Rectal Carcinogenesis Research Articles

Genetic variation of TGF-ΒR2 as a protective genotype for the development of colorectal cancer in men.

BACKGROUNDThe role of transforming growth factor beta (TGF-β) signaling, including both the cytokine and their receptors, in the etiology of colorectal cancer (CRC) has been of particular interest lately.AIMTo investigate the association between promoter polymorphism in TGF-β receptor 2 TGF-ΒR2G[-875]A with a CRC risk in a cohort of Bulgarian patients using a case-control gene association study approach, as well as the protein levels of TGF-β1 in the peripheral blood. METHODSA cohort of 184 CRC patients and 307 sex and age-matched healthy subjects were recruited in the study. A genotyping of the TGF-ΒR2G[-875]A (rs3087465) polymorphism was performed by primer-introduced restriction analyses-polymerase chain reaction approaches.RESULTSThe frequency of TGF-ΒR2G[-875]A genotype was decreased in male patients with CRC than in healthy men (31.3% vs 44.8%; P = 0.058). Among males, the TGF-ΒR2G[-509]G genotype was related to a significantly increased risk of CRC development (OR = 1.820, 95%CI: 0.985-3.362, P = 0.055) than the GA + AA genotype. Also, TGF-ΒR2[-875]*A-allele itself was rarer in men with CRC than healthy men (19.1% vs 26.9%, P = 0.086) and was associated with a protective effect (OR = 0.644; 95%CI: 0.389-1.066; P = 0.086). Regarding the genotypes, we found that TGF-β1 serum levels were higher in GG genotype in healthy persons above 50 years than the CRC patients [36.3 ng/mL interquartile range (IQR) 19.9-56.5 vs 22.4 ng/mL IQR 14.8-29.7, P = 0.014]. We found significant differences between higher levels of TGF-β1 serum levels in healthy controls above 50 years (GG genotype) and CRC patients (GG genotype) at the early stage (36.3 ng/mL IQR 19.9-56.5 vs 22.8 ng/mL IQR 14.6-28.6, P = 0.037) and advanced CRC (36.3 ng/mL IQR 19.9-56.5 vs 21.6 ng/mL IQR 15.9-33.9, P = 0.039).CONCLUSIONIn summary, our results demonstrated that TGF-ΒR2 AG and AA genotypes were associated with a reduced risk of CRC, as well as circulating levels of TGF-β could prevent CRC development in a gender-specific manner. Notably, male carriers of TGF-ΒR2 -875A allele genotypes had a lower risk of CRC development and progression, suggesting that TGF-ΒR2 -875A/G polymorphism significantly affects the protective biological factors that also impact the risk of colon and rectal carcinogenesis.

Human papillomavirus (HPV) 16 infection is not detected in rectal carcinoma

IntroductionPersistence of human papillomavirus (HPV) infections is associated with squamous cell carcinomas of different human anatomic sites. Several studies have suggested a potential role for HPV infection, particularly HPV16 genotype, in rectal cancer carcinogenesis.. The aim of this study was to assess the frequency of oncogenic HPV 16 viral DNA sequences in rectal carcinomas cases retrieved from the pathology archive of Braga Hospital, North Portuga.MethodsTaqMan-based type-specific real-time PCR for HPV 16 was performed using primers and probe targeting HPV16 E7 region.ResultsMost of the rectal cancer patients (88.5%, n = 206 patients), were symptomatic at diagnosis. The majority of the lesions (55.3%, n = 129) presented malignancies of polypoid/vegetant phenotype. 26.8% (n = 63) had synchronic metastasis at diagnosis. 26.2% (n = 61) patients had clinical indication for neoadjuvant therapy. Most patients with rectal cancer were stage IV (19.7% patients), followed by stage IIA (19.3%) and stage I (18.5%). All cases of the present series tested negative for HPV16.ConclusionThe total of negative tests for HPV 16 infection is a robust argument to support the assumption that HPV 16 infection, despite of previous evidences, is not involved in rectal cancer carcinogenesis and progression.

Experimental Model of Rectal Carcinogenesis Induced by N-Methyl-N-Nitrosoguanidine in Mice with Endoscopic Evaluation.

