Overview of the epidemiology of colorectal cancer

INTRODUCTION: The epidemiology of colorectal cancer has generated more interest recently, because recent developments in genetics, molecular biology, and genetic epidemiology have increased our understanding of the role of genes in the etiology of colorectal cancer. Interactions between genetic susceptibility and environmental factors in the etiology of cancer may be easier to define. EPIDEMIOLOGY: Colorectal cancer is common in the Western world and is rare in developing countries. A sharp increase is seen in Eastern Europe and Japan. ETIOLOGY: Molecular genetics has shown that accumulation of genetic changes is important in the development of colorectal cancer. Mutations in at least four to five genes are required for the formation of a malignant tumor. Environmental mutagenic factors may determine which susceptible individuals grow carcinomas. Environmental risk factors for colorectal cancer are found in a western diet, rich in fat, meat, and animal protein and low in fiber, fruit, and vegetables. The complex interrelations between food components make it difficult to define the precise role of specific food factors. PREVENTION: Conclusive evidence of the effectiveness of primary prevention of colorectal cancer via dietary measures or nonsteroidal anti-inflammatory drugs is lacking. Secondary prevention by interrupting the adenoma carcinoma sequence is an actual possibility, its effectiveness, however, needs to be determined. Molecular genetics holds a promise for identifying populations at high risk for colorectal cancer, therefore, targeting the screening to make it more cost-effective.Supported by a Health Services Research grant of the Anglia and Oxford Regional Health Authority, Milton Keynes, United Kingdom.     

Mutations in APC,Kirsten-ras,and p53--alternative genetic pathways to colorectal cancer

Colorectal cancer is one of the most significant causes of cancer death. A genetic model for colorectal cancer has been proposed in which the sequential accumulation of mutations in specific genes, including adenomatous polyposis coli (APC), Kirsten-ras (K-ras), and p53, drives the transition from healthy colonic epithelia through increasingly dysplastic adenoma to colorectal cancer. We have characterized tumor mutation spectra in a large cohort of colorectal cancer patients. In marked contrast to the predictions of the sequential model of mutation accumulation, only 6.6% of tumors were found to contain mutations in APC, K-ras, and p53, with 38.7% of tumors containing mutations in only one of these genes. The most common combination of mutations was p53 and APC (27.1%), whereas mutations in both p53 and K-ras were extremely rare. Statistical analysis (two-sided Fisher's exact test) confirmed that mutations in K-ras and p53 co-occurred less frequently than expected by chance (P < 0.01, Fisher's exact test). This finding suggests that these mutations lie on alternate pathways of colorectal tumor development. The heterogeneous pattern of tumor mutations in our patient cohort suggests that multiple alternative genetic pathways to colorectal cancer exist and that the widely accepted genetic model of cancer development is not representative of the majority of colorectal tumors.     

Molecular pathways in colorectal cancer

Colorectal cancer (CRC) is the second most common newly diagnosed cancer and accounts for the second highest number of cancer related deaths in Australia, the third worldwide and of increasing importance in Asia. It arises through cumulative effects of inherited genetic predispositions and environmental factors. Genomic instability is an integral part in the transformation of normal colonic or rectal mucosa into carcinoma. Three molecular pathways have been identified: these are the chromosomal instability (CIN), the microsatellite instability (MSI), and the CpG Island Methylator Phenotype (CIMP) pathways. These pathways are not mutually exclusive, with some tumors exhibiting features of multiple pathways. Germline mutations are responsible for hereditary CRC syndromes (accounting for less than 5% of all CRC) while a stepwise accumulation of genetic and epigenetic alterations results in sporadic CRC. This review aims to discuss the genetic basis of hereditary CRC and the different pathways involved in the process of colorectal carcinogenesis.     

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.     

Colon cancer: a civilization disorder

Colorectal cancer arises in individuals with acquired or inherited genetic predisposition who are exposed to a range of risk factors. Many of these risk factors are associated with affluent Western societies. More than 95% of colorectal cancers are sporadic, arising in individuals without a significant hereditary risk. Geographic variation in the incidence of colorectal cancer is considerable with a higher incidence observed in the West. Environmental factors contribute substantially to this variation. A number of these risk factors are associated with a Western lifestyle and could be considered a product of 'civilization'. Recently, smoking has been recognized as a risk factor. Energy consumption also influences colorectal cancer risk, with obesity increasing risk and exercise reducing risk. However, the strongest contribution to environmental risk for colorectal cancer is dietary. Consumption of fat, alcohol and red meat is associated with an increased risk. Fresh fruit and vegetables and dietary fibre may be protective. Much has been learnt recently about the molecular pathogenesis of colorectal cancer. Colorectal cancer always arises in the context of genomic instability. There is inactivation of the tumour suppressor genes adenomatous polyposis coli, p53, transforming growth factor-β, activation of oncogene pathways including K-ras, and activation of the cyclooxygenase-2, epidermal growth factor receptor and vascular endothelial growth factor pathways. The mechanisms by which some environmental factors modify the mutation risk in these pathways have been described.     

