Article

Analysis of molecular alterations in left- and right-sided colorectal carcinomas reveals distinct pathways of carcinogenesis: proposal for new molecular profile of colorectal carcinomas.

Division of Pathology, Central Clinical Laboratory, Iwate Medical University, 19-1 Morioka, 020-8505, Japan.
Journal of Molecular Diagnostics (Impact Factor: 3.96). 06/2006; 8(2):193-201. DOI: 10.2353/jmoldx.2006.050052
Source: PubMed

ABSTRACT To clarify distinct genetic profiles of colorectal cancers based on tumor location (left- and right-sided), we evaluated the status of loss of heterozygosity (LOH), CpG islands methylation phenotype (CIMP), microsatellite instability (MSI), and mutations of p53, Ki-ras, and APC genes in 119 colorectal cancers. Statuses of LOH (at 5q, 8p, 17p, 18q, and 22q), MSI, and CIMP (MINT1, MINT2, MINT31, MLH-1, MGMT, p14, p16, and RASSF1A) were determined using microsatellite polymerase chain reaction and methylation-specific polymerase chain reaction coupled with a crypt isolation method, respectively. In addition, mutations of p53, Ki-ras, and APC genes were also examined. LOH, MSI, and CIMP status allowed us to classify samples into two groups: low or negative and high or positive. Whereas the frequency of p53 mutations in the LOH-high status was significantly higher in left-sided cancers than in right-sided cancers, CIMP-high in the LOH-high status and MSI-positive status were more frequently found in right-sided cancers compared with left-sided cancers. Finally, location-specific methylated loci were seen in colorectal cancers: type I (dominant in right-sided cancer) and type II (common in both segments of cancer). Our data confirm that distinct molecular pathways to colorectal cancer dominate in the left and right sides of the bowel.

0 Bookmarks
 · 
79 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose The findings from epidemiologic studies of dyslipidemia and colorectal cancer risk have been conflicting. We performed a dose–response meta-analysis of published prospective studies to assess the aforementioned association. Methods Relevant studies that reported the association between the components of dyslipidemia (serum triglyceride, total cholesterol, and high-/low-density lipoprotein cholesterol) and colorectal cancer risk were identified by searching PubMed until the end of May 2014. We pooled the relative risks (RRs) from individual studies using a random- and fixed-effects models and performed dose–response, heterogeneity, and publication bias analyses. Results Seventeen prospective studies, including 1,987,753 individuals with 10,876 colorectal cancer events, were included in the meta-analysis. The overall pooled RR for high versus low concentrations for triglyceride (n = 9 studies) was 1.18 (95 % CI 1.04–1.34; I 2 = 47.8 %), for total cholesterol (n = 10 studies) was 1.11 (95 % CI 1.01–1.21; I 2 = 46.7 %), for high-density lipoprotein cholesterol (n = 6 studies) was 0.84 (95 % CI 0.69–1.02; I 2 = 42.5 %), and for low-density lipoprotein cholesterol (n = 3 studies) was 1.04 (95 % CI 0.60–1.81; I 2 = 82.7 %). In the dose–response analysis, the overall pooled RR was 1.01 (95 % CI 1.00–1.03; I 2 = 0 %) per 50 mg/dL of triglyceride and 1.01 (95 % CI 0.97–1.05; I 2 = 64.3 %) per 100 mg/dL of total cholesterol. Conclusions This meta-analysis of prospective studies suggests that dyslipidemia, especially high levels of serum triglyceride and total cholesterol, is associated with an increased risk of colorectal cancer, whereas high-density lipoprotein cholesterol might associate with a decreased risk of colorectal cancer. Further studies are warranted to determine whether altering the concentrations of these metabolic variables may reduce colorectal cancer risk.
    Cancer Causes and Control 12/2014; 26(2). DOI:10.1007/s10552-014-0507-y · 2.96 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BackgroundA large proportion of US Medicare beneficiaries undergo earlier-than-recommended follow-up colonoscopies after negative screening colonoscopy. Such practice entails substantial cost and added risk.AimsTo compare the risk of colorectal cancer (CRC) associated with varying follow-up colonoscopy intervals following a negative colonoscopy, and to determine whether the potential benefit of a shorter colonoscopy follow-up interval would differ by gender.Methods We conducted a weighted cohort study using the Surveillance, Epidemiology and End Results-Medicare linked database (1991–2006) among 932 370 Medicare enrollees who are representative of the entire US elderly population. We compared the cumulative incidence of CRC among patients who underwent follow-up colonoscopies at different intervals following a negative colonoscopy. The primary outcome was incident CRC.ResultsThe eligible study cohort (n = 480 864) included 106 924 patients who underwent ≥1 colonoscopy. Men were more likely to require polypectomy during their initial colonoscopy than women. Compared to the recommended 9–10 year follow-up colonoscopy interval, an interval of 5–6 years was associated with the largest CRC cumulative risk reduction [i.e. 0.17% (95% CI: 0.009–0.32%)]. The magnitude of risk reduction associated with shorter colonoscopy follow-up intervals was not significantly different between men and women.Conclusions Among elderly individuals who undergo a negative colonoscopy, the magnitude of reduction in the cumulative CRC risk afforded by earlier-than-recommended follow-up colonoscopy is quite small, and probably cannot justify the risk and cost of increased colonoscopy frequency. In addition, there are insufficient differences between men and women to warrant gender-specific recommendations.
    Alimentary Pharmacology & Therapeutics 08/2014; 40(7). DOI:10.1111/apt.12902 · 4.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Upon binding their cognate receptors, ERα (ESR1) and ERβ (ESR2), estrogens activate intracellular signaling cascades that have important consequences for cellular behavior. Historically linked to carcinogenesis in reproductive organs, estrogens have also been implicated in the pathogenesis of different cancer types of non-reproductive tissues including the colon. ERβ is the predominant estrogen receptor expressed in both normal and malignant colonic epithelium. However, during colon cancer progression ERβ expression is lost, suggesting estrogen signaling may play a role in disease progression. Estrogens may in fact exert an anti-tumor effect through selective activation of pro-apoptotic signaling mediated by ERβ, inhibition of inflammatory signals and modulation of the tumor microenvironment. In this review we analyze the estrogen pathway as a possible therapeutic avenue in colorectal cancer, we report the most recent experimental evidence to explain the cellular and molecular mechanisms of estrogen-mediated protection against colorectal tumorigenesis, and we discuss future challenges and potential avenues for targeted therapy.
    Frontiers in Oncology 01/2015; 5. DOI:10.3389/fonc.2015.00019

Preview

Download
1 Download
Available from