Kegg Pathway: Colorectal cancer

Cell Cycle. 2009 Dec 17; 8(23):
Glinskii AB, Ma J, Ma S, Grant D, Lim CU, Sell S, Glinsky GV

Meta-analysis of genomic coordinates of SNP variations identified in genome-wide association studies (GWAS) of up to 712,253 samples (comprising 221,158 disease cases, 322,862 controls, and 168,233 case/control subjects of obesity GWAS) reveals that 39% of SNPs associated with 22 common human disorders are located within intergenic regions. Chromatin-state maps based on H3K4me3-H3K36me3 signatures show that many intergenic disease-linked SNPs are located within the boundaries of the K4-K36 domains, suggesting that SNP-harboring genomic regions are transcribed. Here we report identification of 13 trans-regulatory RNAs (transRNAs) 100 to 200 nucleotides in length containing intergenic SNP sequences associated with Crohn's disease, rheumatoid arthritis, type 1 diabetes, vitiligo, hypertension and multiple types of epithelial malignancies (prostate, breast, ovarian and Colorectal cancers). We demonstrate that NALP1 loci intergenic SNP sequence, rs2670660, is expressed in human cells and may contribute to clinical manifestations of autoimmune and autoimflammatory phenotypes by generating distinct allelic variants of transRNAs. Stable expression of allele-specific sense and anti-sense variants of transRNAs markedly alters cellular behavior, affect cell cycle progression, and interfere with monocyte/macrophage transdifferentiation. On a molecular level, forced expression of allele-specific sense and anti-sense variants of transRNAs asserts allele-specific genome-wide effects on abundance of hundreds microRNAs and mRNAs. Using lentiviral gene transfer, microarray and Q-RT-PCR technologies, we identify rs2670660 allele-specific gene expression signatures (GES) which appear useful for detecting the activated states of innate immunity/inflammasome pathways in approximately 700 clinical samples from 185 control subjects and 350 patients diagnosed with 9 common human disorders, including Crohn's disease, ulcerative colitis, rheumatoid arthritis, Huntington disease, autism, Alzheimer disease, obesity, prostate and breast cancers. Microarray analysis of clinical samples demonstrates that rs2670660 allele-specific GES are engaged in patients' peripheral blood mononuclear cells (PBMC) which encounter pathological conditions in coherent tissues of a human body during immune surveillance and homeostasis monitoring. These data indicate that expression of transRNAs encoded by specific intergenic sequences can trigger activation of innate immunity/inflammasome pathways and contribute to clinical development of autoinflammatory and autoimmune syndromes. Documented in this work single-base substitution-driven molecular and biological antagonisms of intergenic SNP-containing transRNAs suggest a guiding mechanism of selection and retention of phenotype-compatible intergenic variations during evolution. According to this model, random genetic variations which generate transRNAs asserting antagonistic phenotype-altering effects compared to ancestral alleles will be selected and retained as SNP variants.

Dig Surg. 2009 Nov 13; 26(5): 400-405
Noura S, Ohue M, Seki Y, Tanaka K, Motoori M, Kishi K, Miyashiro I, Ohigashi H, Yano M, Ishikawa O, Tsukuma H, Murata K, Kameyama M

Background: Colorectal cancer (CRC) patients have an increased risk of developing other malignancies. Understanding the characteristics of the second primary cancer is important to establish an effective surveillance program. Methods: This study investigated 301 CRC patients to assess the risk factors for postoperative primary cancers arising from organs distinct from the Colorectal area (extraColorectal cancers). The observed/expected ratio (O/E ratio) was calculated using the Osaka cancer Registry, to determine the rate of increase in extraColorectal cancers. Results: The frequency of postoperative extraColorectal cancers was 12.6%. A logistic regression analysis showed only age to be an independent risk factor for postoperative extraColorectal cancer development. The O/E ratio of overall postoperative extraColorectal cancer was significantly higher than one (O/E ratio 2.6, p < 0.01). In each organ, the frequency of lung and gastric cancers were significantly higher than one, with O/E ratios of 3.2 and 2.7 (p < 0.01 and p < 0.05, respectively). Conclusion: The frequency of postoperative extraColorectal cancers in CRC patients was significantly higher than that in the normal population, especially for lung and gastric cancers. Clinicians should carefully follow patients for a possible recurrence of CRC and educate CRC patients with regard to the high risk of a second primary cancer.

