Sporadic Colorectal Neoplasia Research Articles

CA 19.9 and HDL-cholesterol behaviour in a sporadic colorectal carcinoma sample

We have carried out a comparative prediction analysis in sporadic colorectal carcinoma of plasmatic lipids and currently tumor markers used in this neoplasia (carcinoembrionary antigen - CEA, CA 19.9 and sialic acid -SA). Transversal hospital-based case-control study. Sample was composed by 53 sporadic colorectal neoplasia patients just before surgery and 40 non matched controls. A 90 per cent of cases were at Dukes A and B stages. A multivariable model was fitted with non-conditional logistic regression. Confidence intervals were calculated at 95 per cent of confidence. Model sensibility and specificity were performed at 50 per cent cutting point. We also explored possible interactions. All three tumor markers (CEA, CA 19.9 and SA) were elevated in cases (p<0.01). Multivariable model included: Total cholesterol (TC) (OR= 0.69; CI: 0.50-0.96) high density lipoprotein fraction (HDL) (OR = 0.30; CI: 0.11-0.83) very low density lipoprotein fraction (VLDL) (OR = 2.21; CI = 1.07-4.55) years of age (OR = 1.11; CI = 0.98-1.26) CA 19.9 (OR = 1.20; CI = 1.02-1.42) and alkaline phosphatase (OR = 1.09; CI = 1.01 - 1.19). No interactions were found out. Model sensibility reached 96.23% and a specificity of 92.50%. HDL showed a similar diagnostic strength than CA 19.9 in this sporadic colorectal carcinoma sample but with an inverse OR. This multivariable model is going to be validated.

Frequent loss of SMAD4/DPC4 protein in colorectal cancers

Background and aims: Loss of DNA sequences from chromosome 18q21 is a major genetic change in colorectal tumorigenesis. Multiple genes have been identified in this area. One of these, DPC4...

Cyclo-oxygenase 2 inhibitors: emerging roles in the gut.

Discovery of an isoform of Cyclo-oxygenase (COX) 1, the inducible COX-2, has made it possible to avoid some side effects of non-specific COX inhibitors. The COX-2 gene is over-expressed in reflux oesophagitis, Barrett's oesophagus, gastric and colon cancer, familial adenomatous polyposis, pancreatic cancer, hepatocellular carcinoma, hepatotoxicity, cirrhosis, and inflammatory bowel disease, and specific COX-2 inhibitors have been tried experimentally and clinically and found effective. A Medline search was performed of English-language experimental studies and controlled clinical trials from January 1980 to January 2002, and relevant citations were noted. Review of available literature shows that sulindac and COX-2 inhibitors are effective in preventing as well as regressing familial adenomatous polyposis. However, they have not been shown to prevent cancer in these patients. Studies evaluating NSAIDs and COX-2 inhibitors in carcinogen-induced and genetically manipulated animal models of various cancers have been promising especially in conditions such as Barrett's oesophagus, oesophageal and hepatocellular carcinoma and pancreatic cancer. COX-2 inhibitors may be of value in the treatment of reflux oesophagitis, pancreatitis and hepatitis, although carefully planned randomized controlled clinical trials demonstrating their efficacy need to be conducted. At present NSAIDs and COX-2 inhibitors cannot be recommended for average-risk individuals or for those with sporadic colorectal neoplasia (or other forms of cancers) as chemo-preventive agents. COX-2 inhibitors may open up a new therapeutic era in which these drugs can be used for chemo-prophylaxis. However, COX-2 selective inhibitors retain renal adverse effects of the non-selective inhibitors and the concern regarding the pro-thrombotic potential of COX-2 inhibitors will limit their value as chemo-preventive agents.

Clinical and screening implications of the I1307K adenomatous polyposis coli gene variant in Israeli Ashkenazi Jews with familial colorectal neoplasia. Evidence for a founder effect.