The cause of colorectal cancer

Colorectal cancer continues to represent one of the major causes of cancer-related morbidity in all western countries. A review has been made of the main aetiological factors which have been related to colorectal cancer development with particular attention being focused on: a) new advancements in molecular biology, and b) the interaction between genetic predisposition and environmental factors. Worldwide, approximately 900,000 cases of colorectal malignancies have been diagnosed in 1996 and this accounts for 8.5% of all new cases of cancer. Crude incidence rates range from 0.6 – 5.0 cases/100,000/year in Senegal and India to 50–70 cases in developed countries. Environmental factors, such as meat, saturated fat, low physical activity, obesity, smiking, alcoholic beverages, and inflammatory bowel diseases seem to increase the risk of colorectal cancer. In contrast, fruit, vegetables, fibre, antioxidant vitamins, calcium, folate, physical exercise and non-steroidal anti-inflammatory drugs seem to show a orotective effect. For some of these factors, the molecular basis of their mechanism of action begins to be elucidated. Colorectal cancer develops from benign precursors, the adenomatous polyps; there is extensive evidence that polyps transform into cancer in a stepwise manner, and that several molecular abnormalities (mutations of oncogenes, inactivation of tumour suppressor genes and microsatellite instability) accompany and, somehow, determine colorectal tumourigenesis. Two major Hereditary Colorectal Cancer syndromes — Familial Adenomatous Polyposis and Hereditary Non polyposis Colorectal Cancer — have been described and characterized at molecular levels; it is estimated that these inherited conditions might account for up to 5% of all large bowel malignancies. Familial colorectal cancer remains undefined and is presumably due to multifactorial inheritance. Recently, identified germline mutations (such as l1307K in the APC gene) might account for a fraction of these familial cases, at least in some populations. At variance with many other tumours, the aetiology and pathogenesis of colorectal cancer have been partially clarified, so that we are now in the position to take preventive measures and to design surveillance programmes which might lead to a certain reduction in incidence and mortality. However, since many of the aetiological factors are strictly related to modern customs and lifestyle, they will be difficult to eradicate; this awareness should stimulate further investigations in this exciting field of research.     

Minnesota Colorectal Cancer Initiative: Successful Development and Implementation of a Community-Based Colorectal Cancer Registry

PURPOSE The aim of the Minnesota Colorectal Cancer Initiative is to implement risk-specific interventions to decrease colorectal cancer morbidity and mortality by 1) assisting clinicians to identify and educate individuals and families at high and increased risk for colorectal cancer; 2) providing professional and community education; 3) maintaining a database to evaluate the effectiveness of preventive intervention strategies; and 4) facilitating colorectal cancer research.METHODS Two physician groups and the University Cancer Center founded the Minnesota Colorectal Cancer Initiative as a not-for-profit organization. Health care organizations, pharmaceutical companies, a consulting firm, and other practice groups provide continuing financial and other support. A database registry, risk-assessment survey, and consent document were developed and then were approved by an institutional review board. A trial enrollment was conducted. Minnesota Colorectal Cancer Initiative services are available to the public. Participants are actively recruited through member organizations. Minnesota Colorectal Cancer Initiative assesses hereditary risk and will document family history in the medical record on request. A personally targeted reply letter reviews risk factors and recommends specific screening and surveillance strategies for participants and their family members, and when appropriate, provides information regarding genetic counseling and testing services. Minnesota Colorectal Cancer Initiative services are free to participants.RESULTS Since 1999, Minnesota Colorectal Cancer Initiative has sent individually tailored reply letters providing risk-specific information about colorectal cancer to 717 participants and more than 3200 of their first-degree and second-degree relatives. More than 200 families, previously unidentified as having histories suggestive of hereditary colorectal cancer (attenuated familial polyposis and hereditary nonpolyposis colorectal cancer), have been identified; genetic services were explained and recommended. A formal program evaluation confirmed that Minnesota Colorectal Cancer Initiative provides useful information and materials and promotes intrafamilial communication about colon cancer risk and recommendations.CONCLUSIONS Minnesota Colorectal Cancer Initiative is a model of effective collaboration between academic and community health care providers. A community-based registry is a unique way to identify and provide personal, risk-specific information to large numbers of people at increased or high risk for colorectal cancer.Poster presentation at the meeting of the American Society of Colon and Rectal Surgeons, June 21 to 26, 2003, New Orleans, Louisiana.     