Background and purpose: The discovery of chemical substances with carcinogenic properties has allowed the development of several experimental models of colorectal cancer (CRC). Classically, experimental models of CRC in mice have been evaluated through clinical or serial euthanasia. The present study aims to investigate the role of low endoscopy in the analysis of carcinogenesis induced by N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG).Methods: Thirty C57BL6 mice were divided into two groups: a control group with fifteen animals that underwent rectal instillation of saline solution on day 0 and a carcinogen group with fifteen animals that underwent a 100 mg/kg MNNG rectal instillation on day 0. In both groups, low endoscopies were performed on weeks 4 and 8. We used a validated endoscopic scoring system to evaluate the severity of colitis and colorectal tumor. Euthanasia was carried out at week 12.Results: We observed higher inflammation scores (p <0.001) and a higher number of tumors (p <0.05) in the MNNG group than the control group, both at weeks 4 and 8. A worsening of inflammation scores from the first to the second endoscopy was also noticeable in the MNNG group. There were no bowel perforations related to the procedure, and there was one death in the control group.Conclusion: Low endoscopy in experimental animals allows safe macroscopic evaluation of colorectal carcinogenesis without the need for euthanasia.

The prevalence of HPV infection in rectal cancer – Report from South – Central Poland (Cracow region)

Some studies suggest that HPV infection may be important carcinogenic factor in development of some part of colorectal cancers. However, in the worldwide literature concerning this type of tumours, the great variability in HPV frequency is noticed. In Poland, the incidence of HPV infection in colorectal cancers was examined in five studies so far and their results are also conflicting. Therefore, the aim of the present study was to assess the HPV presence in the group of 120 patients with adenocarcinomas of rectum. HPV infection was assessed on the basis of DNA extracted from collected formalin fixed paraffin embedded tumour specimens. Viral presence was evaluated using two PCR based methods: nested PCR and quantitative PCR (qPCR) with primers specific for HPV16. All HPV positive samples were subjected to virus genotyping using AmoyDx® Human papillomavirus (HPV) Genotyping Detection Kit and P16 immunostaining. Among 120 evaluated colorectal tumours, HPV DNA was detected in 2 cancers (1.67%) by nested PCR and in 2 (1.67%) tumours by qPCR, including 1 sample diagnosed as HPV positive on the basis of both PCR variants. Two HPV positive cancers had HPV16 infection and other one HPV18. All three tumours with positivity of HPV DNA were P16 negative. In south – central Poland, HPV infection in rectal cancers probably has not influence on rectal carcinogenesis.

Clinicopathological, endoscopic, and molecular characteristics of the "skirt" - a new entity of lesions at the margin of laterally spreading tumors.

A slightly elevated flat lesion with wide pits has occasionally been observed at the margin of laterally spreading tumors (LSTs) and is known as a "skirt." The aim of this study was to evaluate the clinicopathological, endoscopic, and genetic characteristics of a skirt. Consecutive LSTs were examined to evaluate the pathological, endoscopic, and genetic characteristics. Pathological characteristics, including the dimension of the cryptic opening (DCO), width of the individual gland (WIG), DCO to WIG ratio, and microvessel diameter were elucidated and compared with those of hyperplastic polyps, low grade dysplasia (LGD), and normal mucosa. The endoscopic findings of pit and microvascular patterns were assessed. Gene mutation analyses were performed for the KRAS, BRAF, NRAS, and PIK3CA genes. A skirt was identified in 35 of 1023 LSTs, and 80 % of lesions with a skirt had a component of either intramucosal or submucosal adenocarcinoma. The DCO, WIG, and DCO to WIG ratio of the skirt were significantly larger than those of other lesions. The microvessel diameters in skirts were significantly smaller than those in LGDs. Regarding the endoscopic findings, 30 skirts showed pits with a coral reef-like appearance, and all skirt regions were found to have a type I capillary pattern. KRAS mutation at codon 146 was found in the nodular part in one of five LSTs with a skirt. The skirt is a newly identified lesion distinct from hyperplastic polyps and LGDs, suggesting the presence of a novel pathway for rectal carcinogenesis from LSTs with a skirt.