The authors previously found the I1307K adenomatous polyposis coli (APC) gene variant in 5% of Ashkenazi control participants, in 15.4% of those who had familial colorectal neoplasia, but also in 1.6% of non-Ashkenazi control participants. In this study, they evaluated its use in a screening program for familial colorectal neoplasia and examined for a founder effect. Consecutive Ashkenazim with a personal and/or family history of colorectal neoplasia had the DNA test. Markers flanking the APC gene were examined in Ashkenazi and non-Ashkenazi I1307K carriers and noncarriers. Among 718 persons, I1307K occurred in 6.2% of Ashkenazi participants, in 1.5% of non-Ashkenazi control participants (P = 0.02), and in 10.7% of Ashkenazim with familial neoplasia (relative risk, 1.73 [not significant compared with controls]; 95% confidence interval, 0.7-3.2). Colorectal neoplasia was detected in carriers at a younger age (P < 0.05) without excess risk for multiple colorectal neoplasia or noncolorectal neoplasia. I1307K attributable risk for colorectal neoplasia was 0.5-0.6%. Compared with noncarriers, both Ashkenazi and non-Ashkenazi I1307K carriers had similar flanking polymorphic alleles (P < 0.01). I1307K is a low-penetrance genetic variant that indicates a 1.7 relative risk for neoplasia in carriers who have familial carcinoma, clinically equivalent to obtaining a family history of sporadic colorectal neoplasia and promoting early screening. I1307K is a founder genetic variant in Jews of different ethnic origin, mainly Ashkenazim, but it explains only partially their higher incidence of colorectal carcinoma.

Chemoprevention of colorectal cancer.

Colorectal cancer is the third most incident cancer in the United States and is second only to lung cancer as a cause of cancer-related mortality. Colorectal cancer develops through a multistep process characterized by histopathological precursor lesions and molecular genetic alterations. This sequential process of tumorigenesis provides opportunities for the development and testing of both primary and secondary prevention strategies. This review focuses on chemoprevention, which is defined as the use of natural or synthetic agents to reverse the process of carcinogenesis. Epidemiological studies have consistently shown that chronic intake of nonsteroidal anti-inflammatory drugs (NSAIDs), principally aspirin, can reduce the incidence of colorectal adenomas and carcinomas. Evaluation of NSAIDs, including newer selective cyclo-oxygenase-2 inhibitors, in carcinogen-induced and genetically manipulated animal models of colorectal cancer demonstrates that these drugs are effective chemopreventive agents. In humans, the NSAID sulindac has been studied in familial adenomatous polyposis patients and was found to regress colorectal adenomas in a placebo-controlled trial. More recently, the selective cyclo-oxygenase-2 inhibitor Celebrex was also shown to be effective in familial adenomatous polyposis and was approved by the Food and Drug Administration as a adjuct to usual care in these patients. NSAIDs, as well as other chemopreventive agents, are currently being studied in patients at increased risk of colorectal cancer, including those with sporadic adenomas. The outcome of these studies has the potential to impact patient management practices. However, chemopreventive agents cannot be recommeded at present for average-risk individuals or for those with sporadic colorectal neoplasia. In addition to demonstrating efficacy, chemopreventive agents must be safe and well tolerated for chronic administration and should be relatively cost-effective. Although still in its infancy, the field of chemoprevention is an exciting and rapidly advancing area of investigation. Chemopreventive strategies, if effective, offer the promise of producing a paradigm shift in our current approach to colorectal cancer.

Epigenetics in colorectal cancer

Malignant transformation is now known to require a series of molecular alterations that disrupt a limited number of pathways including autocrine and paracrine responses to growth factors, cell-cycle control, senescence, motility, and invasion. Studies on hereditary cancers have established genetic changes as the primary driving force for these molecular alterations. Recently, however, it has been recognized that epigenetic changes, defined as clonal changes in gene expression without accompanying changes in primary DNA coding sequence, can also be a driving force in neoplastic transformation, for selected genes, and in specific tumors. DNA methylation within gene promoters and associated alterations in histone acetylation appear primary mediators of epigenetic inheritance in cancer cells. In the large intestine, aberrant DNA methylation arises very early, initially in normal-appearing mucosa, and may be part of the age-related field defect observed in sporadic colorectal neoplasia. Aberrant methylation also contributes to later stages of colon cancer formation and progression through a hypermethylator phenotype termed cytosine phosphoguanosine (CpG) island methylator phenotype (CIMP), which appears to be a defining event in approximately half of all sporadic tumors. In sporadic colon cancer, CIMP has distinct epidemiologic and clinical features and is responsible for most cases of microsatellite instability related to hMLH1 inactivation. The recognition of epigenetic changes as a driving force in colorectal neoplasia opens new areas of research in disease epidemiology, risk assessment, screening, and treatment.

Molecular genetics of dysplasia in ulcerative colitis.

