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Shuji Ogino, MD, PhD, MS
Associate Pathologist, Brigham and Women's Hospital
Professor of Pathology, Harvard Medical School

Brigham and Women's Hospital
Department of Pathology
75 Francis Street
Boston, MA 02115


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Research Narrative:
 
 
As the first Chief of Division of MPE Molecular Pathological Epidemiology, in the Department of Pathology, Brigham and Women's Hospital, I have been developing the integrative transdisciplinary field of MPE. 
   
The relationship between exposures and molecular changes in tumors has been examined for decades (eg, smoking -> KRAS mutation), under the umbrella of "molecular epidemiology". However, this type of analysis needs a consideration of disease heterogeneity (for a simple example, KRAS mutation present vs. absent), which necessitates a paradigm shift from conventional epidemiology. Conventional epidemiology is based on the premise that individuals with a given disease (by name) are homogeneous and can be lumped together to analyze the associations with exposures.
 
Considering this paradigm shift, “Molecular Pathological Epidemiology (MPE)” (or Molecular Pathologic Epidemiology) was established as a unique integrative transdisciplinary (interdisciplinary) science which can consider inherent disease heterogeneity in epidemiology research (Ogino et al. J Natl Cancer Inst 2010; Ogino et al. Gut 2011; Ogino et al. Nat Rev Clin Oncol 2011; Ogino et al. Int J Epidemiol 2012; Ogino et al. Am J Epidemiol 2012). I have been advancing the MPE field as the first “Molecular Pathological Epidemiologist (MPEist, MPE’ist, MPE-ist)” (Ogino et al. Am J Epidemiol 2012). The power and promise of MPE has been well attested by our recent studies (X Liao et al. N Engl J Med 2012; R Nishihara et al. N Engl J Med 2013). MPE encompasses ALL HUMAN DISEASES (just as pathology and epidemiology encompass the entire spectrum of human illnesses) (Ogino et al. Mod Pathol 2013).  As I am "the only one" unique Harvard faculty member with appointments in pathology (Harvard Medical School) and epidemiology (Harvard T.H. Chan School of Public Health, SPH), my long-term goal is to transform pathology and epidemiology into an integrative science for both education and research. I am also the only pathologist among the faculty members of Master of Science in Computational Biology and Quantitative Genetics at Harvard Chan SPH (directed by Dr. John Quanckenbush).  
 
In MPE, we try to dissect complex interrelationship between; (1) environmental, dietary, lifestyle and genetic factors; (2) alterations in the tumor microenvironment and cellular genetics and epigenetics; and (3) disease pathways and evolution. MPE encompasses all human diseases (most of which are complex multifactorial diseases), and takes into account genome, epigenome, methylome, transcriptome, proteome, metabolome, microbiome, metagenome, reactome, and interactome. MPE is based on the "Unique Tumor Principle" (Ogino et al. Int J Epidemiol 2012; Ogino et al. Expert Rev Mol Diagn 2012) and the “Unique Disease Principle” (Ogino et al. Mod Pathol 2013). MPE design can be used as the next step of genome-wide association study (GWAS) (“GWAS-MPE Approach”; Ogino et al. Gut 2011). Other new concepts related to MPE include "Colorectal Continuum Paradigm / Theory / Hypothesis" (Yamauchi, Morikawa, et al. Gut 2012; Yamauchi, Lochhead, et al. Gut 2012), which underscores the importance of interplay of gut microbiota, microbiome, host factors (diet, immunity, inflammation, etc.), and carcinogenesis. "The lifecourse-MPE model" is an integrative science of lifecourse epidemiology and MPE (A Nishi et al. Am J Prev Med 2015). "Immuno-MPE" is an integrative science of cancer immunology, molecular pathology and epidemiology, and the first study examined plasma vitamin D and risk of colorectal carcinoma according to level of lymphocytic or T-cell infiltrate in tumor (M Song et al. Gut 2015). The MPE paradigm has been accepted worldwide (e.g., Hughes et al. PLoS ONE 2011; Hughes et al. Int J Epidemiol 2012; Curtin et al. Pathol Res Int 2011; Kelley et al. J Natl Compr Canc Netw 2011; Campbell et al. J Clin Oncol 2012; Ku et al. Mod Pathol 2012; Kanthan et al. Pathol Res Int 2012; Rex et al. Am J Gastroenterol 2012; Koshiol et al. Ann Epidemiol 2012; Greystoke et al. Gastroenterol Res Practice 2012; Chia et al. Nat Rev Clin Oncol 2012; Beggs et al. J Pathol 2013).  
 
