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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 the early 1980s, epidemiological studies drew attention to sex and age disparities in site-specific colon cancer incidence, while contemporaneous reports highlighted an apparent upward trend in the incidence ratio of proximal to distal cancers.3 16 17 Consequently, it was proposed that proximal and distal cancers may represent distinct disease entities.3 16 18 The credibility of this hypothesis was bolstered by emerging cytogenetic and molecular data on the heterogeneity of colorectal cancer,18 19 including evidence that large-scale chromosomal aberrations were relatively more frequent in distal cancers.19

An authoritative review of the evidence for genetically distinct proximal versus distal colorectal cancer phenotypes was published by Bufill in 1990.20 Numerous reports thereafter have supported the concept that proximal and distal cancers arise through distinct molecular pathways, and the two-colon concept has become the prevailing dogma.11–14

Genetic and epigenetic geography of colorectal cancer

In addition to clinical and pathological characteristics, cellular genomic and epigenomic determinants serve as important predictors of tumour evolution and progression.21 Chromosomal instability (CIN), a common type of genomic instability in colorectal cancer, is characterised by widespread numerical chromosomal aberrations, subchromosomal amplifications and loss of heterozygosity.22 CIN is implicated in 60–70% of colorectal cancers, and is more commonly observed in distal compared to proximal cancers.23 24

Microsatellite instability (MSI), characterised by somatic alterations in microsatellite repeat length, represents another distinct form of genomic instability observed in colorectal cancer.25–27 In contrast to CIN, cancers that display a high degree of MSI (MSI-high) preferentially occur in the proximal colon.23 24 28 MSI-high cancers constitute approximately 15% of all colorectal cancers and most frequently result from aberrant promoter hypermethylation and epigenetic silencing of the mismatch repair (MMR) gene MLH1.23 24 28 MLH1 promoter hypermethylation is most commonly a consequence of the CpG island methylator phenotype (CIMP-high), a form of epigenomic instability.21 29–32 MSI-high is also the hallmark of cancers arising in the context of the Lynch syndrome, where genetic predisposition is attributable to germline mutations in MMR genes.23 24 28

BRAF mutations are also more common in proximal colon cancers.33–37 BRAF mutations are strongly associated with CIMP-high cancer, which, in turn, correlates strongly with MSI-high cancer.33–37 Although CIMP-high and MSI-high cancers are independently associated with proximal colonic location, only CIMP-high cancers are independently associated with BRAF mutation.33–36

An epidemiological scission

The apparent ‘left-to-right shift’ in colorectal cancer incidence reported by epidemiological studies from the USA in the late 1970s and early 1980s16 led to the adoption of the two-colon model by numerous incidence trend studies internationally.38 39 A true site-specific shift in incidence has not been a consistent finding of such studies. Nonetheless, age-specific and sex-specific differences in proximal and distal cancer incidence continue to be described.40

Epidemiological studies, including molecular pathological epidemiology research,1 2 41 have also used the splenic flexure divide when investigating the effect of potential aetiological exposures. For example, prospective data from the Iowa Women's Health Study demonstrate that the relationship between smoking and colorectal cancer risk is strongest for proximal cancers, and for MSI-high, CIMP-high and BRAF-mutated phenotypes.42 The possible association between red or processed meat consumption and colorectal cancer risk is reportedly greater for distal cancers,4 while the protective effect of regular aspirin use appears strongest for proximal cancers.6

Two colons, two outcomes?

Data relating to colon cancer location and mortality are conflicting. Based on data from the German ‘Colon/Rectal Carcinoma’ multicentre observational study, including 17 641 patients, it was reported that proximal colon cancers carry a significantly worse prognosis compared with distal cancers.5 The size of this effect, however, diminished substantially following adjustment and stratification by disease stage. Furthermore, data from 53 801 colorectal cancer cases in the Surveillance, Epidemiology and End Results (SEER) Medicare database demonstrated no overall difference in 5-year survival.8 Interestingly, both of these studies showed a lower mortality for proximal versus distal cancers for patients with stage II disease. To date, tumour location has been largely neglected by oncology clinical trialists, and there is therefore a paucity of data on differences in outcome between proximal and distal colon cancers in relation to adjuvant therapy.7

A colorectal continuum

Despite clear epidemiological, molecular and clinicopathological correlates with colorectal cancer location, many consider it implausible that these associations change abruptly at the splenic flexure. Nonetheless, the two-colon model predominates. It therefore remains uncertain whether the splenic flexure represents a genuine demarcation or whether it is more a divide of convenience that polarises proximal–distal associations for markers that actually change gradually along the length of the colorectum. LaPointe and colleagues undertook an analysis of normal colonic tissue transcripts by microarray.43 The gene expression data indicate the existence of two distinct groups of transcripts: a dominant group, whose expression pattern follows the classical dichotomous model, and a second group, where expression levels appear to change gradually along the proximal–distal axis of the bowel.43 Worthley and colleagues observed a similar gradual transition along the normal colon for certain methylation markers, including ESR1, HIC1 and APBA2.44

Recent interest has focused on whether colorectal carcinogenesis might occur, through specific molecular mechanisms as a result of interactions between the gut microbiota, innate immune system and other host factors, such as diet.2 45–48 Luminal contents, including gut microbial communities and their metabolites, might trigger initiating molecular events or, alternatively, influence the tumour microenvironment and promote neoplastic progression. Microbial and biochemical components of the luminal ecosystem and interactions occurring within the mucosal–luminal interface are likely to vary gradually along the proximal–distal axis of the colorectum.49 50 Indeed, this underlying continuum was postulated by LaPointe and colleagues to be responsible for the apparent continuity observed in their gene expression data.43

