Shuji Ogino, MD, PhD, MS (Epidemiology)

I established the novel interdisciplinary science, “Molecular Pathological Epidemiology (MPE)” (or Molecular Pathologic Epidemiology) (Ogino et al. J Natl Cancer Inst 2010; Ogino et al. Gut 2011; Ogino et al. Nat Rev Clin Oncol 2011), and have been advancing the MPE field as the first “Molecular Pathological Epidemiologist (MPEist, MPE’ist, MPE-ist)” (Ogino et al. Am J Epidemiol, in press). As I am a unique faculty member of both Harvard Medical School (Pathology) and Harvard School of Public Health (Epidemiology), my long-term goal is to transform pathology and epidemiology in an integrative way. Because of my pioneering effort in this new MPE area, in 2011, I received the prestigious “Ramzi Cotran Young Investigator Award” from United States and Canadian Academy of Pathology (USCAP).

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 of cancer is based on the "Unique Tumor Principle" (Ogino et al. Int J Epidemiol 2012; Ogino et al. Expert Rev Mol Diagn 2012). 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 MPE paradigm has been adopted worldwide (e.g., 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; Boyle et al. Am J Epidemiol 2011; Limsui et al. Gut 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).

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); 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 (?-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); 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); gut microbiota (fusobactrium) and colorectal cancer (Kostic et al. Genome Res 2012). 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 recently launched two programs. One is the “MPE Method Working Group (MMWG)”, to establish standardized methodologies in MPE research. MMWG currently consists of researchers in the MPE areas mainly based on Harvard School of Public Health, Brigham and Women’s Hospital, and Dana-Farber Cancer Institute. The second program is the “STROBE-MPE” initiative (Ogino et al. Am J Epidemiol, in press). 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), 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 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). This novel “Colorectal Continuum Paradigm” has a considerable impact on gastrointestinal research and clinical practice.