Früherkennung des kolorektalen Karzinoms

Colorectal cancer is one of the leading causes of cancer-related morbidity and mortality. Colorectal cancer commonly develops slowly via adenomatous polyps, a process usually requiring ≥?10 years. This allows for early detection. Endoscopic polypectomy and surgery of early disease can reduce the incidence and mortality of colorectal cancer. Both hemoccult testing and colonoscopy are the most widely used tests for colorectal cancer screening; however, colonoscopy has the highest sensitivity for colorectal neoplasia. Sigmoidoscopy is not commonly used for screening in Germany. Colon contrast enema is no longer recommended for screening. As colonoscopy serves as a diagnostic and therapeutic tool and is the reference method in hemoccult and sigmoidoscopy studies, it is viewed as the gold standard for the diagnosis of colonic disease. New methods including capsule colonoscopy and virtual colonoscopy have great potential but are currently not recommended for early detection of colonic neoplasia.     

Früherkennung des kolorektalen Karzinoms

Colorectal cancer is one of the leading causes of cancer-related morbidity and mortality. Colorectal cancer commonly develops slowly via adenomatous polyps, a process usually requiring ≥?10 years. This allows for early detection. Endoscopic polypectomy and surgery of early disease can reduce the incidence and mortality of colorectal cancer. Both hemoccult testing and colonoscopy are the most widely used tests for colorectal cancer screening; however, colonoscopy has the highest sensitivity for colorectal neoplasia. Sigmoidoscopy is not commonly used for screening in Germany. Colon contrast enema is no longer recommended for screening. As colonoscopy serves as a diagnostic and therapeutic tool and is the reference method in hemoccult and sigmoidoscopy studies, it is viewed as the gold standard for the diagnosis of colonic disease. New methods including capsule colonoscopy and virtual colonoscopy have great potential but are currently not recommended for early detection of colonic neoplasia.     

Distance burning

Gut microbes play a major role in carcinogenesis of the gastrointestinal tract. We and others have shown in mouse models that colonic bacteria also influence the development of extraintestinal cancers including hepatocellular and mammary carcinomas. Microbes such as Helicobacter hepaticus invoke a proinflammatory microenvironment in the lower bowel that may extend to distant organs, often in the absence of histologically evident inflammation. Innate immunity plays a crucial role in the promotion of liver cancer and other systemic diseases by gut microbes. Additional mechanisms include type 1 adaptive immunity, altered metabolism, and oxidative stress. Emerging links between host genetics, gut microbes, inflammatory bowel disease and colorectal cancer also may prove useful for the correlation of specific bacterial populations with extraintestinal neoplasms. Interruption of deleterious host-microbe networks through judicious use of antibiotics and targeted molecular therapies may help reduce the incidence of liver, breast, and other human cancers.     

Distance burning: how gut microbes promote extraintestinal cancers

Gut microbes play a major role in carcinogenesis of the gastrointestinal tract. We and others have shown in mouse models that colonic bacteria also influence the development of extraintestinal cancers including hepatocellular and mammary carcinomas. Microbes such as Helicobacter hepaticus invoke a proinflammatory microenvironment in the lower bowel that may extend to distant organs, often in the absence of histologically evident inflammation. Innate immunity plays a crucial role in the promotion of liver cancer and other systemic diseases by gut microbes. Additional mechanisms include type 1 adaptive immunity, altered metabolism, and oxidative stress. Emerging links between host genetics, gut microbes, inflammatory bowel disease and colorectal cancer also may prove useful for the correlation of specific bacterial populations with extraintestinal neoplasms. Interruption of deleterious host-microbe networks through judicious use of antibiotics and targeted molecular therapies may help reduce the incidence of liver, breast, and other human cancers.     

MYH and colorectal cancer. A significant advance?

Colorectal cancer is the second most common neoplasm and the second most frequent cause of cancer-related deaths in Spain. This neoplasm has an important genetic component, although relatively few of the genes involved in its hereditary or familial forms have been identified. One of the latest genes to be identified is the MYH gene. Colorectal polyposis associated with mutations in the MYH gene is an autosomal recessive syndrome characterized by the development of colorectal adenomas and cancer. It is the first disease predisposing to cancer to be associated with defects in base excision repair.     