Taking into account luminal biogeography, and the potential influence of host–microbial interactions, we recently investigated whether the frequencies of key colorectal cancer-related molecular characteristics also changed gradually through the multiple anatomic subsites.15 Using a database of over 1400 colorectal cancers from two US nationwide prospective cohort studies, we examined the frequencies of several molecular markers (CIMP, MSI, BRAF, KRAS and PIK3CA mutations, and LINE-1 methylation) in cancers arising throughout the colorectum.15 We assessed the linearity and non-linearity of molecular relationships by bowel subsite, with subsites defined as caecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon, rectosigmoid junction and rectum.15 Notably, we found that the frequencies of CIMP-high, MSI-high and BRAF mutation increased in a statistically linear fashion from the rectum to the ascending colon. Interestingly, caecal cancers appeared to represent a unique subtype, characterised by a high frequency of KRAS mutation. Our data demonstrate that the frequencies of molecular pathological changes in colorectal cancer evolve gradually through bowel subsites, rather than after abruptly at the splenic flexure.15 Figure 1 illustrates the disparity between the prevailing two-colon concept and the continuum model. Importantly, our findings and the continuum model are not incompatible with previous observations. However, our data support the necessity for a paradigm shift. We therefore propose a transition from the established dichotomous, or trichotomous (if one distinguishes rectum from distal colon), model towards a more detailed approach to the topography of colorectal carcinogenesis. Translation of the continuum model into a clinically practicable tool must be tempered by an appreciation of the limitations of lesion position reporting by clinicians, and by an awareness of inter-individual variability in colon length and mobility. Nonetheless, the adoption of a multisegmental model should be readily achievable.

Figure 1

Illustration of the disparity between the continuum model and the two-colon concept. The frequencies of molecular features such as a high degree of CpG island methylator phenotype (CIMP-high), a high degree of microsatellite instability (MSI-high) and BRAF mutation increase linearly from the rectum to the ascending colon according to the continuum model, and as supported by our recent data (left).15 Previous studies have typically grouped together all distal tumours, and all proximal tumours, and compared the frequencies of various molecular features. Data from numerous previous two-colon studies appear to support the two-colon concept (right, top), even when it is likely that a continuum exists for the measured marker along the proximal–distal axis of the bowel (right, bottom). The design of two-colon studies does not permit adequate evaluation of the linearity of marker frequency by colon subsite.

Future perspectives

The potential limitations of the two-colon model for molecular biomarkers may extend to its application in other arenas. A recent examination of data from 39 568 participants in the German ‘Colon/Rectal Carcinoma’ study suggests that certain clinicopathological features, such as histological subtype, show a seemingly linear correlation with anatomic subsite, while others, including disease stage, nodal status and lymphatic invasion, vary by subsite and do not fit neatly into a dichotomous model.51 Indeed, our findings suggesting molecular linearity from rectum to ascending colon and a potential unique molecular phenotype for caecal cancers might have been masked by a two-colon study design.

We are at the dawn of the era of personalised colorectal cancer therapy and prevention.52 As the oncological armament of chemotherapeutic and chemopreventive agents increases, careful disease phenotyping and subgroup identification is vital to ensure optimal disease control while minimising toxicity.52 For stage II disease, where site-specific survival differences appear to exist, adjuvant therapy remains controversial.52 There is therefore a clear need to define subgroups that might derive benefit from chemotherapy. However, few colon cancer outcome studies have considered the influence of tumour location and its potential interactions with molecular characteristics beyond the simple proximal–distal division.5 7 53 In terms of screening, it is generally accepted that colonoscopy impacts less on mortality for proximal cancers compared with cancers arising in the distal colon.13 If molecular strategies are to be used in an attempt to increase the sensitivity of colonoscopy for proximal premalignant lesions, then a detailed appreciation of marker variation by subsite is essential.

Thus, a move towards the continuum model and multisegmental research design may prove informative not only for molecular and epidemiological investigators, but also for clinical outcome research. Furthermore, the ability to resolve variation in gut biogeography at subsite level seems imperative for ‘omics’ research, and for a better understanding of the effects of gut microbiome and host interactions on disease susceptibility and evolution.

In the first instance, multisegmental research design demands the collection of detailed colorectal subsite data for each neoplastic lesion in clinical, epidemiological and pathological studies. One inevitable consequence of this study design will be the requirement for an increase in total sample size. This will be necessary to provide the adequate statistical power necessary to permit meaningful subsite analyses. The larger sample size demanded by this model is therefore likely to promote pooling projects and multicentre or multi-cohort collaborations in the near future.


The two-colon model has served us for over three decades.11–14 Nonetheless, the emergence of data suggesting linearity in the frequencies of certain tumour molecular characteristics, and subsite-specific clinicopathological differences beyond the simple proximal–distal divide, support the need for a paradigm shift. In the era of personalised cancer therapy and prevention, future studies should consider adopting a multisegmental approach to bowel subsite in order both to advance our understanding of the complex aetiology of colorectal carcinogenesis, and to improve tailored preventive and therapeutic strategies.


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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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