Numerous molecular genetic events occurring in the development of sporadic colorectal neoplasia have been previously defined. The most frequent genetic alterations are mutations of the APC, KRAS, and TP53 genes, as well as loss of the DCC gene and of the second TP53 allele. The data from several groups indicate that these genes play an important role in ulcerative colitis-associated dysplasias and cancer, as they do in sporadic colorectal adenomas and carcinomas. KRAS and TP53 mutations were detected in dysplasia, but also in villous regeneration and active colitis, and affect a subpopulation of the cells composing these lesions. We conclude that in histologically defined dysplasia, clones can be found that genetically represent precancerous lesions in ulcerative colitis. Seen in this way, part of the active colitis and villous regeneration lesions might be considered as preneoplastic. When present, KRAS mutation is an excellent genetic marker to map populations of preneoplastic cells.

Hereditary Predisposition to Colorectal Cancer: New Insights

Hereditary predisposition to colorectal cancer assumes two well-defined forms: familial adenomatous polyposis and hereditary nonpolyposis colon cancer. These tumors segregate as autosomal dominant conditions whose penetrance increases with age; cancer is expected to develop ultimately in as much as 50% of the offspring of affected individuals. These traits account for less than 1% and approximately 5% of all colorectal cancer, respectively. In addition, first-degree relatives of patients with common (sporadic) colorectal neoplasia are at increased risk of colorectal cancer. This relative risk averages approximately twofold but is significantly higher for relatives of younger patients (age at diagnosis, < 55 years). Familial adenomatous polyposis and a major subset of hereditary nonpolyposis colon cancer are due to loss-of-function germline mutations of genes located on chromosomes 5q and 2p, respectively. Both of these genes have been cloned recently. The gene affected in familial polyposis, APC, encodes a protein of unknown function that normally is found on the surface of maturing cells in the upper colonic crypts. The relevant gene in many hereditary nonpolyposis colon cancer kindreds is hMSH2. This gene encodes the human homologue of a bacterial protein MutS, which is part of a system known to repair base mismatches in newly replicated DNA. Loss of hMSH2 function may explain the strikingly erroneous replication of short DNA repeats (microsatellites) in colon tumors from patients with hereditary nonpolyposis colon cancer. Because this error-prone replication is found in approximately 13% of nonfamilial colon cancers, defective mismatch repair may contribute to the development of both hereditary and sporadic colon neoplasia. Molecular genetic assays to detect mutated alleles of these genes will facilitate presymptomatic identification of carriers in families with familial polyposis and hereditary nonpolyposis colon cancer. Current recommendations for surveillance of family members are presented in the light of the new genetic understanding of these diseases.

Molecular genetic profiles of colitis-associated neoplasms

Background/Aims: A major long-term risk for patients with chronic idiopathic colitis is the development of colorectal dysplasia and adenocarcinoma. The presence or absence of specific genetic changes in these lesions will provide important insights into the relationship of colitis-associated dysplasia and the development of carcinoma. Methods: A case-study approach was used to develop detailed molecular genetic profiles of advanced dysplasias and carcinomas from six patients with ulcerative colitis or Crohn's colitis. Results: Numerous genetic alterations were identified in each of the dysplasias and carcinomas profiled. These genetic alterations involved many of the same targets found in sporadic colorectal tumors and included multiple sites of allelic deletion, microsatellite instabilities, and mutations of the K-ras, p53, and APC genes. The progression of dysplasia to carcinoma was often accompanied by an accumulation of these mutations. Conclusions: Genetic alterations are common in colitis-associated neoplasia, just as in sporadic colorectal neoplasia. This could have important implications for the evaluation and treatment of patients with colitis.

Expression Pattern of Metalloproteinases and Their Inhibitors Changes with the Progression of Human Sporadic Colorectal Neoplasia

Expression Pattern of Metalloproteinases and Their Inhibitors Changes with the Progression of Human Sporadic Colorectal Neoplasia

Expression Pattern of Metalloproteinases and Their Inhibitors Changes with the Progression of Human Sporadic Colorectal Neoplasia

Expression Pattern of Metalloproteinases and Their Inhibitors Changes with the Progression of Human Sporadic Colorectal Neoplasia

Expression Pattern of Metalloproteinases and Their Inhibitors Changes with the Progression of Human Sporadic Colorectal Neoplasia