Association between colonic screening, subject characteristics, and stage of colorectal cancer

OBJECTIVES: Colorectal cancer remains a significant cause of mortality and morbidity in North America. Colorectal cancer survival is highly dependent on stage at diagnosis, therefore it is important to identify factors related to stage. This study evaluated the association between subject factors (e.g., colonic screening, family history) and stage of colorectal cancer at diagnosis. METHODS: Population-based colorectal cancer cases recruited by the Ontario Familial Colon Cancer Registry between 1997 and 1999 were staged according to the tumor-nodal-metastasis (TNM) staging system and classified as early (TNM I/II) or late (TNM III/IV) stage. Epidemiologic information and stage was available for 768 cases. Multivariate logistic regression was used to obtain odds ratios (OR) estimates. RESULTS: Having had screening endoscopy reduced the risk of late stage diagnosis (OR = 0.46, 95% CI 0.22-0.98). Being older (>45 yr) was associated with a reduced risk of late stage cancer (OR = 0.36, 95% CI 0.18-0.74), as was having a first degree relative with colorectal cancer (OR =0.66, 95% CI 0.46-0.95). Rural residence (OR = 1.48, 95% CI 1.01-2.17) and non-white ethnicity (OR = 3.34, 95% CI 1.20-9.36) were associated with an increased risk of late stage cancer. CONCLUSIONS: Several factors are independently associated with late stage colorectal cancer. Colorectal cancer screening awareness and education programs need to consider targeting persons most likely to present with late stage colorectal cancer.     

K- ras Mutations in Sera of Patients with Colorectal Neoplasias and Long-standing Inflammatory Bowel Disease

Background: About 50% of colorectal carcinomas and adenomas display K- ras mutations, which have also been described in stool or colonic lavage fluid. Moreover, the presence of K- ras mutations in plasma samples originating from patients with colorectal cancer has been reported recently. Methods: DNA was extracted from sera of 16 patients with colorectal carcinomas, 6 with large adenomas, 3 with Crohn disease and 4 with ulcerative colitis. Sera of 20 healthy blood donors served as negative controls. K- ras mutations at the first or second position of codon 12 were detected by an enriched RFLP-PCR method and confirmed by sequencing. Results: Mutations were found in sera of 5 patients with colorectal carcinomas (31%) and 2 patients with long-standing ulcerative pancolitis (50%), but not in patients with adenomas, Crohn disease or the controls. Conclusions: K- ras mutations can be detected in serum samples from patients with manifest colorectal cancer and in patients who display an increased risk for malignant transformation of the colonic mucosa. This observation may have clinical application concerning noninvasive surveillance of these patients. Because of the low sensitivity of this approach it may be useful to combine it with other molecular markers.     

K-ras mutations in sera of patients with colorectal neoplasias and long-standing inflammatory bowel disease

BACKGROUND: About 50% of colorectal carcinomas and adenomas display K-ras mutations, which have also been described in stool or colonic lavage fluid. Moreover, the presence of K-ras mutations in plasma samples originating from patients with colorectal cancer has been reported recently. METHODS: DNA was extracted from sera of 16 patients with colorectal carcinomas, 6 with large adenomas, 3 with Crohn disease and 4 with ulcerative colitis. Sera of 20 healthy blood donors served as negative controls. K-ras mutations at the first or second position of codon 12 were detected by an enriched RFLP-PCR method and confirmed by sequencing. RESULTS: Mutations were found in sera of 5 patients with colorectal carcinomas (31%) and 2 patients with long-standing ulcerative pancolitis (50%), but not in patients with adenomas, Crohn disease or the controls. CONCLUSIONS: K-ras mutations can be detected in serum samples from patients with manifest colorectal cancer and in patients who display an increased risk for malignant transformation of the colonic mucosa. This observation may have clinical application concerning noninvasive surveillance of these patients. Because of the low sensitivity of this approach it may be useful to combine it with other molecular markers.     

Colorectal Cancer Screening: Stool DNA and Other Noninvasive Modalities

Colorectal cancer screening dates to the discovery of pre-cancerous adenomatous tissue. Screening modalities and guidelines directed at prevention and early detection have evolved and resulted in a significant decrease in the prevalence and mortality of colorectal cancer via direct visualization or using specific markers. Despite continued efforts and an overall reduction in deaths attributed to colorectal cancer over the last 25 years, colorectal cancer remains one of the most common causes of malignancy-associated deaths. In attempt to further reduce the prevalence of colorectal cancer and associated deaths, continued improvement in screening quality and adherence remains key. Noninvasive screening modalities are actively being explored. Identification of specific genetic alterations in the adenoma-cancer sequence allow for the study and development of noninvasive screening modalities beyond guaiac-based fecal occult blood testing which target specific alterations or a panel of alterations. The stool DNA test is the first noninvasive screening tool that targets both human hemoglobin and specific genetic alterations. In this review we discuss stool DNA and other commercially available noninvasive colorectal cancer screening modalities in addition to other targets which previously have been or are currently under study.     