Digestion. 2009 Nov 13; 80(4): 267-270
Loffeld RJ, van der Putten AB

Background: Colonoscopy is an important diagnostic procedure for screening as well as for patients presenting with complaints. The completion of a colonoscopy is defined as cecal intubation. A large single center study was done in order to evaluate the completion rate of colonoscopy and identify reasons for failure. Patients and Methods: We reviewed all consecutive endoscopies of the lower digestive tract done over a period of 15 years by 2 endoscopists. The main outcome measure was a successful cecal intubation. Results: 14,139 consecutive colonoscopies were done. Overall cecal intubation was successful in 11,787 procedures (83.3%). Three hundred and sixty-one of the nonsuccessful procedures were due to insufficient colon cleansing, and no significant abnormalities were seen in 362 procedures. In the remaining 1,629 endoscopies, significant diagnoses were made. The presence of Colorectal cancer, diverticula and inflammatory bowel disease were significant findings in nonsuccessful procedures. Conclusion: In normal daily practice, colonoscopy is completed in 83.3% of the procedures. Reasons for failure are obstructing tumors, diverticula and insufficient colon cleansing.

Am J Health Syst Pharm. 2009 Dec 1; 66(23): 2105-2112
Mancl EE, Kolesar JM, Vermeulen LC

PURPOSE: The clinical and economic value of screening for Kras mutations as predictors of response to cetuximab and panitumumab are reviewed. SUMMARY: Epidermal growth factor receptor (EGFR) inhibitors cetuximab and panitumumab are agents currently used in the treatment of metastatic Colorectal cancer. Cetuximab is approved in combination with irinotecan for second-line therapy or as a single agent in the third-line setting, and panitumumab is approved as a single agent for third-line therapy. Historically, response rates to EGFR inhibitors have been low; therefore, predictors of response or lack of response have been highly sought after. Mutations in the Kras oncogene, which encodes for the RAS protein located downstream from EGFR, have been associated with poor response to EGFR inhibitor therapy. Numerous studies have confirmed a Kras mutation frequency in approximately 40% of all metastatic Colorectal cancers, as well as an associated lack of response to EGFR inhibitor therapy. Screening for Kras mutations before selecting a therapy may be clinically beneficial by avoiding the cost and toxicity of ineffective therapy. A simple breakeven analysis using a group of 100 hypothetical patients with metastatic Colorectal cancer revealed that cost savings will be achieved if screening can be conducted for less than $3460 per patient, regardless of which EGFR inhibitor is used. CONCLUSION: Mutations in the Kras oncogene are associated with a poor response to EGFR inhibitor therapy in metastatic Colorectal cancer. Implementing routine Kras screening and limiting the use of EGFR inhibitors to patients with wild-type (not mutated) Kras may have the potential for cost savings.

Am J Epidemiol. 2009 Nov 18;
Yamaji T, Iwasaki M, Sasazuki S, Kurahashi N, Mutoh M, Yamamoto S, Suzuki M, Moriyama N, Wakabayashi K, Tsugane S

