Colorectal Cancer: A Tale of Two Sides or a Continuum?
There are incontrovertible differences between the ontogeny, morphology, biochemistry and physiology of the proximal and distal colon. Furthermore, gross macroscopic differences are well described between proximal and distal colorectal tumours. 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. Consequently, it was proposed that proximal and distal cancers may represent distinct disease entities. The credibility of this hypothesis was bolstered by emerging cytogenetic and molecular data on the heterogeneity of colorectal cancer, including evidence that large-scale chromosomal aberrations were relatively more frequent in distal cancers.
An authoritative review of the evidence for genetically distinct proximal versus distal colorectal cancer phenotypes was published by Bufill in 1990. 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.
In addition to clinical and pathological characteristics, cellular genomic and epigenomic determinants serve as important predictors of tumour evolution and progression. 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. CIN is implicated in 60–70% of colorectal cancers, and is more commonly observed in distal compared to proximal cancers.
Microsatellite instability (MSI), characterised by somatic alterations in microsatellite repeat length, represents another distinct form of genomic instability observed in colorectal cancer. In contrast to CIN, cancers that display a high degree of MSI (MSI-high) preferentially occur in the proximal colon. 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.MLH1 promoter hypermethylation is most commonly a consequence of the CpG island methylator phenotype (CIMP-high), a form of epigenomic instability. 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.
BRAF mutations are also more common in proximal colon cancers.BRAF mutations are strongly associated with CIMP-high cancer, which, in turn, correlates strongly with MSI-high cancer. Although CIMP-high and MSI-high cancers are independently associated with proximal colonic location, only CIMP-high cancers are independently associated with BRAF mutation.
The apparent 'left-to-right shift' in colorectal cancer incidence reported by epidemiological studies from the USA in the late 1970s and early 1980s led to the adoption of the two-colon model by numerous incidence trend studies internationally. 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.
Epidemiological studies, including molecular pathological epidemiology research, 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. The possible association between red or processed meat consumption and colorectal cancer risk is reportedly greater for distal cancers, while the protective effect of regular aspirin use appears strongest for proximal cancers.
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. 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. 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.
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. Furthermore, gross macroscopic differences are well described between proximal and distal colorectal tumours. 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. Consequently, it was proposed that proximal and distal cancers may represent distinct disease entities. The credibility of this hypothesis was bolstered by emerging cytogenetic and molecular data on the heterogeneity of colorectal cancer, including evidence that large-scale chromosomal aberrations were relatively more frequent in distal cancers.
An authoritative review of the evidence for genetically distinct proximal versus distal colorectal cancer phenotypes was published by Bufill in 1990. 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.
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. 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. CIN is implicated in 60–70% of colorectal cancers, and is more commonly observed in distal compared to proximal cancers.
Microsatellite instability (MSI), characterised by somatic alterations in microsatellite repeat length, represents another distinct form of genomic instability observed in colorectal cancer. In contrast to CIN, cancers that display a high degree of MSI (MSI-high) preferentially occur in the proximal colon. 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.MLH1 promoter hypermethylation is most commonly a consequence of the CpG island methylator phenotype (CIMP-high), a form of epigenomic instability. 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.
BRAF mutations are also more common in proximal colon cancers.BRAF mutations are strongly associated with CIMP-high cancer, which, in turn, correlates strongly with MSI-high cancer. Although CIMP-high and MSI-high cancers are independently associated with proximal colonic location, only CIMP-high cancers are independently associated with BRAF mutation.
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 1980s led to the adoption of the two-colon model by numerous incidence trend studies internationally. 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.
Epidemiological studies, including molecular pathological epidemiology research, 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. The possible association between red or processed meat consumption and colorectal cancer risk is reportedly greater for distal cancers, while the protective effect of regular aspirin use appears strongest for proximal cancers.
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. 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. 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.
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