Research Theme
Our research has two intersecting scientific themes. One is scientific disciplinarity and the other is a focus on specific diseases (colorectal carcinoma, colorectal polyp, colorectal adenoma, pancreatic adenocarcinoma, neuroendocrine tumor, pancreatic endocrine tumor, carcinoid tumor). Other diseases are studied on collaborative basis (esophageal carcinoma, gastro-esophageal GE junction carcinoma, Barrett’s esophagus) or on theoretical basis [non-neoplastic diseases such as obesity, inflammatory bowel diseases (IBD), ulcerative colitis, Crohn’s disease, etc]. We also deal with some diseases as exposure variables (eg., obesity, type 2 diabetes mellitus, IBD, and other immune-related diseases). Our research is interdisciplinary, transdisciplinary and multidisciplinary in nature. We are developing several emerging fields of biomedical and population health sciences, generating novel concepts, paradigms and research frameworks. Please contact me (sogino[at]bwh.harvard.edu) if you are interested in collaborating with me in following emerging disciplines.
EMERGING SCIENTIFIC DISCIPLINES:
Many of these are core themes of my NCI R35 (Outstanding Investigator Award) project.
Molecular Pathological Epidemiology (MPE) (first described in S Ogino and M Stampfer. J Natl Cancer Inst 2010). We collaborate with Dr. Edward Giovannucci (https://www.hsph.harvard.edu/edward-giovannucci/), Dr. Charles Fuchs (http://doctors.dana-farber.org/directory/profile.asp?pict_id=0000279&gs=r), Dr. Andrew T Chan (http://www.massgeneral.org/gastroenterology/doctors/doctor.aspx?ID=17158), and many other colleagues. Please see further below for more detail.
Immuno-MPE (Immuno-epidemiology, immunoepidemiology, immuno-prevention, immunoprevention) is an integrative field of immunology and MPE for prevention and treatment of many diseases. Innate and adaptive immunity plays major roles in human health and diseases including cancer. The journal Science selected cancer immunotherapy as “the Breakthrough of the Year for 2013″. Utilizing anti-tumor immunity is a promising strategy with definite advantages; our immune system can adapt enemies – tumor cells which are molecularly heterogeneous even intra-personally. While immunotherapy is under intense investigation, strategies to prevent cancer through immune modulators (“immuno-prevention”) are also promising. Diet and lifestyle can be routine immunoprevention strategy, since evidence indicates that modifiable factors such as vitamin D, ω-3 polyunsaturated fatty acid (PUFA) intake, physical activity, and aspirin use can influence not only cancer risk but also host immunity. Thus, we need to consider environmental exposures, tumor molecular features and host immunity in cancer. We plan to investigate many different immune cell types including helper T cell, memory T cell, regulatory T cell, cytotoxic T cell, suppressor T cell, B cell, plasma cell, natural killer cell (NK cell), other lymphocytes, myeloid derived suppressor cell (MDSC), neutrophil, eosinophil, basophil, macrophage, histiocyte, dendritic cell, etc. We utilize our MPE analytical strategy to investigate the combined role of exposures and immunity in colorectal carcinogenesis and cancer progression.
The integrative GWAS-MPE approach (S Ogino et al. Gut 2011) aims to examine roles of putative germline genetic risk variants in pathogenesis of specific tumor subtypes. We collaborate with Dr. Andrew T Chan (http://www.massgeneral.org/gastroenterology/doctors/doctor.aspx?ID=17158), Dr. Ulrike Peters (http://depts.washington.edu/epidem/fac/facBio.shtml?Peters_Ulrike) and other colleagues in this area. This is a fundamental theme in the current 5-year cycle of GECCO (Genetics and Epidemiology of Colorectal Cancer Concortium) U01 grant entitled “Molecular Pathological Epidemiology of Colorectal Cancer” (PI, Dr. Ulrike Peters). We have been active in this area (E.g., X Garcia-Albeniz et al. Carcinogenesis 2013; H Nan et al. JNCI 2013) and a number of studies are ongoing in GECCO.
Pharmaco-MPE is integration of pharmacoepidemiology and MPE. We collaborate with Dr. Charles Fuchs (http://doctors.dana-farber.org/directory/profile.asp?pict_id=0000279&gs=r), Dr. Andrew T Chan (http://www.massgeneral.org/gastroenterology/doctors/doctor.aspx?ID=17158), Dr. Edward Giovannucci (https://www.hsph.harvard.edu/edward-giovannucci/) and other colleagues. We have made seminal discoveries of unanticipated effects of common medications on specific pathogenic mechanisms, which has opened new opportunities of disease prevention. E.g., we have published novel epidemiologic evidence for effects of aspirin on specific tumor evolution pathways (AT Chan et al. NEJM 2007; AT Chan et al. JAMA 2009; X Liao et al. NEJM 2012; R Nishihara et al. JAMA 2013; H Nan et al. JNCI 2013; S Fink et al. Sci Transl Med 2014). We have also published MPE research on use of statin (HMA-CoA reductase inhibitor to lower blood cholesterol level) and CRC risk and survival according to tumor molecular subtypes (K Ng et al. JNCI 2011; JE Lee et al. Cancer Prev Res 2011).