Few epidemiologic investigations of visceral adiposity and Colorectal neoplasms have attempted the direct quantification of visceral fat. The authors measured visceral fat volume among middle-aged and elderly Japanese men and women who underwent colonoscopy and positron emission tomography/computed tomography for cancer screening in Tokyo, Japan, between February 2004 and February 2005, and examined the association between visceral adiposity and Colorectal adenoma in 1,205 eligible subjects. Odds ratios and 95% confidence intervals for Colorectal adenoma were estimated by using an unconditional logistic regression model after adjustment for potential confounders. Despite its high correlation with body mass index, visceral fat volume was associated with the prevalence of Colorectal adenoma independently of body mass index in both sexes. After further adjustment for body mass index, the odds ratio of Colorectal adenoma for the highest compared with the lowest quartile of visceral fat volume was 1.58 (95% confidence interval: 1.11, 2.24) for men and women combined. Conversely, body mass index was unlikely to modify the association between visceral fat volume and Colorectal adenoma (P(interaction) = 0.39). These findings add to accumulating evidence that visceral adiposity exerts an important influence on the pathogenesis of Colorectal neoplasms. The mechanisms of this potential association between visceral adiposity and Colorectal carcinogenesis warrant further investigation.

IEEE Trans Med Imaging. 2009 Nov 17;
Stadler G, Ghattas O, Araujo A

The aim of this paper is to introduce a variational image segmentation method for assessing the aberrant crypt foci (ACF) in the human colon captured in vivo by endoscopy. ACF are thought to be precursors for Colorectal cancer, and therefore their early detection may play an important clinical role. We enhance the active contours without edges model of Chan and Vese to account for the ACF's particular structure. We employ level sets to represent the segmentation boundaries, and discretize in space by finite elements and in (artificial) time by finite differences. The approach is able to identify the ACF, their boundaries, and some of the internal crypts' orifices.

J Chir (Paris). 2009 Nov 16;
Hornez E, Monchal T, Ottomani S, Bourgouin S, Platel JP, Fournier B, Thouard H

This study reports a case of pyoderma gangrenosum arising at a drainage orifice after a colostomy for cancer. The initial clinical presentation suggested intra-abdominal sepsis but the clinical assessment did not fit with laboratory findings or the CT scan. Forty hours later, the patient developed a reddish-purple ulcer at the drainage orifice. A diagnosis of pyoderma gangrenosum was made and systemic corticosteroid therapy was started. A dramatic response occurred over the next two days, obviating the need for surgical re-intervention. Pyoderma gangrenosum is an ulcerating necrotizing skin disorder of unknown etiology. It usually arises in association with underlying disease (mainly inflammatory bowel disease) and often occurs in para-stomal sites. Pyoderma gangrenosum arising at surgical sites is often mistaken for a postoperative infection and treated inappropriately with debridement and reopening of the wound which only exacerbates the pathology. Pyoderma gangrenosum is effectively treated with systemic corticosteroids.

Gastrointest Endosc. 2009 Nov 16;
Bretagne JF, Hamonic S, Piette C, Manfredi S, Leray E, Durand G, Riou F

BACKGROUND: There are few data about the performance variability among endoscopists participating to nationwide or regionwide Colorectal cancer screening programs. OBJECTIVE: To assess the variability of neoplasia detection rates among endoscopists participating in a regional Colorectal cancer screening program based on colonoscopy after biennial fecal occult blood testing (FOBT). DESIGN: Two rounds of colonoscopy were performed: round 1 took place in 2003 and 2004, and round 2 took place in 2005 and 2006. Secondary analysis of colonoscopy findings from the first 2 rounds was performed by using data drawn from all endoscopists who performed more than 30 colonoscopies in each round. Detection rates were adjusted for patient age and sex, and logistic regression analyses were conducted including these 2 variables and round number (1 or 2). SETTING: District of Ille-et-Vilaine in Brittany (population >900,000) between 2003 and 2007. MAIN OUTCOME MEASUREMENTS: The per-endoscopist adjusted rates of colonoscopies with at least 1, 2, or 3 adenomas, 1 adenoma 10 mm or larger, or a cancer. RESULTS: Among the 18 endoscopists who performed 3462 colonoscopies, the adjusted detection rates were in the following ranges: at least 1 adenoma, 25.4% to 46.8%; 2 adenomas, 5.1% to 21.7%; 3 adenomas, 2.7% to 12.4%; 1 adenoma 10 mm or larger, 14.2% to 28.0%; and cancer, 6.3% to 16.4%. Multivariate analyses showed that the endoscopist was not an independent predictor of cancer detection, but was an independent predictor of detecting adenomas, regardless of category; the R(2) of the models ranged from 6% to 13% only. LIMITATIONS: Other factors known to influence Colorectal neoplasia occurrence and withdrawal time could not be taken into account. CONCLUSIONS: In a screening program with a high compliance rate with colonoscopy after FOBT, interendoscopist variability had no effect on cancer detection, but did influence identification of adenomas. The clinical impact of such findings merits further evaluation.

