Colon Cancer

Timothy J Yeatman, University of South Florida, Tampa, Florida, USA

Colon cancer is a neoplastic disease of the large intestine, which can be derived from both inherited or somatic genetic alterations that develop over the course of a lifetime. Prevention together with early detection and treatment are the keys to a successful outcome for this very common disease.

Secondary article
Article Contents
. Definition . Epidemiology . Genetics . Familial Adenomatous Polyposis . Hereditary Nonpolyposis Colon Cancer . Detection

Definition
Colon cancer is a disease of the large intestine which begins at a structure called the caecum, located in the right lower quadrant of the abdomen, and continues through all portions of the abdomen to its junction with the rectum, located in the deep pelvis. The colon is an organ shaped like a question mark (?) (Figure 1). It is approximately 1.5 metres long and is divided into four segments based on the vascular supply to each segment. The right colon, otherwise known as the ascending colon, receives its blood supply from the right colic and the ileocolic artery. The most proximal portion of the right colon is termed the caecum and is identied by the appendix, which is a small appendage attached to three longitudinal bands of muscle called the taeniae coli. The transverse colon connects the right colon to the left colon. Its blood supply is derived from the middle colic artery and, like the right colic artery, it is derived from the superior mesenteric artery, a branch of the aorta. The juncture at which the right and transverse colon join its

. Treatment

Transverse Ascending Descending

Caecum

Sigmoid

Rectum

Figure 1 Anatomy of the large intestine. The colon is divided into four sections: caecum and ascending, transverse, descending, and sigmoid. The rectum forms the most distal portion of the large intestine.

termed the hepatic exure and the juncture at which the transverse colon and left colon join is termed the splenic exure. Flexures are points at which the large bowel is tethered and supported in order to prevent excessive twisting that could lead to a condition called volvulus. Volvulus is a serious problem that can result in diminished blood supply to the bowel, with subsequent necrosis and perforation. The transverse colon also serves as a tethering point for the greater omentum, which is a large fatty apron of tissue that essentially covers the entire abdomen, separating the small and large bowel from the anterior abdominal wall. The purpose of the omentum is to police the abdomen, identifying holes or perforations of the bowel wall and sealing them. In addition, it seems to be an adhesive target for neoplastic cells, which otherwise oat free in the abdomen. The left colon connects the transverse colon to the sigmoid colon, which is named for its S-shaped appearance in the abdomen. The left colon and sigmoid colon are supplied by the left colic and sigmoidal arteries, branches of the inferior mesenteric artery. While the wall of the right colon generally has the largest diameter, the sigmoid colon frequently has a narrow diameter and a thicker wall. It is often the site of formation of diverticula, which are small herniations through the bowel wall and can be sites for faecal impaction, abscess formation and perforation. The colon proper ends at the junction of the sigmoid colon with the rectum, which is marked by its disappearance into the deep pelvis and is covered by visceral peritoneum and perirectal (mesorectal) fat. Colon cancer is a mucosal disease. In other words, all colon cancers are derived from the mucosal lining of the bowel wall. From the inside out, the bowel wall is composed of multiple layers, which include the mucosa, the submucosa, the muscularis propria (containing circular and smooth muscle layers) and the serosa. The innermost layer of the bowel wall, the mucosa, is a single layer of columnar epithelial cells, some of which produce large amounts of mucus and are thus termed goblet cells. This is the site of the earliest genetic changes that lead to the development of cancer cells. It is a region where normally cells are continuously dividing to replenish those that are
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shed from the bowel wall into the lumen. This recycling process begins in the crypts of Lieberku hn, at the base of microvilli. Underneath this mucosal layer lies the submucosa, the strength layer of the bowel. This layer contains blood vessels, lymphatics and terminal nerve bres. It is an important layer with regards to the genesis of cancer because once a tumour has invaded into this region of the bowel wall it can gain entrance to the blood supply and lymphatic system, permitting distant spread throughout the body. Thus, the earliest stage of colon cancer, termed Dukes stage A, represents a stage at which cancer is limited to the submucosa and has not spread to lymph nodes or distant organ sites. The likelihood of survival following resection of these early stage cancers is very high. Dukes B tumours have invaded into and through the muscular layer of the bowel wall and thus carry an increased risk of distant spread; Dukes C tumours have already spread to regional lymph nodes.

