers in cancer prevention research; 2013 Oct 27–30. National Harbor, MD: Cancer Prev Res (Phila); 2013;6:CN06-01.Google Scholar
- 77.Febbo PG, Ladanyi M, Aldape KD, et al. NCCN Task Force report: evaluating the clinical utility of tumor markers in oncology. J Natl Compr Cancer Netw. 2011;9(Suppl 5):S1–32 (quiz S3).Google Scholar
- 82.VanderWeele TJ, Knol MJ. Interactions and complexity: goals and limitations. Epidemiol Method. 2014;3(1):79–81.Google Scholar
- 83.Song M, Nishihara R, Wang M, et al. Plasma 25-hydroxyvitamin D and colorectal cancer risk according to tumour immunity status. Gut. 2015. doi: 10.1136/gutjnl-2014-308852.