Several studies have implicated the extracellular matrix-degrading metalloproteinases (MMPs) as essential agents in tumor cell invasion and metastasis. In the present study, we have investigated the patterns of expression of a number of MMPs and their specific tissue inhibitors (TIMP-1 and TIMP-2) in human colonic tissue samples that represent various stages of progression from adenomas showing different degrees of dysplasia to adenocarcinomas. We assessed levels of mRNA by Northern blot analysis and the results were measured semiquantitatively by densitometry. In total, we analyzed nine adenomas of varying size and with varying degrees of dysplasia, three adenomas with adenocarcinoma (malignant polyps), and five adenocarcinomas. Although expression of MMP and TIMP mRNA was highly intercorrelated, transcripts for stromelysin 3 and TIMP-2 (high) showed the strongest relation to the neoplastic process. Detection of stromelysin 3 mRNA accompanied a diagnosis of severe dysplasia or malignancy, whereas levels of TIMP-2 (high) mRNA transcripts permitted finer distinctions on the neoplastic continuum. These data indicate changes within extracellular matrix acquired during the process of malignant transformation of human sporadic colorectal neoplasia.

The significance of idiopathic osteosclerosis found in panoramic radiographs of sporadic colorectal neoplasia patients and their relatives

Osteosclerotic lesions in the mandible are reported with increased frequency in patients with colorectal neoplasia. Panoramic radiography has been suggested to detect high-risk patients among relatives of patients with hereditary adenomatous disease and sporadic colorectal cancer. The present study was undertaken to compare the incidence of idiopathic osteosclerotic lesions in patients with sporadic colorectal cancer and their first-degree relatives with the incidence in the general population and to determine whether panoramic radiographs are a reliable method to screen for early detection of risk of colorectal cancer. A total of 283 patients were interviewed and radiographically examined. Idiopathic osteosclerosis appeared in significantly increased incidence only in patients with colorectal cancer or adenomas and a first-degree relative with CRC (χ 2 = 7.214; p < 0.01,andχ 2 = 4.1827; p < 0.05 respectively). The incidence was not increased in first-degree relatives of patients with colorectal cancer or adenoma. Therefore panoramic radiographs cannot be the only screening tool for early detection of patients at high risk of colorectal cancer.

Cell proliferation biomarkers in the gastrointestinal tract.

Measurements of epithelial cell proliferation in the mucosa of the gastrointestinal tract pointed out the existence of cell kinetic abnormalities which can be involved in the first steps of carcinogenesis. In particular, an increase in the cell proliferation rate and an abnormal distribution of proliferating cells were found both in animals exposed to carcinogens and in human subjects at high risk of gastrointestinal cancer. In some diseases which predispose to cancer (i.e., chronic atropic gastritis, hereditary gastrointestinal cancer, sporadic colorectal neoplasia, chronic ulcerative colitis) we observed an expansion of the proliferative compartment even when the mucosa was not affected by morphological abnormalities. This proliferative feature seems to be associated with the presence of defects in cell differentiation. The abnormality is well detected by the histological examination of the proliferative pattern using microautoradiography after incorporation of tritiated thymidine, or using immunohistochemistry after bromodeoxyuridine uptake. The literature, and our own results, indicate that the search for abnormalities of epithelial cell proliferation can be useful in studying the earliest mechanisms leading to gastrointestinal cancer, in detecting subjects at high cancer risk, and for pilot chemoprevention studies using these abnormalities as intermediate biomarkers of gastrointestinal cancer risk.

Rectal epithelial proliferation in persons post sporadic colorectal neoplasia

Some studies have shown diffuse large bowel epithelial hyperproliferation in persons having colorectal neoplasia. Thus, measurements of rectal epithelial proliferation (REP) could be useful as a screening biomarker of risk for sporadic neoplasia. We examined REP, by autoradiography with tritiated thymidine, in 84 persons: 32 healthy volunteers, 37 who had had sporadic adenomas and 15 post cured sporadic colorectal cancer. Measurements of the labelling index (ratio of labelled to total number of crypt cells) showed a statistically insignificant but increasing gradient of hyperproliferation related to degree and invasiveness of neoplasia. However, this became significant when examining the proportion of labelled crypt compartments in each group and by comparing combined compartments 3 and 4 of cancer patients to non-cancer patients. Gender and age were found to be parameters that influenced the results. Using standard methods of analysis of REP, the lack of clear separation between risk groups limits the usefulness of REP measurements as a screening biomarker of risk for sporadic large bowel neoplasia.