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Colorectal cancer: a tale of two sides or a continuum?
  1. Mai Yamauchi1,
  2. Paul Lochhead1,
  3. Teppei Morikawa1,
  4. Curtis Huttenhower2,
  5. Andrew T Chan3,4,
  6. Edward Giovannucci4,5,
  7. Charles Fuchs1,4,
  8. Shuji Ogino1,6
  1. 1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
  2. 2Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA
  3. 3Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
  4. 4Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA
  5. 5Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
  6. 6Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, 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, 450 Brookline Ave., Room JF-215C, Boston, MA 02215, USA; shuji_ogino{at}

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Colorectal cancer comprises a heterogeneous group of diseases that arise through varying molecular carcinogenic pathways, involving complex interactions between tumour cells and the host microenvironment.1 2 It has long been appreciated that developmental and physiological differences exist between anatomic segments of the colorectum, and that colorectal cancers occur with distinctly different frequencies at different subsites.3 While approaches to surgical and adjuvant therapy have set rectal cancer as a separate entity, colon cancers still tend to get grouped together.

In the 1980s, epidemiological and molecular data suggested that cancers arising at different subsites may be biologically disparate, implying different cancer aetiologies or evolutions. These observations prompted the suggestion that the proximal and distal colon should be considered separately in aetiological studies, with the splenic flexure as a demarcation point.3 This dichotomisation has been propagated by subsequent clinical, translational and epidemiological studies,4–10 while evolving molecular data have galvanised and lent further support to the two-colon concept.11–14 It remains uncertain, however, whether the splenic flexure represents a genuine or arbitrary divide in the aetiological spectrum of colon cancers. Notably, our recent study,15 demonstrating that the frequencies of key tumour molecular features change gradually along the length of the colon (rather than abruptly at the splenic flexure), challenges the current two-colon paradigm. The aim of this article is to review data relevant to the current concept of distinct molecular pathogeneses for proximal versus distal colon cancers, to describe the impact of our recent findings and to discuss the implications for future research.

The evolution of the two-colon concept

Historical overture

There are incontrovertible differences between the ontogeny, morphology, biochemistry and physiology of the proximal and distal colon.11–14 Furthermore, gross macroscopic differences are well described between proximal and distal colorectal tumours.9 11–14 In …

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  • MY and PL contributed equally.

  • Funding This work was supported by US National Institute of Health grants (P01 CA87969 to S E Hankinson, P01 CA55075 to W C Willett, P50 CA127003 to CSF, R01 CA118553 to CSF, R01 CA151993 to SO and R01 CA137178 to ATC) and a US National Science Foundation grant (DBI-1053486 to CH). PL is a Scottish Government Clinical Academic Fellow and is supported by a Harvard University Knox Memorial Fellowship. TM was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of US NIH. Funding agencies did not have any role in the design of the study; the collection, analysis, or interpretation of the data; the decision to submit the manuscript for publication; or the writing of the manuscript.

  • Competing interests None.

  • Provenance and peer review Commissioned; externally peer reviewed.

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