A similar concept has been named "etiologic heterogeneity" by Dr. Colin Begg (Int J Cancer 2011; Am J Epidemiol 2012). Dr. Margaret Spitz, et al. has named "integrative epidemiology" to describe integration of molecular and genomic analyses (exposures and tumors) into epidemiology (Cancer Discovery 2012). This "integrative epidemiology" encompasses MPE and conventional molecular epidemiology.
 
We have been utilizing comprehensive databases of two large U.S. nationwide prospective cohort studies, the Nurses’ Health Study (N=121,000 followed since 1976) and the Health Professionals Follow-up Study (N=51,500 followed since 1986), as well as CALGB trials (Alliance for Clinical Trials in Oncology).  Our discoveries by the MPE approach include (to mention just several); influence of the tumor microenvironment on tumor phenotype (Straussman et al. Nature 2012); YAP1 (yes-associated protein 1; or YAP) in colorectal cancer (Barry et al. Nature, published online); interactions between aspirin use and PTGS2 (cyclooxygenase-2, COX-2) expression in colorectal cancer (Chan et al. New Engl J Med 2007; Chan et al. JAMA 2009); interactions between obesity (host energetics) and FASN (fatty acid synthase) expression in colorectal cancer (Ogino et al. J Clin Oncol 2008; Kuchiba et al. J Natl Cancer Inst 2012); interactions between host energetics and CTNNB1 (b-catenin) activation in colorectal cancer (Morikawa et al. JAMA 2011); LINE-1 (long interspersed nucleotide element-1) hypomethylation and colon cancer aggression (Ogino et al. J Natl Cancer Inst 2008) and colorectal cancer family history (Ogino et al. J Natl Cancer Inst 2013); one-carbon nutrients, alcohol and colon cancer risk according to TP53 (p53) status and LINE-1 methylation level (Schernhammer et al. Gastroenterology 2008; Schernhammer et al. Gut 2010); fusobacterium (microbiota) in colorectal cancer (Kostic et al. Genome Res 2012); CDK8 in colorectal cancer (Firestein et al. Nature 2008; Firestein et al. Int J Cancer 2010); VTI1A-TCF7L2  fusion (translocation) in colorectal cancer (Bass et al. Nat Genet 2011).  In summary, a better understanding of heterogeneity of carcinogenic processes and influences of exogenous and endogenous factors will further contribute to personalized prevention as well as personalized treatment strategy.
 
To transform pathology and epidemiology by the integrative MPE field and concept, I launched three unique transformative programs. One is The International Molecular Pathological Epidemiology (MPE) Meeting Series (since 2013).  The Third International MPE Meeting (chaired by Shuji Ogino and Peter T Campbell) will be held in Boston on May 12 and 13, 2016 (http://ogino-mpe-lab.dana-farber.org/).  Second the “MPE Working Group (MPE WG)”, to establish standardized methodologies in MPE research. MPE WG currently consists of researchers in the MPE areas (including biostatistics experts such as Professor Donna Spiegelman and Professor Bernard Rosner), mainly based on Harvard T.H. Chan School of Public Health, Brigham and Women’s Hospital, and Dana-Farber Cancer Institute,. The third program is the “STROBE-MPE” initiative (Ogino et al. Am J Epidemiol 2012).  STROBE stands for “STrengthening of the Reporting of OBservational Epidemiology” (von Elm et al. PLoS Med 2007), and is an international guideline for epidemiology research.  I always call for collaboration in this STROBE-MPE international initiative.
 
