Risk Of Developing Colorectal Cancer Research Articles

Características de los pacientes con poliposis adenomatosa familiar en España. Resultados iniciales del Registro Español de Poliposis Adenomatosa Familiar

Background and objectives Familial adenomatous polyposis is an inherited disorder characterized by the presence of multiple colorectal adenomas (more than 100 in the classic form and between 10 and 100 in the attenuated one), with a high risk of colorectal cancer development. To improve the diagnostic and therapeutic management of these patients, the Spanish Registry of Familial Adenomatous Polyposis was created in 2007.We aimed to evaluate the clinicopathological characteristics of patients with familial adenomatous polyposis in Spain. Patients and methods All patients included in the Registry during one year were evaluated with respect to their demographic, clinical, pathological, and genetic characteristics. Results 243 patients of 156 unrelated families from 15 Spanish centers were included. One hundred thirty patients were male, and the mean age at diagnosis was 40 years. According to the clinical presentation, 127 corresponded to the classic form and 116 to the attenuated one. Colorectal adenoma with high-grade dysplasia was identified in 67 (28%) patients, and colorectal cancer in 42 (17%). Extracolonic manifestations were: duodenal involvement (n=46), gastric involvement (n=44), desmoid tumors (n=24), thyroid cancer (n=8), osteomas (n=6) and brain tumor (n=1). APC and/or MYH gene testing was performed in 140 (90%) families, detecting the causative mutation in 75 (54%) of them (70 in the APC gene and 5 in the MYH gene). Conclusions During its first year of operability, a large number of patients and families were included in the Registry. The reduced prevalence of colorectal cancer as well as the large proportion of families submitted to gene testing demonstrated a high-quality clinical practice in Spain.

R72P Polymorphism of TP53 in Ulcerative Colitis Patients is Associated with the Incidence of Colectomy, Use of Steroids and the Presence of a Positive Family History

P53 tumor suppressor protein is one of the pivotal regulators for genome integrity, cell cycle and apoptosis. The most commonly and extensively studied single nucleotide polymorphism (SNP) of p53 is Arg>Pro substitution on codon 72 (R72P). Although we know that the SNP has unique functional effects on the protein, its clinical significance is not clearly identified yet. Aim of the study was to access the relationship between R72P genotype distribution and clinical variables in patients with ulcerative colitis (UC) and colorectal cancer (CRC). Genomic DNA samples were extracted from 95 UC, 50 CRC, and 219 healthy controls. R72P genotype analysis was carried out with polymerase chain reaction following by restriction enzyme digestion. We observed that Pro allele carriage is a strong risk factor for CRC (OR = 3.03; 95%CI = 1.91-2.40; p = 0.003), but only modest association with UC (OR = 1.61; 95%CI = 0.98-2.65; p = 0.059) (Pro/Pro and Pro/Arg genotypes vs. Arg/Arg genotype). We did not find any correlation between genotype distribution of the polymorphism and clinical parameters of CRC, but in UC, Pro/Pro genotype was significantly related to an inflammatory bowel disease family history (OR = 8.0; 95%CI = 1.68-38.08, p = 0.015), and Arg/Pro genotype was significantly associated with the history of disease-related colectomy (OR = 17.77; 95%CI = 0.98-323.34, p = 0.012) and steroid use (OR = 10.14; 95%CI = 2.63-39.12, p = 0.0002). Our data suggest that R72P variant seems to be associated with high risk for development of CRC but carries low risk for development of UC. R72P genotypes might be a useful predictive marker for surgical and medical treatment of UC.

Methylenetetrahydrofolate reductase gene polymorphisms and the risk of colorectal carcinoma in a sample of Egyptian individuals