cancer Sci. 2009 Oct 28;
Chen YC, Tzeng CH, Chen PM, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, Wang WS

Glutathione S-transferase P1 (GSTP1) participates in detoxification of potentially genotoxic compounds that may alter the efficacy and toxicity of platinum-based chemotherapy. We analyzed the influence of I105V polymorphism of GSTP1 on clinico-pathological features and outcomes in 166 Chinese patients with metastatic Colorectal carcinoma who had been treated with first-line FOLFOX-4. Combined analysis of GSTP1 I105V, ERCC1-118, and XPD-751 polymorphisms was also conducted. The results showed that, in comparison with Caucasian populations, a remarkably lower prevalence of Val105 allele variants was noted (24.7%). Patients with Val105 allele variants had a higher response to FOLFOX-4 (56.1%vs 37.6%, P = 0.04), and a longer progression-free (P < 0.01) as well as overall (P < 0.01) survival. By adjusted analysis, this polymorphism was identified as an independent prognostic factor (P = 0.01). In combined analysis, patients without any risk genotype, including GSTP1-105 Ile/Ile, ERCC1-118 C/T or T/T, and XPD-751 Lys/Gln, had significantly longer progression-free and overall survivals (P < 0.01). In addition, patients with Val105 allele variants had a higher incidence of grade 3/4 cumulative neuropathy after different cycles of treatment. These data suggest that Asian populations have a lower prevalence of I105V polymorphism in GSTP1. I105V polymorphism in GSTP1, by reducing its enzymatic activity and consequential detoxification to oxaliplatin, could be a key determinant for a better outcome, but more neurotoxicity, to FOLFOX-4 treatment. (cancer Sci 2009).

Org Lett. 2009 Nov 18;
Rho JR, Hwang BS, Sim CJ, Joung S, Lee HY, Kim HJ

Three new sesterterpenoids, phorbaketals A (1), B (2), and C (3) which have a spiroketal of the hydrobenzopyran moiety, were isolated from the Korean marine sponge Phorbas sp. Their complete structures were elucidated by spectral and chemical methods. They exhibited moderate cytotoxicity against human Colorectal, hepatoma, and lung cancer cell lines. Furthermore, the cultivation of the bacterial fraction from the sponge afforded compound 1.

Am J Ind Med. 2009 Nov 17;
Strand LA, Martinsen JI, Koefoed VF, Sommerfelt-Pettersen J, Grimsrud TK