Female-specific rectal carcinogenesis in cyclin D1b transgenic mice

Human cyclin D1 generates two major isoforms via alternative splicing: cyclin D1a and cyclin D1b. Cyclin D1b is hardly expressed in normal tissues but is frequently expressed in certain types of cancer tissues. To clarify the oncogenic potential of cyclin D1b variant, we developed cyclin D1b transgenic (Tg) mice and analyzed their phenotypes. We detected rectal tumors in 63% (15/24) of the female Tg mice. All rectal tumors had the histological characteristics similar to human sessile serrated adenoma/polyps (SSA/Ps). Adenocarcinomas were also found in 53% (8/15) of the rectal tumors, suggesting that these adenocarcinomas originated from the SSA/P-like lesions. No rectal tumors were found in the ovariectomized female cyclin D1b Tg mice (0/10), indicating that ovarian hormones played a critical role in rectal carcinogenesis in these Tg mice. Both phosphorylation of Erk, without activating MEK, and expression of estrogen receptor β were elevated in the rectal tumors of female cyclin D1b Tg mice compared with normal rectums of female wild-type mice. In addition, we established a cell line, D1bTgRT, derived from a rectal cancer of female Tg mouse. Small interfering RNA-induced cyclin D1b knockdown in this cell line suppressed Erk phosphorylation, anchorage-independent growth, cell invasiveness and tumorigenicity in nude mice. In humans, expression of cyclin D1b messenger RNA was detected in 17% (1/6) of colorectal cancer cell lines and 9.7% (3/31) of colorectal cancer tissues. Taken together, these results indicate that cyclin D1b expression contributes to the female- specific rectal carcinogenesis in mouse model.

Chromosome instability for tumor progression inference

Chromosome instability for tumor progression inference

Analysis of differentially expressed genes in human rectal carcinoma using suppression subtractive hybridization

The existence and treatment of rectal cancer are important for the function of defecation and the quality of life. However, the precise mechanisms of rectal carcinogenesis remain unclear. To screen the overexpressed gene in rectal carcinoma, we performed suppressive subtractive hybridization (SSH) on rectal carcinoma cells and the corresponding normal rectal cells. A total of 64 recombinant clones were subjected to DNA sequencing analysis, and 9 known genes were found to overexpressed in the tumors compared with those of the normal tissues. The genes are ST3 beta-galactoside alpha-2,3-sialyltransferase (ST3GAL5), interferon-induced transmembrane protein 3 (IFITM3), platelet-derived growth factor A-associated protein 1 (PDAP1), AlkB alkylating repair homolog 3 (ALKBH3), nucleoside diphosphate linked moiety X (Nudix)-type motif 14 (NUDT14), calponin 2 (CNN2), mitogen-activated protein kinase 14 (MAPK14), aconitase 1 (ACO1), and selenophosphate synthetase 1 (SEPHS1). The expression profiles of the genes were further confirmed in rectal carcinoma cells and the corresponding normal rectal cells of 12 patients by quantitative real-time RT-PCR. Our results revealed that ST3GAL5, IFITM3, PDAP1, ALKBH3, NUDT14, CNN2, MAPK14, ACO1, and SEPHS1 may be involved in rectal carcinogenesis.

Analysis of BRAF and KRAS mutations in colorectal cancer and rectal carcinogenesis via fluorescent allele-specific PCR.

436 Background: Molecular analysis has become increasingly relevant in the evaluation of colorectal carcinomas. Mutations in Ras-MAPK pathway proteins KRAS (present in 30-40% of colorectal cancer) and BRAF (10-14% of colorectal cancer) or mismatch repair (MMR) enzymes can impact response to therapy and/or can assist in defining hereditary predisposition. High frequency microsatellite instability (MSI) in colorectal cancer is associated with improved outcomes. Targeted therapies against BRAF and other components of the Ras-MAPK signaling pathway are becoming important aspects of treatment in colorectal and other cancers. Methods: A retrospective study was performed on 111 paraffin-embedded tumor specimens submitted between 1/07 and 3/09 for MSI testing based on family history and/or histologic features. DNA samples were screened for the BRAF V600E mutation and 7 KRAS mutations in codons 12 and 13 using fluorescent allele specific PCR with capillary electrophoresis. Clinical data was collected via chart review. Results: 58 males and 53 females were studied. The incidence of KRAS and BRAF mutations among the 111 samples was 49.5% and 6.3%, respectively. KRAS G12D and G12V were the most common mutations, representing 57% of total KRAS mutations. Dually positive KRAS and MSI tumors exclusively demonstrated G12D and G13D mutations. KRAS and BRAF mutations were mutually exclusive. Rectal cancers did not show evidence of BRAF V600E mutation (p=0.04). KRAS, BRAF, and MSI status did not correlate with survival, however pre-operative and post-operative carcinoembryonic antigen (CEA) levels were significantly associated with survival both in univariate and multivariate analyses. Conclusions: We demonstrate that BRAF V600E mutation is significantly associated with colon cancer and not rectal cancer, suggesting that BRAF mutations are not relevant in rectal carcinogenesis. Correlation between specific KRAS mutation and outcome may require larger populations. No significant financial relationships to disclose.

KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy

Background and purpose KRAS and BRAF are mutated in 35% and 10% of colorectal cancers, respectively. However, data specifically for locally advanced rectal cancers are scarce, and the frequency of KRAS mutations in codons 61 and 146 remains to be established. Materials and methods DNA was isolated from pre-therapeutic biopsies of 94 patients who were treated within two phase-III clinical trials receiving preoperative chemoradiotherapy. Mutation status of KRAS exons 1–3 and BRAF exon 15 was established using the ABI PRISM Big Dye Sequencing Kit and subsequently correlated with clinical parameters. Results Overall, KRAS was mutated in 45 patients (48%). Twenty-nine mutations (64%) were located in codon 12, 10 mutations (22%) in codon 13, and 3 mutations (7%) in codons 61 and 146. No V600E BRAF mutation was detected. The presence of KRAS mutations was correlated neither with tumor response or lymph node status after preoperative chemoradiotherapy nor with overall survival or disease-free survival. When KRAS exon 1 mutations were separated based on the amino-acid exchange, we again failed to detect significant correlations ( p = 0.052). However, G12V mutations appeared to be associated with higher rates of tumor regression than G13D mutations ( p = 0.012). Conclusion We are the first to report the mutation status of KRAS and BRAF in pre-therapeutic biopsies from locally advanced rectal cancers. The high number of KRAS mutations in codons 61 and 146 emphasizes the importance to expand current mutation analyses, whereas BRAF mutations are not relevant for rectal carcinogenesis. Although the KRAS mutation status was not correlated with response, the subtle difference between G12V and G13D mutations warrants analysis of a larger patient population.

Molecular Genetic Changes Associated With Colorectal Carcinogenesis Are Not Prognostic for Tumor Regression Following Preoperative Chemoradiation of Rectal Carcinoma

Preoperative chemotherapy and radiation has become the standard of care for many patients with rectal cancer. The therapy may have toxicity and delays definitive surgery. It would therefore be desirable to identify those cancers that will not regress with preoperative therapy. We assessed a series of rectal cancers for the molecular changes of loss of heterozygosity of the APC and DCC genes, K-ras mutations, and microsatellite instability, changes that have clearly been associated with rectal carcinogenesis. Diagnostic colonoscopic biopsies from 53 patients who received preoperative chemotherapy and radiation were assayed using polymerase chain reaction techniques followed by single-stranded conformation polymorphism and DNA sequencing. Regression of the primary tumor was evaluated using the surgically removed specimen. Twenty-three lesions (45%) were found to have a high degree of regression. None of the molecular changes were useful as indicators of regression. Recognized molecular changes critical for rectal carcinogenesis including APC and DCC loss of heterozygosity, K-ras mutations, and microsatellite instability are not useful as indicators of tumor regression following chemoradiation for rectal carcinoma.

Expression of C-Reactive Protein in Rectal Cancer.

BackgroundThe possible involvement of inflammation on colorectal carcinogenesis has potential prognostic, preventive and therapeutic implications. We investigated immunohistochemically whether C-reactive protein is expressed in human primary rectal adenocarcinoma and assessed its relationship with clinicopathological findings.MethodsNinety-one rectal cancer samples and 22 normal control samples were immunohistochemically analysed.ResultsCell accumulation of C-reactive protein was observed in 65 (71%) out of 91 patients with rectal adenocarcinoma and in all 22 control cases (p < 0.01). No significant difference was observed regarding to clinicopathological features or survival rates, but a linear correlation between the positivity proportion of C-reactive protein and Dukes-Turnbull stage (p = 0.005) was observed.ConclusionsThese data suggest that C-reactive protein might play a role in rectal carcinogenesis, but seems not to affect prognosis. Additional studies are warranted in larger population samples.