The study was planned as a pilot study to investigate two common polymorphisms in the MTHFR gene c.677C > T and c.1298A > C and their association with enhanced risk of colorectal cancer (CRC) in a sample of Egyptian individuals. Venous blood samples were withdrawn from 35 cases of CRC and 68 healthy controls. Specimens from colonic and rectal carcinoma tissues in addition to cancer free tissues were obtained from all cases. Frequencies of MTHFR677T and 1298C alleles were significantly higher among cases of CRC tumor tissues (50% and 56%, respectively) than germ line alleles in CRC patients (33% and 41%, respectively) and healthy controls (21% and 35%, respectively). Frequencies of heterozygous and homoyzgous polymorphisms of MTHFR at positions 677 and 1298 in carcinoma tissues were always the highest. At position 677, TT and CT genotype frequencies were 17% and 66% with an odds ratio {OR} of 11 [95% confidence interval {CI} 2.39-50.59] and OR 8.34 [95%CI 2.97-23.92], respectively, in carcinoma tissues. While in the germ line of patients the genotype frequencies of 677TT and CT were 6% and 54% with OR 1.57 [95%CI 0.26-9.51] and 2.99 [95%CI 1.25-7.12], respectively, compared to controls (6% and 29%, respectively). The combined genotype MTHFR 1298CC + AC frequencies were 86% with OR 3.71 [95%CI 1.28-10.78] in carcinoma tissues, 69% with OR 1.35 [95%CI 0.57-3.21] in germ line of patients and 62% in controls. The combined genotype 677CT plus any of the following genotypes 1298AA, AC or CC enhanced risk of CRC, when comparing germ line DNA polymorphism of patients versus peripheral blood DNA of control subjects with OR 4.5 [95%CI 0.94-21.56], OR 3.12 [95%CI 0.79-12.36] and OR 18 [95%CI 1.56-207.5], respectively, suggesting strong genetic predisposition of certain Egyptian population to CRC. These results suggested that at least one C to T polymorphism at 677MTHFR gene is required to significantly increase the risk for CRC development. Further large scale studies are required to confirm the present findings.

Mesalamine Protects Against Colorectal Cancer in Inflammatory Bowel Disease

Individuals with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC) compared with the general population. Previous studies show this risk is strongly associated with dysplasia, extent of disease, duration of disease, and degree of inflammation, while chemoprevention of CRC has less support. Evaluate factors influencing risk of colorectal cancer development in inflammatory bowel disease patients. IBD patients with CRC were matched to controls by IBD type, age at diagnosis, sex, race, extent of disease, and disease duration. We compared body mass index, family history of IBD, family history of CRC, tobacco use, and cumulative and daily use of aminosalicylates, immunomodulators, folic acid, steroids, and nonsteroidal anti-inflammatory drugs. Statistical analysis was performed with logistic regression and receiver operating characteristic (ROC) curves. Of 1,594 IBD patients, 30 CRC patients were identified. Of these, 18 CRC patients were matched to 30 controls. More control patients used a cumulative aminosalicylate dose of >or=4,500 g (46.6% versus 5.6%; P = 0.047), folic acid (40.0% versus 16.7%; P = 0.002), cumulative folic acid dose of >or=1,400 mg (30.0% versus 11.1%; P = 0.014), and average daily folic acid dose of >or=1 mg (30.0% versus 16.7%; P = 0.002) compared with CRC patients. Multivariate analysis showed that a cumulative aminosalicylate dose of >or=4,500 g reduced the risk of CRC by 97.6% (P = 0.047). Folic acid reduced CRC risk by 89% (P = 0.002). Aminosalicylate and folic acid use may decrease the risk of CRC among IBD patients.

Association Between Two Functional Polymorphisms of Insulin-Like Growth Factor Binding Protein 3 and Colorectal Cancer Risk in a Chinese Population

Circulating levels of insulin-like growth factor binding protein 3 (IGFBP3) are modulated by functional variants of IGFBP3 and therefore may be associated with higher risk of colorectal cancer development. However, few studies have investigated the role of IGFBP3 polymorphisms in colorectal cancer in Chinese individuals. In this study, two common polymorphisms of IGFBP3 were determined by the Taqman genotyping platform in 202 Chinese colorectal cancer cases diagnosed between 2006 and 2008 and 212 cancer-free population controls. Data showed that the genotype distribution of G2133C (rs2864746), but not A-202C (rs2864744), was significantly different between cancer cases and controls. Unconditional logistic regression analyses revealed that participants carrying the G2133C GC heterozygote or CC homozygote had a significant 1.55-fold increased risk of colorectal cancer development in an allele dose-responsive manner. However, there was no evidence of a dose-effect relationship between number of variants and risk for CRC occurrence. Data suggest that the exon 1 G2133C missense variant of IGFBP3 may be a susceptibility factor for colorectal cancer in Chinese subjects. Larger studies are warranted to validate our findings in a Chinese population.

Will Virtual Colonoscopy Replace Optical Colonoscopy for Colorectal Cancer Screening?

Will Virtual Colonoscopy Replace Optical Colonoscopy for Colorectal Cancer Screening?