The second focus of my research (which is very much related to MPE) is epigenetics and epigenomics of colorectal cancer. We have found that LINE-1 hypomethylation is highly correlated with mortality in colorectal cancer (Ogino et al. J Natl Cancer Inst 2008); that LINE-1 hypomethylated colorectal cancer is associated with family history of colorectal cancer (Ogino et al. J Natl Cancer Inst 2013); and that it is preventable by folate (leafy vegetables) and avoidance of excessive alcohol consumption (Schernhammer et al. Gut 2010).  I have been characterizing the CpG island methylator phenotype (CIMP), a unique molecular phenotype in colorectal cancer. Especially, my investigation led to the discovery of “CIMP-low (CIMP-L)”, a unique phenotype in colorectal cancer which is associated with KRAS mutation (Ogino et al. J Mol Diagn 2006), which was confirmed by other investigators including Peter Laird’s group (Hinoue et al. Genome Res 2012).  We were the first to apply "structural equation modeling (SEM)" to correlation structure analysis of CpG island methylation and genetic changes in colorectal cancer (Tanaka et al. Am J Pathol 2010); We have been deciphering prognostic roles of CIMP, MSI and KRAS, BRAF and PIK3CA mutations in colorectal cancer (Ogino et al. Gut 2009; Ogino et al. Clin Cancer Res 2009; Ogino et al. Clin Cancer Res 2012; Liao et al. Clin Cancer Res 2012; Imamura et al. Clin Cancer Res 2012).  Recently, we have found that frequencies of colorectal cancer genetic and epigenetic features (CIMP-high, MSI-high, and BRAF mutation) change gradually along subsites, which has led to the “Colorectal Continuum Concept / Paradigm / Theorem” (Yamauchi, Morikawa et al. Gut 2012; Yamauchi, Lochhead et al. Gut 2012) as mentioned above. This novel “Colorectal Continuum Paradigm” has a considerable impact on gastrointestinal research and clinical practice.

Education:
Harvard School of Public Health, 2010, MS (SM)
University of Tokyo, 2001, PhD
University of Tokyo, 1993, MD

Honors/Awards:
Ramzi Cotran Young Investigator Award 2011, United States and Canadian Academy of Pathology (USCAP)
Elected Member, American Society for Clinical Investigation
Executive Officer's Award 2004, Association for Molecular Pathology (AMP)
Meritorious Service Award 2012, Association for Molecular Pathology (AMP)
Most Influential Scientific Minds: 2014, selected by Thomson Reuters
Most Influential Scientific Minds: 2015, selected by Thomson Reuters
NCI R35 Outstanding Investigator Award (OIA) recipient (2015-2022)

Lab Members:

Yu Imamura, MD, PhD, Postdoctoral Research Fellow

Akihiro Nishi, MD, MPH, Research Fellow

Xiaoyun Liao, MD, PhD, Postdoctoral Research Fellow

Aya Kuchiba, PhD, Postdoctoral Research Fellow

Mai Yamauchi, PhD, Postdoctoral Research Fellow

Reiko Nishihara, PhD, Instructor

Kentaro Inamura, MD, PhD, Postdoctoral Research Fellow

Sun A Kim, MD, PhD, Postdoctoral Research Fellow

Zhi-Rong Qian, MD, PhD, Instructor

Seungyoun Jung, ScD, Research Fellow

Collaborators:
Charles S. Fuchs, MD, MPH, Dana-Farber Cancer Institute, null

Donna Spiegelman, ScD, Harvard School of Public Health, null

Giovanni Parmigiani, PhD, Dana-Farber Cancer Institute, null

Matthew H. Kulke, MD, MMSc, Dana-Farber Cancer Institute, null

Brian M. Wolpin, MD, MPH, Dana-Farber Cancer Institute, null

Walter C. Willett, MD, DrPH, Harvard School of Public Health, null

Edward Giovannucci, MD, MPH, ScD, Harvard School of Public Health, null

Jeffrey A. Meyerhardt, MD, MPH, Dana-Farber Cancer Institute, null

Andrew T. Chan, MD, MPH, Massachusetts General Hospital, null

Curtis Huttenhower, PhD, Harvard School of Public Health, null


Other Professional Activities:
Member, Excellence in Science Award Committee, FASEB (Federation of American Societies of Experimental Biology)
Chairperson, The International Molecular Pathological Epidemiology (MPE) Meeting Series
Leader, Molecular Pathological Epidemiology (MPE) Working Group
Member, NCI Study Section: Special Emphasis Panel for R35 Outstanding Investigator Award (OIA), 2016
Chief, Division of MPE Molecular Pathological Epidemiology of Brigham and Women's Hospital

Publications (Pulled from Harvard Catalyst Profiles):

1. Hamada T, Yuan C, Yurgelun MB, Perez K, Khalaf N, Morales-Oyarvide V, Babic A, Nowak JA, Rubinson DA, Giannakis M, Ng K, Kraft P, Stampfer MJ, Giovannucci EL, Fuchs CS, Ogino S, Wolpin BM. Family history of cancer, Ashkenazi Jewish ancestry, and pancreatic cancer risk. Br J Cancer. 2019 Mar 14.