components, such as the amount of fat and bre in the diet (Cummings and Southgate, 1999) and perhaps the intake of calcium (Bresalier, 1999; Faivre and Bonithon-Kopp, 1999; Mobarhan, 1999), vitamins of the antioxidant class (Slattery et al., 1999), and nonsteroidal antiinammatory agents such as aspirin and more specic inhibitors of cyclooxygenase (Lipsky, 1999). The risk of colon cancer increases with age, the history of previous polyps or cancer, the family history of cancer, and the history of long-standing inammatory bowel disease, including ulcerative colitis and even Crohn disease.

Genetics
Whereas cancer is a genetic disease, only 10% of colon cancers are actually inherited from family members. In fact, the majority of colon cancers are considered sporadic in nature and are derived from accumulated genetic changes. These changes occur within the epithelial cells of the mucosal surface of the bowel wall throughout the lifespan of the person. Once a critical number of genetic changes have occurred (usually 56), a cancer may develop. A genetic model for the development of colon cancer has recently evolved (Vogelstein and Kinzler, 1993); this is largely due to extensive gains in our understanding of human genetics, as a direct result of the human genome project (Figure 2). Our current understanding suggests that colon cancer is a disease of disrupted growth control. Early genetic alterations occur in the colonic epithelial cells lining the bowel wall. The genetic changes involve mutations or alterations in the genetic code responsible for producing specic proteins. These mutational alterations or deletions result in the production of malformed proteins, which are absent or can no longer function normally. As a result, cells may be turned on to grow without limits and may resist normal mechanisms that result in cell death, a process of cellular suicide called apoptosis. We now know that two basic types of important growth genes are aected in cancer, oncogenes and tumour suppressor genes. Oncogenes represent the mutated forms of preexisting normal genes, called protooncogenes, which have normal growth-stimulatory functions in the cell. Only when these genes are mutated in specic regions can they

Epidemiology
While the incidence of colon cancer varies widely from country to country throughout the world, colon cancer is a common disease in the United States. Adenocarcinoma of the colon and rectum accounted for approximately 35 000 cases and 55 000 deaths in 1999 (Landis et al., 1999). While the mean age of diagnosis is approximately 67 years of age, the incidence rises steadily from age 50 to age 80. Thus fewer than 10% of cancers are diagnosed before age 40. The majority of colon cancers are not inherited but rather are considered sporadic, having developed from an accumulation of mutations throughout the course of a lifetime. Approximately 10% of colon cancers are considered inherited: a genetic mutation in genomic deoxyribonucleic acid (DNA) (involving all cells in the body) has been passed on from one generation to another. In addition to inherited cancers, familial cancer predispositions may exist that are independent of the hereditary nonpolyposis colon cancer (HNPCC) and familial adenomatous polyposis (FAP) diseases. To date, these predisposing factors are not well dened. Current data suggest that epidemiological risk factors for cancer, other than genetic risk factors, include dietary
MCC APC Normal mucosa RAS Early adenoma p53

DCC/DPC4 (Smad4) Carcinoma Mucosa

Late adenoma

Oncogene activation Tumour suppressor deletion Genetic alteration necessary

Figure 2 Multistep model of colon cancer progression includes alterations in both oncogenes and tumour suppressor genes.