Epigenetic alterations in colorectal carcinomas and precancerous lesions

Colorectal carcinomas are the third most common malignant tumours worldwide with an incidence of 570,000 per year. According to their molecular mechanisms, sporadic colorectal carcinomas can be divided into two different phenotypes. The genetic phenotype, 50 to 70 % of all sporadic colorectal carcinomas, is characterised by a chromosomal instability (CIN) with the classical adenoma-carcinoma sequence due to alteration of the APC-betacatenin pathway with p53 mutations, SMAD alterations and LOH (loss of heterozygositiy) of 5q, 17 p 18q. On the other, the CpG island methylator phenotype (CIMP+) was described with an epigenetic inactivation of tumour suppressor genes that are typically inactivated by germline mutations in familiar cancer syndromes, e. g., Rb, VHL, hMLH1, p16 or BRCA. Colorectal carcinomas of the CIMP+ type often show a high microsatellite instability (MSI+) caused by aberrant promoter methylation of the missmatch repair gene hMLH1. Further CIMP+ are located in the proximal right-side colon and show a poor grading with mucinous or signet-cell differentiation.     

Mutations in c-K-ras 2 gene codon 12 during colorectal tumorigenesis in familial adenomatous polyposis.

Colorectal carcinomas may be induced from adenomas, or they may occur de novo. To clarify the histogenesis of colorectal carcinomas, point mutations in codon 12 of the c-K-ras 2 gene in neoplasias of familial adenomatous polyposis patients were examined. Nineteen colorectal advanced carcinomas, 135 adenomatous polyps, 9 hyperplastic polyps, and 27 normal colonic mucosae were obtained from 48 patients. In 27 normal mucosae and 9 hyperplastic polyps, a mutation in the K-ras gene was not detected. Mutations were detected as follows: 0 of 24 in adenomas with mild atypia, 10 of 77 in adenomas with moderate atypia, and 24 of 34 in adenomas with severe atypia. The incidence of mutations in c-K-ras 2 codon 12 is correlated with the degree of atypia of adenomas. However, only 5 such mutations were detected in 19 advanced carcinomas, indicating that the mutation frequency in advanced carcinomas is much lower than that in adenomas with severe atypia. If a mutation of c-K-ras 2 gene is an important component in the formation of adenocarcinoma, these results did not confirm the successive development from adenomas with severe atypia to advanced carcinomas as the main route for colorectal carcinogenesis in familial adenomatous polyposis patients.     

The molecular genetics of colorectal cancer

Colorectal cancer is a major cause of morbidity and mortality among types of cancer in the United States. Significant progress has been made in understanding the molecular mechanisms that lead to it. Much knowledge was obtained through study of genetic changes that occur in individuals with a familial predisposition to colorectal cancer, including familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) syndromes. The gene with mutations that result in FAP has been identified as adenomatous polyposis coli (APC). Similarly, mutations in several genes that normally function in DNA mismatch repair result in HNPCC. Colorectal cancer is the result of accumulated mutations in several additional oncogenes or tumor suppressor genes, and this information leads to the formulation of a genetic model for the disease. Recent studies have also identified a relatively prevalent polymorphism in the APC gene in Ashkenazi Jews that is associated with an increased risk for colorectal cancer. These studies present a paradigm based on the APC mutation (APC I1307K) for the screening of cancer susceptibility genes in the population at large. Currently available techniques for genetic testing of colorectal cancer are also discussed in this review, along with their ethical implications.     

In vitro tetraploidy in patients with ulcerative colitis

One hundred and seven patients (57 patients with ulcerative colitis and 50 controls) were investigated for in vitro tetraploidy (IVT) in dermal fibroblast monolayer cultures. There was no difference in incidence of IVT between patients with ulcerative colitis and controls. We advance the hypothesis that the genetic background of the colorectal cancer type found in ulcerative colitis differs from that found in the colon cancer syndromes and in non-hereditary colorectal cancers. Colorectal cancer in ulcerative colitis is probably only dependent on the degree of inflammatory lesions of the colonic mucosa.