Integrative MPE – network analysis (network medicine) is a widely open area. Dr. Reiko Nishihara has been leading this area in collaboration with Dr. Jukka-Pekka Onnela. https://www.hsph.harvard.edu/onnela-lab/
This is one of big themes in Dr. Nishihara’s NCI K07 Grant project.
Integrative Lifecourse Epidemiology – MPE (Lifecourse-MPE) (first described in A Nishi et al. Am J Prev Med 2015)
Integrative Social Epidemiology – MPE (Social-MPE) is another forefront of epidemiology (A Nishi et al. Expert Rev Mol Diagn online http://www.tandfonline.com/doi/full/10.1586/14737159.2016.1115346). We aim to address health disparities by means of this integrated science. We collaborate with Dr. Ichiro Kawachi (https://www.hsph.harvard.edu/ichiro-kawachi/) in this area.
Integrative Causal Inference – MPE. We collaborate with Dr. Tyler VanderWeele (https://www.hsph.harvard.edu/tyler-vanderweele/) in this integrative area. Causal inference and MPE share a common goal of elucidating causality in the association between exposure and disease, and can synergize by virtue of complementary strengths of each field. Recently, we used the MPE approach to solve some of the paradoxical findings in the literature (R Nishihara, et al. Eur J Epidemiol, online http://link.springer.com/article/10.1007/s10654-015-0088-4). Mendelian randomization (MR) has been used in causal inference, and utilizes a genetic marker as an instrumental variable. A genetic marker such as SNP may have effects on expression and/or function of the gene or neighboring genes. Analysis of possible downstream consequences of the genetic variant may shed lights on pathogenic role of the variant. Practically, molecular pathologic features of disease can be examined and fully integrated into MR design or any other causal inference models.
Integrative MPE – Health Communication Research (HCR). We collaborate with Dr. Andy Tan (https://www.hsph.harvard.edu/andy-tan/) in this area. The social-MPE integration can link social and behavioral factors to molecular signatures of cancer. However, it remains to be a challenge to actually change behavior of each individual based on evidence. The field of health communication is the study and practice of communicating health information (such as in public health campaigns, health education, and daily medical practice), and has recently been growing. The purpose of disseminating health information is to influence personal health choices by improving health literacy. Because effective health communication must be tailored for the audience and the situation, health communication research seeks to refine communication strategies to inform people about ways to enhance health and to avoid health risks. MPE research has strengths of linking behavioral factors to molecular signatures of disease, and can work synergistically with health communication research to implement behavioral intervention tailored to individuals based on disease susceptibilities.
Integrative MPE – Comparative Effectiveness Research (CER). The purpose of CER is to improve health care at both the individual and population levels by assisting in informed decision making. As MPE indicates, each individual has unique susceptibilities to various diseases, and each patient has unique features of disease. Essentially, a population consists of uniquely different individuals. Hence, CER must assess impacts of this fundamental unique nature of individual and disease. In MPE, molecular signatures of disease are used to subgroup patients based on similarities. However, biological similarities which justify disease molecular subtyping may not be directly translated into similarities of effectiveness of intervention. Hence, CER is needed when MPE research findings are utilized to maximize both efficacy and effectiveness in clinical medicine and public health.
Rationale, strengths and challenges of MPE
The relationship between exposures and molecular changes in tumors has been examined for decades (eg, smoking -> KRAS mutation), usually under the umbrella of “molecular epidemiology”. However, this type of analysis needs a consideration of disease heterogeneity (eg, 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 exposure associations.