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net

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take on constitutively active (always turned on) growth functions. Tumour suppressor genes are the second class of genes that are aected in the genesis of colon cancer. While the specic function and identity of many of these genes in this class are not yet identied, it is clear that specic genes are deleted in the development of cancers and that their absence results directly in tumour formation. In the normal cell, protooncogenes provide growth stimulus and tumour suppressor genes provide growth control. In the tumour cell, mutated protooncogenes and mutated or deleted tumour suppressor genes permit continuous unchecked growth stimuli. Two of the earliest genes aected in the development of colon cancer are the adenomatous polyposis coli (APC) gene and the RAS gene (Fearon and Vogelstein, 1990). The APC gene was identied in a group of patients with familial colon cancer characterized by hundreds to thousands of adenomatous polyps throughout the colon (familial polyposis), each with malignant potential. In these patients, the APC gene represents a tumour suppressor gene. When both copies of this gene are aected or lost, colon polyps will develop, frequently at a very early age. The mechanisms for the formation of polyps and cancer in patients with familial polyposis has been validated by murine models in which the APC gene has been mutated or completely knocked out. In these models, mice develop numerous adenomatous polyps throughout the small bowel, with some in the colon. While these polyps generally do not develop into invasive cancers, they frequently bleed and lead to obstruction of the bowel. These mice provide a valuable resource for the testing of new drugs that might prevent polyps or cancer. For example, aspirin and other nonsteroidal agents have been demonstrated to reduce the incidence of polyps in mice, verifying the observation in humans that drugs like these may be benecial in preventing cancer. Interestingly, this gene is also the most commonly aected gene (up to 95% of cases) in noninherited forms of colon cancer, otherwise known as sporadic colon cancer. Because it is the rst gene to be aected in the development of colon cancer, it has been called the gatekeeper. Until recently, its role in the development of colon cancer has remained elusive but now there is evidence to suggest that the mutated APC gene may activate the transcription of two genes downstream, MYC (He et al., 1998) and CYCLIN D through the action of proteins such as b-catenin and TCF/lef-1. The protein products of these genes, c-Myc and cyclin D, have been implicated in cellular transformation and the growth of cancer. In common with APC, the RAS gene is also thought to be involved in the early transition from normal epithelium to premalignant tissue. The RAS gene is commonly mutated (up to 50% of cases) in premalignant colon polyps. It is one of the most well understood protooncogenes. We now know that it has a normal function in activating downstream genes in signal transaction cascades

through phosphorylation events. When the RAS gene is mutated, it is constitutively activated in a guanosine triphosphate (GTP)-locked form, such that it is always capable of phosphorylating downstream targets, targets critical to the growth control of the cell. It results in an activated Ras pathway, whereby Ras activates downstream proteins such as Raf, MEK, MAPK and Erk, with the end result being increased transcriptional activity in the nucleus. This transcriptional activity is presumed to maintain continuous growth characteristic of the cancer cell. More recently, the mechanism by which Ras is attached to the cytoplasmic membrane has been elucidated. A farnesyl group is transferred to the Ras protein by an enzyme called farnesyltransferase, which is now the intense target of drug discovery eorts (farnesyltransferase inhibitors, FTIs). FTIs are already in clinical trials that seek to inhibit this enzyme and thus prohibit the interaction of Ras with the cytoplasmic membrane, thereby blocking the growth eects of Ras. For signal transduction cascades, location is critical, and without membrane association even mutated Ras becomes inactive without farneslyation. Once a number of early genetic changes have occurred, additional changes may snowball. This process is termed genetic instability. The predisposition to cellular division results in increased potential for mutational events, and subsequent genetic changes can accumulate. One prominent genetic change occurs in the p53 gene. The p53 gene is the most commonly mutated gene in human cancer (up to 50% of all human cancers contain a p53 mutation) (Koshland, 1993). Because its deletion results in spontaneous tumour formation in both animal models and in humans, it is thought to represent a tumour suppressor gene where both alleles or genetic copies must be aected to result in a phenotypic change. The normal function of p53 appears to be related to DNA repair following a toxic insult. When DNA is damaged, normal or wild-type p53 signals the cell to self-destruct, a form of cellular suicide called apoptosis. When p53 is mutated, DNA damage may go unrepaired and unrecognized, resulting in the contribution of damaged DNA to subsequent generations of cells. The lack of recognition of abnormal cells, with their associated elimination, is a critical failure common to cancer cells. Mutations spontaneously developing subsequent to the p53 mutation may theoretically be accumulated rapidly without correction. This is precisely why tumours at advanced stages seem to have accumulated larger numbers of genetic defects, engendering the capacity for advanced rates of growth invasion and distant metastasis or spread. Other genes and chromosomal defects that have been reported include the MCC tumour suppressor gene located on chromosome 5 (Gayther et al., 1993; Kopnin, 1993), in the DCC (Chen et al., 1999; Saito et al., 1999; Sturlan et al., 1999) and DPC-4 tumour suppressor genes located on chromosome 18. The DPC-4 gene is now also known as
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Colon Cancer

