Molecular pathological epidemiology

Molecular pathological epidemiology (MPE, also molecular pathologic epidemiology) is a discipline combining epidemiology and pathology. It is defined as "epidemiology of molecular pathology and heterogeneity of disease".[1] Pathology and epidemiology share the same goal of elucidating etiology of disease, and MPE aims to achieve this goal at molecular, individual and population levels. Typically, MPE utilizes tissue pathology resources and data within existing epidemiology studies. Molecular epidemiology broadly encompasses MPE and conventional-type molecular epidemiology with the use of traditional disease designation systems.

Disease process

Data from The Cancer Genome Atlas projects indicate that disease evolution is an inherently heterogeneous process.[2][3] Each patient has a unique disease process (“the unique disease principle”), considering the uniqueness of the exposome and its unique influence on molecular pathologic process.[2] This concept has been adopted in clinical medicine along with precision medicine and personalized medicine.


In MPE, investigators dissect interrelationships between exposures (e.g., environmental, dietary, lifestyle and genetic factors); alterations in cellular or extracellular molecules (disease molecular signatures); and disease evolution and progression.[2] Investigators can analyze genome, methylome, epigenome, metabolome, transcriptome, proteome, microbiome, immunity and interactome. A putative risk factor can be linked to specific molecular signatures.

MPE research enables identification of a new biomarker for potential clinical utility, using large-scale population-based data (e.g., PIK3CA mutation in colorectal cancer to select patients for aspirin therapy).[1] The MPE approach can be used following a genome-wide association study (GWAS), termed "GWAS-MPE approach".[4] Detailed disease endpoint phenotyping can be conducted by means of molecular pathology or surrogate histopathology or immunohistochemistry analysis of diseased tissues and cells within GWAS.[5][6]

As an alternative approach, potential risk variants identified by GWAS can be examined in combination with molecular pathology analysis on diseased tissues.[7][8][9][10] This GWAS-MPE approach can give not only more precise effect estimates, even larger effects, for specific molecular subtypes of the disease, but also insights into pathogenesis by linking genetic variants to molecular pathologic signatures of disease.[4] Since molecular diagnostics is becoming routine clinical practice, molecular pathology data can aid epidemiologic research.


MPE started as analysis of risk factors (such as smoking) and molecular pathologic findings (such as KRAS oncogene mutation in lung cancer).

Studies to examine the relationship between an exposure and molecular pathologic signature of disease (particularly, cancer) became increasingly common throughout the 1990s and early 2000s.[11]

The use of molecular pathology in epidemiology posed lacked standardized methodologies and guidelines as well as interdisciplinary experts and training programs.[12] MPE research required a new conceptual framework and methodologies (epidemiological method) because MPE examines heterogeneity in an outcome variable.[13]

The term "molecular pathological epidemiology" was used by Shuji Ogino and Meir Stampfer in 2010.[14] Specific principles of MPE developed following 2010. The MPE paradigm is in widespread use globally,[15][16][17][18][19][20][21][22][23][24][25][26] and has been a subject in international conferences.[27][28][29] The International Molecular Pathological Epidemiology (MPE) Meeting Series has been open to research community around the world, its second and third meetings were held in Boston, in December 2014 and May 2016,[30][31] respectively.