Considering this paradigm shift, “Molecular Pathological Epidemiology (MPE)” (or Molecular Pathologic Epidemiology) has been coined for integrative (interdisciplinary and transdisciplinary) science (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). MPE is conceptually defined as “epidemiology of molecular pathology and heterogeneity of disease” (Ogino et al. Oncogene 2014). MPE encompasses ALL HUMAN DISEASES (Ogino et al. Mod Pathol 2013), and MPE research can be done in any epidemiology cohorts. MPE of non-neoplastic diseases (such as obesity) is a possible future research area (Field et al. JAMA 2013). I have been advancing the MPE field as the first “Molecular Pathological Epidemiologist (MPE-ist)” (Ogino et al. Am J Epidemiol 2012). The power and promise of MPE has been well attested by our recent studies (eg, Morikawa et al. JAMA 2011; Liao et al. N Engl J Med 2012; Nishihara et al. JAMA 2013; Nishihara et al. N Engl J Med 2013, etc.). As I am a unique faculty in pathology (Harvard Medical School) and epidemiology (Harvard T.H. Chan School of Public Health), my long-term goal is to transform pathology and epidemiology into an integrative science for both education and research.
In MPE, we try to dissect complex interrelationship between; (1) environmental, dietary, lifestyle and genetic factors; (2) alterations in the tumor microenvironment and cellular molecules; 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. Expert Rev Mol Diagn 2012) and more broadly, 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; Garcia-Albeniz et al.Carcinogenesis 2013; Nan et al. J Natl Cancer Inst in press). 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, host factors (diet, immunity, inflammation, etc.), and carcinogenesis. This novel “Colorectal Continuum Paradigm” has a considerable impact on gastrointestinal research and clinical practice. The “Etiologic Field Effect” (EFE) concept (Lochhead et al. Mod Pathol 2014) is an expansion of the conventional “field effect” paradigm, considering contribution of the exposome from environment as well as the interactome in the tumor microenvironment. EFE is applicable to all steps of cancer evolution, while the traditional notion of fied effect only considers early phases of neoplasia.
The MPE paradigm has been in widespread use; e.g., Curtin et al. Pathol Res Int 2011; Hughes et al. PLoS ONE 2011; R Jacobs et al. Curr Opin Pharmacol 2012; Hughes et al. Int J Epidemiol 2012; Ku et al. Mod Pathol 2012; Rex et al. Am J Gastroenterol 2012; Koshiol et al. Ann Epidemiol 2012; Chia et al. Nat Rev Clin Oncol 2012; Spitz et al. Cancer Discovery 2012; Galon et al. J Tranl Med 2012; Rosty et al. Mod Pathol 2013; Lam et al. Cancer Epidemiol Biomarkers Prev 2013; Weijenberg et al. Curr Nutr Rep 2013; Buchanan et al. Cancer Epidemiol Biomarkers Prev 2013; Burnett-Hartman et al. Cancer Res 2013; Alvarez et al. World J Gastroenterol 2013; Hagland et al. Dig Surg 2013; Zaidi et al. Prog Lipid Res 2013; Hughes et al. Cancer Res 2013; Abbenhardt et al. Int J Mol Epidemiol Genet 2013; J Bae et al. Brit J Cancer 2013; Amirian et al. Infectious Agents and Cancer 2013; Ikramuddin and Livingston. JAMA 2013; Hoffmeister et al. Cancer Epidemiol Biomarkers Prev 2013; RF Araujo et al. Pathol Res Pract 2013; MM Esterhuyse et al. Expert Rev Mol Diagn 2013; Y Zhu et al. Brit J Cancer 2014; NJ Shaheen Am J Gastroenterol 2014; HR Hagland, et al. Cancer Lett 2014; J Brandstedt et al. BMC Cancer 2014; F Coppedè. Expert Rev Gastroenterol Hepatol 2014; F Bishehsari et al. World J Gastroenterol 2014; AJ Cross et al. Cancer 2014; BM Ryan et al. Cancer Epidemiol 2014; NL Bragazzi. Omics Group eBooks 2014; T Mikeska et al. Genes 2014; P Li, H Wu, et al. Gut 2014 (published online).
MPE has been a topic in international meetings such as those of American Association for Cancer Research (AACR) (S Ogino. Cancer Prev Res 2013), Society for Epidemiology Research (SER) (L Kuller et al. Am J Epidemiol 2013), and American Society of Preventive Oncology (ASPO) (M Epplein et al. Cancer Epidemiol Biomarkers Prev 2014).
We have been utilizing comprehensive MPE databases of two 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 2013); Interaction between aspirin use and PIK3CAmutation in colorectal cancer (Liao et al. N Engl J Med 2012, which is replicated by Domingo et al. J Clin Oncol 2013); interactions between aspirin use and PTGS2 (cyclooxygenase-2, COX-2) expression in colorectal cancer (Chan et al. N Engl J Med 2007; Chan et al. JAMA 2009); aspirin use and BRAFmutation in colorectal cancer (Nishihara et al. JAMA 2013); endoscopy screening and post-colonoscopy colorectal cancer with CIMP and microsatellite instability MSI (Nishihara et al. N Engl J Med 2013); 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; Morikawa et al. Cancer Res 2013); 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 and treatment strategies.
