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Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field
  1. Shuji Ogino1,2,3,
  2. Andrew T Chan3,4,5,
  3. Charles S Fuchs2,3,5,
  4. Edward Giovannucci3,5,6
  1. 1Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  2. 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
  3. 3Cancer Epidemiology Program and Gastrointestinal Malignancies Program, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA
  4. 4Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
  5. 5Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  6. 6Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
  1. Correspondence to Dr Shuji Ogino, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 44 Binney St, Room JF-215C, Boston, MA 02115, USA; shuji_ogino{at}


Colorectal cancer is a complex disease resulting from somatic genetic and epigenetic alterations, including locus-specific CpG island methylation and global DNA or LINE-1 hypomethylation. Global molecular characteristics such as microsatellite instability (MSI), CpG island methylator phenotype (CIMP), global DNA hypomethylation, and chromosomal instability cause alterations of gene function on a genome-wide scale. Activation of oncogenes including KRAS, BRAF and PIK3CA affects intracellular signalling pathways and has been associated with CIMP and MSI. Traditional epidemiology research has investigated various factors in relation to an overall risk of colon and/or rectal cancer. However, colorectal cancers comprise a heterogeneous group of diseases with different sets of genetic and epigenetic alterations. To better understand how a particular exposure influences the carcinogenic and pathologic process, somatic molecular changes and tumour biomarkers have been studied in relation to the exposure of interest. Moreover, an investigation of interactive effects of tumour molecular changes and the exposures of interest on tumour behaviour (prognosis or clinical outcome) can lead to a better understanding of tumour molecular changes, which may be prognostic or predictive tissue biomarkers. These new research efforts represent ‘molecular pathologic epidemiology’, which is a multidisciplinary field of investigations of the inter-relationship between exogenous and endogenous (eg, genetic) factors, tumoural molecular signatures and tumour progression. Furthermore, integrating genome-wide association studies (GWAS) with molecular pathological investigation is a promising area (GWAS-MPE approach). Examining the relationship between susceptibility alleles identified by GWAS and specific molecular alterations can help elucidate the function of these alleles and provide insights into whether susceptibility alleles are truly causal. Although there are challenges, molecular pathological epidemiology has unique strengths, and can provide insights into the pathogenic process and help optimise personalised prevention and therapy. In this review, we overview this relatively new field of research and discuss measures to overcome challenges and move this field forward.

  • Colorectal carcinoma
  • multistep carcinogenesis
  • etiologic
  • risk factor
  • survival
  • molecular change
  • prevention
  • cancer epidemiology
  • cancer prevention
  • cancer susceptibility
  • carcinogenesis
  • colorectal neoplasia

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  • Funding This work was supported by U.S. National Institute of Health (P01 CA87969, to S.E. Hankinson; P01 CA55075, to W.C. Willett; P50 CA127003, to CSF; R01 CA137178, to ATC; K07 CA122826, to SO; and R01 CA151993, to SO).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.