See also


  1. Ogino S, Lochhead P, Giovannucci E, Meyerhardt JA, Fuchs CS, Chan AT (June 2014). "Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology". review. Oncogene. 33 (23): 2949–55. doi:10.1038/onc.2013.244. PMC 3818472. PMID 23792451.
  2. Ogino S, Lochhead P, Chan AT, Nishihara R, Cho E, Wolpin BM, et al. (April 2013). "Molecular pathological epidemiology of epigenetics: emerging integrative science to analyze environment, host, and disease". review. Modern Pathology. 26 (4): 465–84. doi:10.1038/modpathol.2012.214. PMC 3637979. PMID 23307060.
  3. Ogino S, Fuchs CS, Giovannucci E (2012). "How many molecular subtypes? Implications of the unique tumor principle in personalized medicine". review. Expert Review of Molecular Diagnostics. 12 (6): 621–8. doi:10.1586/erm.12.46. PMC 3492839. PMID 22845482.
  4. Ogino S, Chan AT, Fuchs CS, Giovannucci E (March 2011). "Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field". review. Gut. 60 (3): 397–411. doi:10.1136/gut.2010.217182. PMC 3040598. PMID 21036793.
  5. Shen H, Fridley BL, Song H, Lawrenson K, Cunningham JM, Ramus SJ, et al. (2013). "Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer". primary. Nature Communications. 4: 1628. doi:10.1038/ncomms2629. PMC 3848248. PMID 23535649.
  6. Garcia-Closas M, Couch FJ, Lindstrom S, Michailidou K, Schmidt MK, Brook MN, et al. (April 2013). "Genome-wide association studies identify four ER negative-specific breast cancer risk loci". primary. Nature Genetics. 45 (4): 392–8, 398e1–2. doi:10.1038/ng.2561. PMC 3771695. PMID 23535733.
  7. Gruber SB, Moreno V, Rozek LS, Rennerts HS, Lejbkowicz F, Bonner JD, et al. (July 2007). "Genetic variation in 8q24 associated with risk of colorectal cancer". primary. Cancer Biology & Therapy. 6 (7): 1143–7. doi:10.4161/cbt.6.7.4704. PMID 17630503.
  8. Slattery ML, Herrick J, Curtin K, Samowitz W, Wolff RK, Caan BJ, Duggan D, Potter JD, Peters U (February 2010). "Increased risk of colon cancer associated with a genetic polymorphism of SMAD7". primary. Cancer Research. 70 (4): 1479–85. doi:10.1158/0008-5472.CAN-08-1792. PMC 2925533. PMID 20124488.
  9. Garcia-Albeniz X, Nan H, Valeri L, Morikawa T, Kuchiba A, Phipps AI, et al. (February 2013). "Phenotypic and tumor molecular characterization of colorectal cancer in relation to a susceptibility SMAD7 variant associated with survival". primary. Carcinogenesis. 34 (2): 292–8. doi:10.1093/carcin/bgs335. PMC 3564438. PMID 23104301.
  10. Nan H, Morikawa T, Suuriniemi M, Imamura Y, Werner L, Kuchiba A, et al. (December 2013). "Aspirin use, 8q24 single nucleotide polymorphism rs6983267, and colorectal cancer according to CTNNB1 alterations". primary. Journal of the National Cancer Institute. 105 (24): 1852–61. doi:10.1093/jnci/djt331. PMC 3866156. PMID 24317174.
  11. Slattery ML (October 2002). "The science and art of molecular epidemiology". Journal of Epidemiology and Community Health (Comment). 56 (10): 728–9. doi:10.1136/jech.56.10.728. PMC 1732025. PMID 12239192.
  12. Sherman ME, Howatt W, Blows FM, Pharoah P, Hewitt SM, Garcia-Closas M (April 2010). "Molecular pathology in epidemiologic studies: a primer on key considerations". review. Cancer Epidemiology, Biomarkers & Prevention. 19 (4): 966–72. doi:10.1158/1055-9965.EPI-10-0056. PMC 2852464. PMID 20332257.
  13. Ogino S, Beck AH, King EE, Sherman ME, Milner DA, Giovannucci E (2012). "Ogino et Al. Respond to "the 21st century epidemiologist"". American Journal of Epidemiology. 176 (8): 672–4. doi:10.1093/aje/kws229. PMC 3571249. PMID 22935516.
  14. Ogino S, Stampfer M (March 2010). "Lifestyle factors and microsatellite instability in colorectal cancer: the evolving field of molecular pathological epidemiology". Journal of the National Cancer Institute (Comment). 102 (6): 365–7. doi:10.1093/jnci/djq031. PMC 2841039. PMID 20208016.
  15. Curtin K, Slattery ML, Samowitz WS (April 2011). "CpG island methylation in colorectal cancer: past, present and future". review. Pathology Research International. 2011: 902674. doi:10.4061/2011/902674. PMC 3090226. PMID 21559209.
  16. Galon J, Pagès F, Marincola FM, Angell HK, Thurin M, Lugli A, et al. (October 2012). "Cancer classification using the Immunoscore: a worldwide task force". review. Journal of Translational Medicine. 10: 205. doi:10.1186/1479-5876-10-205. PMC 3554496. PMID 23034130.