INTRODUCTION: This study focus on the incidence of asbestos-related cancers among 28,300 officers and enlisted servicemen in the Royal Norwegian Navy. Until 1987, asbestos aboard the vessels potentially caused exposure to 11,500 crew members. METHODS: Standardized incidence ratios (SIR) were calculated for malignant mesothelioma, lung cancer, and laryngeal, pharyngeal, stomach, and Colorectal cancers according to service aboard between 1950 and 1987 and in other Navy personnel. RESULTS: Increased risk of mesothelioma was seen among engine room crews, with SIRs of 6.23 (95% CI = 2.51-12.8) and 6.49 (95% CI = 2.11-15.1) for personnel who served less than 2 years and those with longer service, respectively. Lung cancer was nearly 20% higher than expected among both engine crews and non-engine crews. An excess of Colorectal cancer bordering on statistical significance was seen among non-engine crews (SIR = 1.14; 95% CI = 0.98-1.32). Land-based personnel and personnel who served aboard after 1987 had lower lung cancer incidence than expected (SIR = 0.77; 95% CI = 0.64-0.92). No elevated risk of laryngeal, pharyngeal, or stomach cancers was seen. CONCLUSION: The overall increase (65%) in mesotheliomas among military Navy servicemen was confined to marine engine crews only. The mesothelioma incidence can be taken as an indicator of the presence or absence of asbestos exposure, but it offered no consistent explanation to the variation in incidence of other asbestos-related cancers. Am. J. Ind. Med. (c) 2009 Wiley-Liss, Inc.

Zhonghua Wei Chang Wai Ke Za Zhi. 2009 Nov; 12(6): 623-626
Zhang Y, Zhou ZG, Wang L, Zhang P, Wang MJ, Cui CF, Guan JT, Chen KL, Zhan L

OBJECTIVE: To investigate the expression of microRNA(miR)-21 and miR-125 in Colorectal cancer(CRC) and its relationship with clinicopathological features. METHODS: Quantitative real-time PCR was applied to examine the expression of miR-21 and miR-125 in 100 primary CRC specimens which were diagnosed and operated in West China Hospital between 2006 and 2007, in comparison with the corresponding normal mucosa specimens. The relationship between the expression of miRNAs and clinicopathological features was analyzed. RESULTS: The expression of miR-21 in CRC was up-regulated by 2.3 times compared to normal mucosa (P =0.025), while the expression of miR-125 was down-regulated by 3.3 times in comparison with normal mucosa(P =0.005). Furthermore, the expression of miR-21 was related to TNM stage(P =0.028) and local invasion(P =0.023). On the other hand, no significant relationship was found between the expression of miR-125 and clinicopathological features (P >0.05). CONCLUSION: The over-expression of miR-21 may play a role in the development and progression of CRC, while miR-125 may not be related to the pathogenesis of CRC.

Zhonghua Wei Chang Wai Ke Za Zhi. 2009 Nov; 12(6): 618-622
Zhang P, Huang L, Ma YL, Peng JY, Shen TY, Chen HQ, Zhou YK, Chu ZX, Zhang M, Qin HL

OBJECTIVE: To explore the potential markers of Colorectal cancer metastasis and the influence of 5-FU on differentially expressed proteins by using proteomic technology, and to elucidate the mechanism of Colorectal cancer metastasis. METHODS: Human Colorectal carcinoma cell lines of different metastatic potential, Lovo and SW480 were conventionally cultured, and the protein was extracted. 50% inhibitory concentration(IC(50)) of 5-FU to these two cell lines was measured by MTT assay. Proteins of these two cell lines after intervention by 5-FU at IC(50) were extracted, then 2-dimensional gel electrophoresis was conducted for the proteins. The differential protein spots were examined by mass spectrometry and analyzed by bioinformatics. Difference of expressed proteins in two cell lines before and after the intervention of 5-FU was validated by Western blot and immunofluorescence. RESULTS: Eleven differentially expressed proteins were identified by 2-dimensional gel electrophoresis and mass spectrometry. The hnRNP K protein and PDI were selected to be examined by Western blot and immunofluorescence. Results revealed that the expression of hnRNP K in Lovo was higher than that in SW480, while the expression of PDI was lower in Lovo. After intervention by 5-FU at IC(50), the expression of hnRNP K in Lovo decreased more as compared to SW480, while the expression of PDI in SW480 increased more as compared to Lovo. CONCLUSION: There are significant differences in expression of hnRNP K and PDI proteins between Lovo and SW480 cell lines, and the proteins alter regularly after 5-FU intervention.