Patients with pancreatic intraductal papillary mucinous neoplasms are at high risk of colorectal cancer development

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has been recognized recently and is being diagnosed with increasing frequency. Although IPMN has a more favorable prognosis than standard invasive ductal carcinoma (IDC) of the pancreas, recent reports suggest that IPMN patients are at higher risks of synchronous or metachronous primary cancers arising from various organs other than the pancreas (extrapancreatic cancers). Records of 370 patients (69 of IPMN, 301 of IDC) who underwent surgery were used to assess risk factors for preoperative or postoperative extrapancreatic cancers. To calculate the rate of increase of extrapancreatic cancers in IPMN patients, compared with the normal population, the observed/expected ratio (O/E ratio) was calculated by using the Osaka Cancer Registry, one of the world largest cancer databases. The incidence of preoperative extrapancreatic cancers was significantly higher in IPMN patients (28%, 19 patients) than that in IDC (9%, 27 patients). In the IPMN-group, the preoperative incidence of colorectal cancer was 12% followed by gastric cancer at 4%. Logistic regression analysis showed IPMN and age to be independent risk factors for preoperative colorectal cancer development. The O/E ratio of preoperative colorectal cancer was significantly high in IPMN patients (5.37; 95% confidence interval, 2.31-10.58) but not in IDC patients (1.24; 95% confidence interval, 0.46-2.70). The incidence of postoperative extrapancreatic cancers also was significantly higher in IPMN patients (15%, 10 patients) than that in IDC (4%, 12 patients). During the postoperative follow-up, 4% of IPMN (3 patients) and 0.7% of IDC (2 patients) died from extrapancreatic cancers. Our results indicate that IPMN patients are at significantly higher risks of extrapancreatic cancers including colorectal cancer. A careful systemic checkup is therefore required for preoperative screening and postoperative follow-up for IPMN patients.

Chronic colitis promotes tumor development

Patients with chronic ulcerative colitis have a significantly increased risk of colorectal cancer development. This study was aimed at clarifying whether colitis promotes tumor development or not. A dose of 200 mg/kg body weight 1,2-dimethylhydrazine was given to male Wistar rats. Four weeks later, 5% acetic acid (colitis group) or 0.9% saline (control group) was administered intrarectally once a week for 12 weeks and the rats were sacrificed after 27 weeks of dimethylhydrazine injection. Macroscopic lesions (ML) were more frequently detected in the colitis group than in the control group without statistical significance. However, the number of ML per rat with ML was largest in the colitis group (4.50 vs. 1.33; p=0.039). Eleven of 13 tumors were sessile in the colitis group, while three of five were pedunculated in the control group (p=0.044). All ML of 3 mm or more in diameter in the control group were intramucosal well-differentiated tumors. In the colitis group, 4 of 13 tumors were poorly or moderately differentiated or mucinous carcinomas, and 11 of 13 invaded the submucosal layer or deeper (p=0.003). The number of aberrant crypt foci per rat was smaller in the colitis group than in the control group. The number of crypt orifices was larger in the colitis group than in the control group (23.6 vs. 8.8: p<0.001). Significantly higher proliferative activity of normal-appearing mucosa was noted in the colitis group in all three parts of the colon. Colitis is suggested to promote colonic tumor development.

Factors associated with colorectal cancer screening in a population-based study: the impact of gender, health care source, and time

Introduction. The effectiveness of colorectal cancer screening in reducing incident colorectal cancer and the risk of death has been shown. Despite campaigns to promote the benefits of and use of colorectal cancer screening, most people are not participating in screening. In this paper, we examine factors associated with screening behavior over time, by health care provider, and by gender and report associations between screening and development of colorectal cancer after adjusting for diet and lifestyle factors. Methods. Data from two population-based case-control studies of colorectal cancer were used to examine risk associations with nonparticipation in colorectal cancer screening. Study participants were identified for the first study between 1991 and 1994 ( N = 1,346 cases and 1,544 controls) and for the second between 1997 and 2001 ( N = 952 cases and 1,205 controls) and were asked to complete a detailed in-person interviewer-administered diet and lifestyle questionnaire. The control population is used to examine changes in screening behavior and associations with screening over time. Results. Significantly, fewer people reported fecal occult blood test (FOBT) in 1997–2001 than in 1991–1994 (62.5% in 1991–1994 vs. 47.2% in 1997–2001); a slight nonsignificant increase in sigmoidoscopy screening was reported for these periods among controls (33.9% vs. 36.6%). In the control population, during these periods, there was a statistically significant increase in the number of people who reported having had a sigmoidoscopy for screening rather than for problems (72.6% in 1997–2001 vs. 63.8% in 1991–1994). There were differences in factors associated with screening behavior by time, by sex, and by health care provider, although having a family history of colorectal cancer, having more education, and being male was associated with more screening in all settings. After adjusting for diet and lifestyle factors, we observed that non-sigmoidoscopy screening significantly influenced risk of incident cancer (rectal OR: 2.9; 95% CI, 2.3–3.7; distal tumor OR: 1.8; 95% CI, 1.4–2.3); proximal tumor: 1.4; 95% CI, 1.1–1.8). Nonuse of FOBT also was associated significantly with tumors in the rectal (OR: 1.6; 95% CI, 1.3–1.9) and distal (OR: 1.4; 95% CI, 1.1–1.8) sites. Summary. These data reinforce the importance of screening to reduce risk of colorectal cancer development. However, flexible sigmoidoscopy screening is increasing only modestly over time, and primarily in settings where a significant investment in screening has been made. FOBT screening, which is effective for rectal cancer prevention, is actually decreasing.