2. Kosumi K, Hamada T, Zhang S, Liu L, da Silva A, Koh H, Twombly TS, Mima K, Morikawa T, Song M, Nowak JA, Nishihara R, Saltz LB, Niedzwiecki D, Ou FS, Zemla T, Mayer RJ, Baba H, Ng K, Giannakis M, Zhang X, Wu K, Giovannucci EL, Chan AT, Fuchs CS, Meyerhardt JA, Ogino S. Prognostic association of PTGS2 (COX-2) over-expression according to BRAF mutation status in colorectal cancer: Results from two prospective cohorts and CALGB 89803 (Alliance) trial. Eur J Cancer. 2019 Apr; 111:82-93.

3. Hamada T, Nowak JA, Milner DA, Song M, Ogino S. Integration of microbiology, molecular pathology, and epidemiology: a new paradigm to explore the pathogenesis of microbiome-driven neoplasms. J Pathol. 2019 Apr; 247(5):615-628.

4. Yang W, Liu L, Keum N, Qian ZR, Nowak JA, Hamada T, Song M, Cao Y, Nosho K, Smith-Warner SA, Zhang S, Masugi Y, Ng K, Kosumi K, Ma Y, Garrett WS, Wang M, Nan H, Giannakis M, Meyerhardt JA, Chan AT, Fuchs CS, Nishihara R, Wu K, Giovannucci EL, Ogino S, Zhang X. Calcium intake and risk of colorectal cancer according to tumor infiltrating T cells. Cancer Prev Res (Phila). 2019 Feb 13.

5. Morales-Oyarvide V, Yuan C, Babic A, Zhang S, Niedzwiecki D, Brand-Miller JC, Sampson-Kent L, Ye X, Li Y, Saltz LB, Mayer RJ, Mowat RB, Whittom R, Hantel A, Benson A, Atienza D, Messino M, Kindler H, Venook A, Ogino S, Wu K, Willett WC, Giovannucci EL, Wolpin BM, Meyerhardt JA, Fuchs CS, Ng K. Dietary Insulin Load and Cancer Recurrence and Survival in Patients With Stage III Colon Cancer: Findings From CALGB 89803 (Alliance). J Natl Cancer Inst. 2019 Feb 01; 111(2):170-179.

6. Song M, Wu K, Meyerhardt JA, Yilmaz O, Wang M, Ogino S, Fuchs CS, Giovannucci EL, Chan AT. Low-Carbohydrate Diet Score and Macronutrient Intake in Relation to Survival After Colorectal Cancer Diagnosis. JNCI Cancer Spectr. 2018 Nov; 2(4):pky077.

7. Nguyen LH, Liu PH, Zheng X, Keum N, Zong X, Li X, Wu K, Fuchs CS, Ogino S, Ng K, Willett WC, Chan AT, Giovannucci EL, Cao Y. Sedentary Behaviors, TV Viewing Time, and Risk of Young-Onset Colorectal Cancer. JNCI Cancer Spectr. 2018 Nov; 2(4):pky073.

8. Liu PH, Wu K, Ng K, Zauber AG, Nguyen LH, Song M, He X, Fuchs CS, Ogino S, Willett WC, Chan AT, Giovannucci EL, Cao Y. Association of Obesity With Risk of Early-Onset Colorectal Cancer Among Women. JAMA Oncol. 2019 Jan 01; 5(1):37-44.

9. Hamada T, Nowak JA, Masugi Y, Drew DA, Song M, Cao Y, Kosumi K, Mima K, Twombly TS, Liu L, Shi Y, da Silva A, Gu M, Li W, Nosho K, Keum N, Giannakis M, Meyerhardt JA, Wu K, Wang M, Chan AT, Giovannucci EL, Fuchs CS, Nishihara R, Zhang X, Ogino S. Smoking and Risk of Colorectal Cancer Sub-Classified by Tumor-Infiltrating T Cells. J Natl Cancer Inst. 2019 Jan 01; 111(1):42-51.

10. Wasserman I, Lee LH, Ogino S, Marco MR, Wu C, Chen X, Datta J, Sadot E, Szeglin B, Guillem JG, Paty PB, Weiser MR, Nash GM, Saltz L, Barlas A, Manova-Todorova K, Uppada SPB, Elghouayel AE, Ntiamoah P, Glickman JN, Hamada T, Kosumi K, Inamura K, Chan AT, Nishihara R, Cercek A, Ganesh K, Kemeny NE, Dhawan P, Yaeger R, Sawyers CL, Garcia-Aguilar J, Giannakis M, Shia J, Smith JJ. SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance. Clin Cancer Res. 2019 Mar 15; 25(6):1948-1956.