Distinct molecular patterns based on proximal and distal sporadic colorectal cancer: Arguments for different mechanisms in the tumorigenesis

Department of Pathology and Laboratory Medicine, Section of Pathological Anatomy, Parma University, Medical School, Parma, Italy.
International Journal of Colorectal Disease (Impact Factor: 2.45). 02/2007; 22(2):115-26. DOI: 10.1007/s00384-006-0093-x
Source: PubMed


Colorectal cancer (CRC) ranks as the fourth most frequently diagnosed cancer worldwide. CRCs that arise proximally or distally to the splenic flexure show differences in epidemiologic incidence, morphology, and molecular alterations, suggesting the existence of two categories of CRC based on the site of origin. The aim of the present work is to investigate the histological and molecular differences between CRCs located proximally and distally to the splenic flexure, and their potential involvement in tumor prognosis and therapeutic strategies.
We evaluated 120 patients affected by sporadic CRC for clinicopathologic features, microsatellite instability (MSI), loss of heterozygosity (LOH) of chromosomes 18q, 8p, and 4p; they were also investigated for hMlh1, hMsh2, Fhit, p27, and Cox-2 immunostaining.
The mucinous histotype was more frequent in the proximal than in the distal CRCs (p<0.004). The frequency of MSI phenotype was higher in proximal than in distal tumors (p<0.001); moreover, reduced or absent hMlh1, Fhit, p27 immunohistochemical expressions were more frequent in proximal than in distal tumors (p<0.001 and 0.01 for p27). In contrast, the frequency of LOH in 18q was higher in distal than in proximal tumors (p=0.002). No significant differences were observed between proximal and distal tumors in the frequency of LOH in 8p and altered expression of hMsh2 and p53 protein.
These different features may reflect different genetic pathways of carcinogenesis and support the hypothesis of a different mechanism of cancer development between the proximal and the distal colon, with potential implications in the therapeutic approach.