  17. Ku CS, Cooper DN, Wu M, Roukos DH, Pawitan Y, Soong R, Iacopetta B (August 2012). "Gene discovery in familial cancer syndromes by exome sequencing: prospects for the elucidation of familial colorectal cancer type X". review. Modern Pathology. 25 (8): 1055–68. doi:10.1038/modpathol.2012.62. PMID 22522846.
  18. Koshiol J, Lin SW (July 2012). "Can tissue-based immune markers be used for studying the natural history of cancer?". review. Annals of Epidemiology. 22 (7): 520–30. doi:10.1016/j.annepidem.2012.03.001. PMC 3596808. PMID 22481034.
  19. Fini L, Grizzi F, Laghi L (2012). "Adaptive and Innate Immunity, Non Clonal Players in Colorectal Cancer Progression". In Ettarh R (ed.). Colorectal Cancer Biology - From Genes to Tumor. review. InTech. pp. 323–40. doi:10.5772/28146. ISBN 978-953-51-0062-1.
  20. Dogan S, Shen R, Ang DC, Johnson ML, D'Angelo SP, Paik PK, et al. (November 2012). "Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers". primary. Clinical Cancer Research. 18 (22): 6169–77. doi:10.1158/1078-0432.CCR-11-3265. PMC 3500422. PMID 23014527.
  21. Spitz MR, Caporaso NE, Sellers TA (December 2012). "Integrative cancer epidemiology--the next generation". Cancer Discovery. 2 (12): 1087–90. doi:10.1158/2159-8290.CD-12-0424. PMC 3531829. PMID 23230187.
  22. Shanmuganathan R, Basheer NB, Amirthalingam L, Muthukumar H, Kaliaperumal R, Shanmugam K (January 2013). "Conventional and nanotechniques for DNA methylation profiling". review. The Journal of Molecular Diagnostics. 15 (1): 17–26. doi:10.1016/j.jmoldx.2012.06.007. PMID 23127612.
  23. Hughes LA, Melotte V, de Schrijver J, de Maat M, Smit VT, Bovée JV, et al. (October 2013). "The CpG island methylator phenotype: what's in a name?". review. Cancer Research. 73 (19): 5858–68. doi:10.1158/0008-5472.CAN-12-4306. PMID 23801749.
  24. Esterhuyse MM, Kaufmann SH (July 2013). "Diagnostic biomarkers are hidden in the infected host's epigenome". review. Expert Review of Molecular Diagnostics. 13 (6): 625–37. doi:10.1586/14737159.2013.811897. PMID 23895131.
  25. Hagland HR, Søreide K (January 2015). "Cellular metabolism in colorectal carcinogenesis: Influence of lifestyle, gut microbiome and metabolic pathways". review. Cancer Letters. 356 (2 Pt A): 273–80. doi:10.1016/j.canlet.2014.02.026. PMID 24614287.
  26. Bishehsari F, Mahdavinia M, Vacca M, Malekzadeh R, Mariani-Costantini R (May 2014). "Epidemiological transition of colorectal cancer in developing countries: environmental factors, molecular pathways, and opportunities for prevention". review. World Journal of Gastroenterology. 20 (20): 6055–72. doi:10.3748/wjg.v20.i20.6055. PMC 4033445. PMID 24876728.
  27. Kuller LH, Bracken MB, Ogino S, Prentice RL, Tracy RP (November 2013). "The role of epidemiology in the era of molecular epidemiology and genomics: Summary of the 2013 AJE-sponsored Society of Epidemiologic Research Symposium". American Journal of Epidemiology. 178 (9): 1350–4. doi:10.1093/aje/kwt239. PMC 3988450. PMID 24105654.
  28. Epplein M, Bostick RM, Mu L, Ogino S, Braithwaite D, Kanetsky PA (2014). "Challenges and opportunities in international molecular cancer prevention research: An ASPO Molecular Epidemiology and the Environment and International Cancer Prevention Interest Groups Report". Cancer Epidemiology, Biomarkers & Prevention. 23 (11): 2613–7. doi:10.1158/1055-9965.EPI-14-0848. PMC 4221505. PMID 25277796.
  29. Ogino S, Campbell PT, Nishihara R, Phipps AI, Beck AH, Sherman ME, et al. (2015). "Proceedings of the second international molecular pathological epidemiology (MPE) meeting". Cancer Causes & Control. 26 (7): 959–72. doi:10.1007/s10552-015-0596-2. PMC 4466011. PMID 25956270.
  30. "The Ogino MPE lab". Dana-Farber Cancer Institute.
  31. Campbell PT, Rebbeck TR, Nishihara R, Beck AH, Begg CB, Bogdanov AA, et al. (2017). "Proceedings of the third international molecular pathological epidemiology (MPE) meeting". review. Cancer Causes & Control. 28 (2): 167–176. doi:10.1007/s10552-016-0845-z. PMC 5303153. PMID 28097472.

Further reading

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