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, 60 (3), 397-411

Molecular Pathological Epidemiology of Colorectal Neoplasia: An Emerging Transdisciplinary and Interdisciplinary Field


Molecular Pathological Epidemiology of Colorectal Neoplasia: An Emerging Transdisciplinary and Interdisciplinary Field

Shuji Ogino et al. Gut.


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.

Conflict of interest statement

Competing interest: None to declare.


Figure 1
Figure 1
Illustration of traditional epidemiology (A), traditional molecular pathology (B), and molecular pathologic epidemiology (C). Note that molecular pathology plays a central role in molecular pathologic epidemiology. Molecular pathologic epidemiology addresses a question whether a particular exposure factor is associated with a specific molecular change in colorectal cancer (C, left side), as well as a question whether a specific molecular change can interact with a particular exposure factor to affect tumor cell behavior (C, right side). The latter represents a new direction of molecular pathologic epidemiology where results can provide additional insights on mechanism of how the tumoral molecular change and the exposure factor of interest influence tumor cell behavior. CRC, colorectal cancer.
Figure 2
Figure 2
Comparison of a case-case study design (A), a case-control study design (B) and a prospective cohort study design (C). Smoking status is used as an example of an exposure variable, and KRAS mutation status in colorectal cancer as an outcome variable. See detailed explanations in text. CRC, colorectal cancer.

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