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    • "Nonpolypoid flat or depressed lesions are more prevalent in the right than in the left side of the colon, and these are more challenging to identify and remove [8]. There may also be differences in biology between proximal and distal lesions; for example, distal and proximal CRCs show genetic and molecular differences [9]. "
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    ABSTRACT: Colonoscopy is widely regarded to be the gold standard for colorectal cancer (CRC) detection. Recent studies, however, suggest that the effectiveness of colonoscopy is mostly confined to tumors on the left side of the colon (descending, sigmoid, rectum), and that the technology has poor tumor detection for right-sided (cecum, ascending, transverse) lesions. A minimally invasive test that can detect both left-sided and right-sided lesions could increase the effectiveness of screening colonoscopy by revealing the potential presence of neoplasms in the right-sided "blind spot". We previously reported on a seven-gene, blood-based biomarker panel that effectively stratifies a patient's risk of having CRC. For the current study, we assessed the effectiveness of the seven-gene panel for the detection of left- and right-sided CRC lesions. Results were evaluated for 314 patients with CRC (left-sided: TNM I, 65; TNM II, 57; TNM III, 60; TNM IV, 17; unknown, 9. right-sided: TNM I, 28; TNM II, 29; TNM III, 38; TNM IV, 12; unknown, 1 and including two samples with both left and right lesions) and 328 control samples. Blood samples were obtained prior to clinical staging and therapy. Most CRC subjects had localized disease (stages I and II, 58%); regional (stage III) and systemic (stage IV) disease represented 32% and 9%, respectively, of the study population. The panel detected left-sided (74%, 154/208) and right-sided (85%, 92/108) lesions with an overall sensitivity of 78% (215/316) at a specificity of 66% (215/328). Treatable cancer (stages I to III) was detected with left-sided lesion sensitivity of 76% (138/182) and right-sided sensitivity of 84% (80/95). This seven-gene biomarker panel detected right-sided CRC lesions across all cancer stages with a sensitivity that is at least equal to that for left-sided lesions. This study supports the use of this panel as the basis for a patient-friendly, blood-based test that can be easily incorporated into a routine physical examination in advance of colonoscopy to provide a convenient companion diagnostic and a pre-screening alert, ultimately leading to enhanced CRC screening effectiveness.
    Full-text · Article · Jul 2013 · Journal of Experimental & Clinical Cancer Research
    • "Depending upon the tumor site, there are genotypic and phenotypic differences that may influence tumorigenesis in CRC. For example, microsatellite instability (MSI) and CpG island methylator phenotype-positive have associations with proximal tumors,[33] whereas distal tumors have been associated with mutations in K-ras and P53, increased COX-2 expression, and loss of heterozygosity (LOH) at chromosome 18.[34] Recently, screening colonoscopy has been observed to be effective at reducing CRC-specific mortality from left-sided but not right-sided CRCs.[35] "
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    ABSTRACT: Patients with history of colorectal cancer (CRC) are at increased risk for developing a second primary colorectal cancer (SPCRC) as compared to the general population. However, the degree of risk is uncertain. Here, we attempt to quantify the risk, using data from the large population-based California Cancer Registry (CCR). We analyzed the CCR data for cases with surgically-treated colon and rectal cancer diagnosed during the period 1990-2005 and followed through up to January 2008. We excluded those patients diagnosed with metastatic disease and those in whom SPCRC was diagnosed within 6 months of the diagnosis of the primary CRC. Standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated to evaluate risk as compared to the underlying population after taking into account age, sex, ethnicity, and time at risk. The study cohort consisted of 69809 cases with colon cancer and 34448 with rectal cancer. Among these patients there were 1443 cases of SPCRCs. The SIR for developing SPCRC was higher in colon cancer survivors (SIR=1.4; 95% CI: 1.3 to 1.5) as compared to the underlying population. The incidence of SPCRC was also higher in females (SIR=1.5; 95% CI: 1.3 to 1.6) and Hispanics (SIR=2.0; 95% CI: 1.7 to 2.4) with primary colon cancer. The SIR for developing an SPCRC was higher only among those whose initial tumor was located in the descending colon (SIR=1.6; 95% CI: 1.3 to 2.0) and proximal colon (SIR=1.4; 95% CI: 1.3 to 1.6). Our results confirm that CRC patients, especially females and Hispanics, are at a higher risk of developing SPCRC than the general population. Differential SPCRC risk by colorectal tumor subsite is dependent on gender and ethnicity, underscoring the heterogeneous nature of CRC.
    No preview · Article · Mar 2011 · Journal of Carcinogenesis
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    • "Use of NSAIDs before diagnosis may lead to the development of tumours expressing lower levels of COX-2, resulting in the diagnosis of tumours that are less aggressive and have a molecular profile that improves survival. Proximal colorectal tumours have a distinct molecular phenotype compared with distal or rectal tumours (Richman and Adlard, 2002; Azzoni et al, 2007; Benedix et al, 2010) and may, therefore, represent a different form of colorectal disease. For example, variation in expression of the NSAID-targeted COX-2 enzyme according to the location of colorectal tissue has been described previously (Dimberg et al, 1999; Wiese et al, 2003; Nasir et al, 2004), and may be a potential explanation for our observed tumour sub-site difference. "
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    ABSTRACT: Non-steroidal anti-inflammatory drugs (NSAIDs) and hormone therapy (HT) independently decrease the risk of colorectal cancer. However, their role in altering survival after a colorectal cancer diagnosis is not well established. We examined the association between the use of these common medications before diagnosis and colorectal cancer survival among women in western Washington State diagnosed with incident colorectal cancer from 1997 to 2002. Cases were ascertained using the Surveillance, Epidemiology and End Results cancer registry; mortality follow-up was completed through linkages to the National Death Index. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). We observed no overall association between colorectal cancer survival and pre-diagnostic NSAID use. However, when stratified by tumour sub-site, NSAID use was associated with a reduced risk of colorectal cancer mortality for women diagnosed with proximal (HR=0.55; 95% CI: 0.32-0.92), but not distal or rectal (HR=1.32; 95% CI: 0.83-2.10) tumours. The usage of HT was not associated with colorectal cancer survival overall or by tumour sub-site. Usage of NSAIDs before diagnosis may be associated with improved colorectal cancer survival among women diagnosed with proximal tumours. The usage of HT does not appear to have a function in altering colorectal cancer mortality.
    Full-text · Article · Feb 2011 · British Journal of Cancer
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