To transform pathology and epidemiology by the integrative MPE field and concept, I recently launched three programs. (1) The MPE Working Group (MPE WG) aims to establish standardized methodologies in MPE research. The MPE WG currently consists of researchers in the MPE areas, including biostatistics experts such as Drs. Donna Spiegelman, Molin Wang and Bernard Rosner. (2) International MPE Meeting (Molecular Pathological Epidemiology Meeting) Series aims to gather selected experts and discuss ways to advance this transdisciplinary science. Both of the first meeting in Boston on April 24, 2013 (my birthday) and the second meeting in Boston on December 4-5, 2014, went very successfully (see the top of this webpage). We are now planning the Third International MPE Meeting in Boston on May 12 and 13, 2016.
(3) The “STROBE-MPE” initiative (Ogino et al. Am J Epidemiol2012) is an extension of STROBE, which 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. In addition, (4) I am a member of Education and Professional Development Committee (chaired by Dr. Jay Kaufman) of Society for Epidemiologic Research (SER) to address paucity of interdisciplinary education opportunities. MPE was one of highlights in the SER Meeting in 2013 (Kuller et al. Am J Epidemiol 2013; AJE Symposium Proceeding).
Eventually, in vivo pathology, in vivo molecular pathology, in vivo imaging, and molecular imaging will advance both pathology and radiology into a single unified field of pathology / diagnostic medicine. This new field will further transform epidemiology, medicine and public health (S Ogino et al. Mod Pathol 2013; S Ogino et al. Oncogene 2014).
Another 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 in colorectal cancer is associated with shorter survival (Ogino et al. J Natl Cancer Inst 2008), family history of colorectal cancer (Ogino et al. J Natl Cancer Inst 2013) and young age of onset (Baba et al. Mol Cancer 2010); and that it is preventable by high folate (leafy vegetables) and low/no alcohol intakes (Schernhammer et al. Gut 2010). I have been characterizing the CpG island methylator phenotype (CIMP), a unique molecular phenotype in colorectal cancer. My investigation led to the discovery of “CIMP-low (CIMP-L)” associated with KRAS mutation (Ogino et al. J Mol Diagn 2006), which has been 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 epigenetic and genetic correlation structure analysis (Tanaka et al. Am J Pathol 2010). We have been deciphering prognostic roles of CIMP, MSI, KRAS, BRAF and PIK3CA mutations, and immune reactions in colorectal cancer (Ogino et al. J Clin Oncol 2009; Ogino et al. Gut 2009; Ogino et al. Clin Cancer Res 2009; Nosho et al. J Pathol 2010; Ogino et al. Clin Cancer Res 2012; Liao et al. Clin Cancer Res 2012; Imamura et al. Clin Cancer Res 2012; Lochhead et al. J Natl Cancer Inst 2013; Ogino et al. J Natl Cancer Inst 2013).
Disease areas: We focus on colorectal cancer and precursors (colon carcinoma, rectal carcinoma, adenocarcinoma, colon cancer, rectal cancer, anal cancer, aberrant crypt foci, hyperplastic polyp, sessile serrated adenoma, sessile serrated polyp, traditional serrated adenoma, tubular adenoma, tubulovillous adenoma, villous adenoma, high-grade dysplasia, intramucosal carcinoma, hamartoma, hamartomatous polyp, neoplasm, neoplasia, mixed polyp, etc.). I am Advisor of Lower GI Panel of American Joint Commission on Cancer (AJCC) which makes colon and rectal cancer staging system. We also investigate pancreatic cancer, neuro-endocrine tumor, carcinoid tumour, gastric carcinoma, gastroesophageal (GE) junction carcinoma, and other upper GI cancers in our collaborations. In theoretical projects, we also deal with other cancers including leukemia, lymphoma, Hodgkin lymphoma, myeloma, myelodysplastic syndrome, sarcoma, melanoma, brain tumor, glioma, glioblastoma, astrocytoma, lung cancer, breast cancer, prostate cancer, liver cancer, hepatocellular carcinoma, gallbladder cancer, head and neck cancer, ovarian cancer, endometrial cancer, uterine cervical cancer, renal cell carcinoma, other kidney cancer, bladder cancer, and non-neoplastic diseases, including obesity, cardiovascular diseases, autoimmune diseases, inflammatory diseases, inflammatory bowel diseases, ulcerative colitis, Crohn’s disease, infectious diseases, neurological diseases, psychiatric diseases, ie, all kinds of human diseases and health conditions. MPE can address disease and pathogenic heterogeneity across all illnesses.