Cigarettes and alcohol in relation to colorectal cancer: the Singapore Chinese Health Study

The relations were examined between colorectal cancer and cigarette smoking and alcohol consumption within the Singapore Chinese Health Study, a population-based, prospective cohort of 63 257 middle-aged and older Chinese men and women enrolled between 1993 and 1998, from whom baseline data on cigarette smoking and alcohol consumption were collected through in-person interviews. By 31 December 2004, 845 cohort participants had developed colorectal cancer (516 colon cancer, 329 rectal cancer). Compared with nondrinkers, subjects who drank seven or more alcoholic drinks per week had a statistically significant, 72% increase in risk of colorectal cancer hazard ratio (HR)=1.72; 95% confidence interval (CI)=1.33–2.22). Cigarette smoking was associated with an increased risk of rectal cancer only. Compared with nonsmokers, HRs (95% CIs) for rectal cancer were 1.43 (1.10–1.87) for light smokers and 2.64 (1.77–3.96) for heavy smokers. Our data indicate that cigarette smoking and alcohol use interact in the Chinese population in an additive manner in affecting risk of rectal cancer, thus suggesting that these two exposures may share a common etiologic pathway in rectal carcinogenesis.

Aneuploidy-Dependent Massive Deregulation of the Cellular Transcriptome and Apparent Divergence of the Wnt/β-catenin Signaling Pathway in Human Rectal Carcinomas

To identify genetic alterations underlying rectal carcinogenesis, we used global gene expression profiling of a series of 17 locally advanced rectal adenocarcinomas and 20 normal rectal mucosa biopsies on oligonucleotide arrays. A total of 351 genes were differentially expressed (P < 1.0e-7) between normal rectal mucosa and rectal carcinomas, 77 genes had a >5-fold difference, and 85 genes always had at least a 2-fold change in all of the matched samples. Twelve genes satisfied all three of these criteria. Altered expression of genes such as PTGS2 (COX-2), WNT1, TGFB1, VEGF, and MYC was confirmed, whereas our data for other genes, like PPARD and LEF1, were inconsistent with previous reports. In addition, we found deregulated expression of many genes whose involvement in rectal carcinogenesis has not been reported. By mapping the genomic imbalances in the tumors using comparative genomic hybridization, we could show that DNA copy number gains of recurrently aneuploid chromosome arms 7p, 8q, 13q, 18q, 20p, and 20q correlated significantly with their average chromosome arm expression profile. Taken together, our results show that both the high-level, significant transcriptional deregulation of specific genes and general modification of the average transcriptional activity of genes residing on aneuploid chromosomes coexist in rectal adenocarcinomas.