Estimation of angiogenesis with anti-CD105 immunostaining in the process of colorectal cancer development

The expression of panendothelial markers (eg, CD34, CD31, and factor VIII) is not always observed in angiogenic vessels, and such markers are not useful for measuring angiogenesis. In contrast, CD105 is preferentially expressed in angiogenic vessels and thus may be valuable for measuring angiogenesis. We hypothesized that microvessel quantification by means of CD105 might be useful for measuring angiogenesis in the colorectal adenoma-carcinoma sequence. We immunohistochemically investigated 54 cases of colorectal adenomas and 20 cases of carcinomas using monoclonal antibodies CD34 and CD105, and microvessel density (MVD) was counted at x200 magnification. Microvessels positive for CD34 were distributed almost uniformly in adenomas. In contrast, microvessels positive for CD105 were preferentially observed in the surface area of adenomas. In carcinomas, CD34 stained only a proportion of blood vessels that were positive for CD105. No significant difference of MVD for CD34 was observed in the colorectal adenoma-carcinoma sequence. In contrast, an increment of MVD for CD105 from low-grade to high-grade dysplasia (P <.0001) and that from high-grade dysplasia to carcinomas (P <.05) was statistically significant. Assessing neovascularization with CD105 in the process of colorectal cancer development may thus be a valuable marker for predicting the risk of colorectal cancer development.

Screening for prevention and early detection of colorectal carcinoma

Colorectal Cancer (CRC) fulfills all the criteria for a successful screening: i) it is a frequent tumor associated with serious morbidity and mortality; ii) recognition and treatment of premalignant lesions or early tumor stages improves prognosis and lowers its incidence, respectively. During recent years, our understanding of the biology, diagnosis and therapy of adenomas and CRCs led to the identification of risk factors. Based on these, screening strategies differ for individuals with average risk (age > or = 50 years, no risk factors) and individuals with increased risk for CRC development (positive personal history [CRC, colorectal adenomas, inflammatory bowel disease]; positive family history [CRC, colorectal adenomas, hereditary syndromes]). The currently available strategies aimed at prevention and early detection of CRCs (past history, family history, rectal digital examination, fecal occult blood testing, endoscopy) are discussed and recommendations for their implementation are formulated.

Calcium phosphate

In an effort to reduce the risk of colorectal cancer development, oral calcium carbonate supplementation has been used in previous studies for the precipitation of cytotoxic bile acids and fatty acids. In human intervention trials its effect on mucosal hyperproliferation in the colorectum has not always been satisfactory. Because the complexation of calcium and bile acids requires the formation of calcium phosphate, we performed an intervention study in 14 healthy volunteers, giving them 1,500 mg calcium as Ca3(PO4)2 for 1 week. The effects of tricalcium phosphate on luminal and faecal parameters of cytolytic activity were evaluated before, during, and after calcium phosphate supplementation. The cytolytic activity of faecal water and intestinal alkaline phosphatase activity in faecal water were not affected by supplemental calcium phosphate. In duodenal bile, the proportion of cholic acid tended to increase, whereas that of chenodeoxycholic acid tended to decrease during calcium phosphate supplementation. Neither concentrations of total and individual faecal bile acids, nor that of faecal fat were affected during calcium phosphate supplementation. It is suggested that, although phosphate is involved in bile acid precipitation, phosphate competes for calcium in the binding of fatty acids. This might possibly explain the unchanged cytolytic potency of faecal water, and therefore does not make tricalcium phosphate a suitable calcium compound for dietary intervention.