Reply

We would like to thank Brenner et al1Brenner D.J. Curtis R.E. Hall E.J. Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery.Cancer. 2000; 88: 398-406Google Scholar for their comments supporting the findings of our study. While we agree that a radiation dose is given to tissues outside of the high-dose radiation volumesduring radiation therapy for cancer, most studies have demonstrated that the major carcinogenic effect from radiation is within the high-dose region.1Brenner D.J. Curtis R.E. Hall E.J. Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery.Cancer. 2000; 88: 398-406Google Scholar, 2Kleinerman R.A. Boice Jr, J.D. Storm H.H. Sparen P. Andersen A. Pukkala E. Lynch C.F. Hankey B.F. Flannery J.T. Second primary cancer after treatment for cervical cancer. An international cancer registries study.Cancer. 1995; 76: 442-452Google Scholar We certainly agree that organs other than the rectum are exposed to a high does of radiation during radiation therapy for prostate cancer, particularly the bladder, and this must be considered for surveillance after prostate irradiation. The increased risk of lung cancer in patients who undergo irradiation for prostate cancer lung is an intriguing finding. Although the lung receives a radiation dose (combination of scatter and leakage) of approximately 60 cGy during prostate cancer treatment, this dose does not produce a major increase in cancer formation in most organs; other exposures, such as cigarette smoking, may act synergistically with irradiation to increase lung cancer incidence (as has been shown in radium miners).3Morrison H.I. Villeneuve P.J. Lubin J.H. Schaubel D.E. Radon-progeny exposure and lung cancer risk in a cohort of Newfoundland fluorspar miners.Radiat Res. 1998; 150: 58-65Google Scholar However, important risk factors for lung cancer, particularly cigarette smoking, may not be equally distributed between those treated with radiation therapy and those treated with surgery, and this may result in an apparent increased risk of lung cancer in the irradiated group due to confounding. Our study4Baxter N.N. Tepper J.E. Durham S.B. Rothenberger D.A. Virnig B.A. Increased risk of rectal cancer after prostate radiation a population-based study.Gastroenterology. 2005; 128: 819-824Abstract Full Text Full Text PDF Scopus (166) Google Scholar and Brenner’s study1Brenner D.J. Curtis R.E. Hall E.J. Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery.Cancer. 2000; 88: 398-406Google Scholar employed cohort designs and therefore confounding due to selection bias is a concern and may account for apparent differences in rectal cancer rates between those who undergo surgery and those who undergo irradiation. For example, in our study, we found that patients undergoing irradiation were significantly older than those undergoing surgery. As increasing age is a known risk factor for rectal cancer, patients undergoing irradiation in both studies were at a higher baseline risk of rectal cancer than patients who had surgery only. Although we controlled for age in our analysis, we could not control for unmeasured confounders, and thus the potential for selection bias remained. By demonstrating a significant increase in cancer in the area in the high-dose region (the rectum) but no significant increase in areas outside the high-dose region (the remainder of the colon), we were able to conclude that irradiation has a direct effect on rectal carcinogenesis, and this effect cannot be explained by any baseline higher risk of colorectal cancer in those undergoing radiation therapy. Our consideration of the potential influence of selection bias represents a major improvement over the methods of previous research in this area1Brenner D.J. Curtis R.E. Hall E.J. Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery.Cancer. 2000; 88: 398-406Google Scholar, 5Neugut A.I. Ahsan H. Robinson E. Ennis R.D. Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma.Cancer. 1997; 79: 1600-1604Google Scholar, 6Pickles T. Phillips N. The risk of second malignancy in men with prostate cancer treated with or without radiation in British Columbia, 1984–2000.Radiother Oncol. 2002; 65: 145-151Google Scholar and greatly strengthens our conclusions. Prostate Radiotherapy Is Associated With Second Cancers in Many Organs, not Just the ColorectumGastroenterologyVol. 129Issue 2PreviewThe recent study by Baxter et al1 on rectal cancer associated with prostate cancer radiotherapy extended by several years the follow-up period from our earlier study,2 based on the same SEER cancer registry database. The more extended follow-up confirms our earlier conclusion that rectal cancer is significantly elevated in long-term survivors of prostate cancer radiotherapy, compared with a comparison group of prostate cancer patients who underwent surgery alone. Baxter et al1 report risks for radiation-associated rectal cancer that are very similar to our earlier estimates; specifically, they estimate a hazard ratio (radiotherapy vs. Full-Text PDF

Different genetic features associated with colon and rectal carcinogenesis.

The issue of whether colon and rectal cancer should be considered as a single entity or two distinct entities is still debated, and there is a need to improve studies addressing the heterogeneity of the pathogenetic pathway leading to sporadic colorectal cancers (SCRCs) as well as to identify biological and/or molecular differences between colon and rectal cancers. Specimens of SCRCs were analyzed for somatic mutations in APC, K-ras, and TP53 genes and loss-of-heterozygosity of chromosome 18. Eleven SCRCs showed microsatellite instability. APC mutation frequency was significantly lower in microsatellite instability (MIN+) than in MIN- SCRCs. All MIN- SCRCs showed beta-catenin overexpression. A combined analysis of the biomarkers revealed two pathways mainly represented by MIN- SCRCs and differently followed on the basis of tumor location, APC-K-ras-TP53-Ch18q and APC-TP53-Ch18q. The APC-beta-catenin pathway is inactivated in MIN- SCRCs and represents the first hit of SCRC development. Two preferential pathways followed by SCRCs occur, one K-ras dependent, in agreement with the Fearon and Vogelstein model, and the other K-ras independent. Significant differences between colon and rectal tumors occur in our series of MIN- SCRCs. The different pathways observed and their distribution can be summarized as follows: (a) K-ras mutations were more commonly detected in colon than in rectum; (b) the number of mutations detected was significantly higher in colon than in rectal tumors; and (c) a mutational pattern restricted to the APC gene was more common in rectal than in colon tumors. This molecular characterization can be translated into a clinical setting to improve diagnosis and to direct a rationale pharmacological treatment.

Nature's perfect food revisited: recent insights on milk consumption and chronic disease risk.

In Swedish volunteers, consuming spaghetti along with milk raises the insulinemic effect of the meal. In Finnish citizens followed for 19 to 24 years for cancer incidence, different consumption patterns of dairy items had different relationships with colon and rectal carcinogenesis. More definitive and conclusive research into how dairy products might influence chronic disease would seem to be warranted.

Dietary iron and cancer of the rectum: a case-control study in Uruguay.

In order to examine the relationship between dietary iron intake and risk of rectal cancer, a case-control study was carried out in Montevideo, Uruguay. In the time period 1994-1998, 216 newly diagnosed and microscopically verified cases of adenocarcinoma and 433 controls hospitalized for diseases not related with long-term changes in diet were enrolled in the study. Controls were frequency matched to cases on age, sex, residence and urban/rural status. Both series of patients were interviewed face-to-face in the four major hospitals in Montevideo by two trained social workers. Dietary iron was associated with significant increases in risk in men, women, and in both sexes together [odds ratio (OR) 3.2, 95% confidence interval (CI) 1.9-5.3 for the highest tertile of consumption versus the lowest one]. Since meat and its major macronutrients were potential confounders, iron intake was adjusted for these variables without major changes in the results. Furthermore, dietary iron and total fat combined its effects according to a multiplicative model (OR 3.3, 95% CI 1.8-5.8). Finally, an interaction between dietary iron and vitamin C was found. According to the results, iron displayed a significant increase in risk at low levels of vitamin C intake (OR 4.9, 95% CI 2.3-10.5). These results, together with the existing epidemiological and experimental evidence, suggest that dietary iron could play an important role in rectal carcinogenesis.

Enhancing effects of immunization with rectal extract on rectal carcinogenesis by local X-irradiation caused in male A/HeJ mice

The influence of preimmunization with a rectal extract on X-irradiation rectal carcinogenesis in the rectum was investigated in male 4-7-week-old A/HeJ mice. They were given 20 Gy per week for a total 40 Gy in the pelvic region with or without 2 prior injections of rectal extract emulsified with complete Freund's adjuvant. Rectal adenocarcinomas were observed in 21 of 34 (62%) immunized animals and in 4 of 22 (18%) non-immunized mice 32 weeks after the last X-irradiation (P<0.01). The total incidences of adenocarcinomas at the 84 week time point were 25/45 (56%) and 12/36 (33%), respectively (P<0.05).

Possible role of acetaldehyde in ethanol-related rectal cocarcinogenesis in the rat

Prospective epidemiologic studies have reported an increased risk of rectal cancer following chronic ethanol ingestion. The effect of ethanol on chemically induced colorectal carcinogenesis is controversial depending on the experimental conditions. In the present study the effect of chronic ethanol administration on acetoxymethylmethylnitrosamine-induced rectal cancer and the possible role of acetaldehyde in this process were investigated. Chronic ethanol administration resulted in an earlier occurrence of rectal tumors in this animal model. Because the concomitant administration of cyanamide, a potent acetaldehyde dehydrogenase inhibitor, showed a positive trend toward increased incidences of tumors, acetaldehyde could be involved in the ethanol-associated carcinogenesis. To measure colonic acetaldehyde, 12 chronically ethanol-fed and control rats received an acute dose of ethanol (2.5 g/kg body wt). The mucosal concentration of acetaldehyde was significantly higher in the rectum compared with the cecum (198 ± 23 vs. 120 ± 23 nmoles · g colon−1, p < 0.05), but was not affected by chronic ethanol feeding. Furthermore, 6 germ-free rats had significantly lower acetaldehyde concentrations in the rectum (84 ± 11 vs. 234 ± 33 nmoles · g colon−1, p < 0.01) and in the cecum (59 ± 13 vs. 121 ± 33 nmoles · g colon−1, p < 0.05) compared with 6 conventional animals, and this was paralleled by the number of fecal bacteria in the 2 intestinal segments. In addition, to determine the effect of chronic ethanol feeding on colorectal cell turnover, 30 animals were pair-fed liquid diets. Using the metaphase-arrest technique, alcohol feeding induced rectal (19.1 ± 2.0 vs. 9.1 ± 1.8 cells · crypt−1 · h−1, p < 0.01), but not cecal (18.9 ± 1.3 vs. 22.2 ± 3.3 cells · crypt−1 · h−1, p > 0.05) hyperregeneration. This was accompanied by an increase in the crypt proliferative compartment and increased mucosal ornithine decarboxylase activity (63 ± 18 vs. 22 ± 6 pmoles · hr−1 · mg protein−1, p < 0.05). The data show that chronic ethanol ingestion accelerates chemically induced rectal carcinogenesis and raise the possibility that acetaldehyde probably generated through bacterial ethanol oxidation may be involved in this process. The secondary hyperregeneration of the mucosa, observed after alcohol feeding, could by itself favour carcinogenesis.