Smad-4 and may be regulated in part by the transforming growth factor b (TGFb) receptor pathway (Korchynskyi et al., 1999). The latter genes appear to be associated with more advanced stages of disease. More recently, a gene such as the SRC oncogene has also been identied as participating in the process of advanced tumour growth (Irby et al., 1999). It is believed that mutations in genes such as SRC, which are generally uncommon, are possible in a milieu of the tumour cell with multiple mutations capable of continuous unchecked growth and DNA repair. SRC overexpression or activation may be responsible for antiapoptotic activity and increased angiogenesis, both of which may contribute to tumour development and progression.

proctocolectomy, with permanent colostomy or with reconstruction by an ileoanal pull-through procedure.

Hereditary Nonpolyposis Colon Cancer

HNPCC is another form of hereditary cancer, accounting for up to 10% of colon cancer cases. It has also been referred to as Lynch syndromes I and II. Patients with this disease tend to have numerous relatives diagnosed with colon cancer, some before the age of 50 or approximately 1015 years before the appearance of most colon cancers. Unlike FAP, this disease has been linked to mutations in proofreading genes coding for mismatch repair enzymes. These genes include MLH1, MSH2, PMS1, PMS2 (Bronner et al., 1994; Nicolaides et al., 1994). This disease is also characterized by the replication error phenotype (RER) which results in micosatellite instability. While instability at multiple microsatellite loci can screen for aected individuals, clinical criteria (Amsterdam) (Syngal et al., 1999) are now also available for attempting to predict the risk of harbouring this disease. The name for this disease is somewhat a misnomer because the majority of patients actually harbour a number of polyps, although many fewer than seen in FAP. This disease may manifest itself in early adulthood and result in the development of invasive cancer. It has also been associated with the formation of tumours in other organs and is predominantly linked to formation of right-sided colon cancers. Genetic testing for the disease is now available for patients meeting specic clinical and family history criteria.

Familial Adenomatous Polyposis

FAP is a rare inherited disease characterized by the development of hundreds to thousands of adenomatous polyps in the colon by early adulthood. Less than 1% of all colon cancers are secondary to FAP. Without treatment, 100% of patients with this disease will develop invasive colon cancer with the risk of metastatic spread. Recently, the genetic lesion responsible for this disease has been identied (Kinzler et al., 1991; Su et al., 1992; Cao et al., 1999; Norheim Andersen et al., 1999). The APC gene has been found to be mutated, such that one copy or allele is defective, generally resulting in a shortened protein product. Interestingly, this is the same gene in which a missense mutation has been found in 6% of Ashkenazi Jews (a dierent, less severe mutation conferring a slightly increased risk of colon cancer) and in most tumours from patients with sporadic or noninherited forms of colon cancer. These common genetic links suggest an important role for the APC gene in the development of colon cancer. More recently, a specic role for the APC gene product in colon cancer cells has been elucidated. A pathway initiated by the mutated APC gene product appears to lead to the increased production of c-Myc, a transcription factor linked to cellular transformation and growth. In addition, the APC pathway may lead to the increased production of cyclin D1, resulting in the stimulation of cell growth via the cell cycle. Because FAP is an inherited genetic disease associated with mutation of genomic DNA, the entire mucosal surface of the large intestine is at risk for the formation of polyps and cancer. Moreover, these patients carry the risk of developing polyps in the duodenum. In addition, variants of the familial polyposis syndrome include Gardner syndrome and Turcot syndrome, presumed also to be linked to defects of the APC gene. Because of this risk, treatment is aimed at the prophylactic removal of the entire colon and rectum at an early age, before the formation of any cancerous changes. Treatment options include total
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Detection
Because the colon is deep within the abdominal cavity, it is common for a developing cancer to go undetected until signicant symptoms develop. Generally, a tumour must bleed, resulting in blood in the stool, or must obstruct the bowel lumen, resulting in abdominal pain, before it can be detected without routine screening measures. It is precisely for this reason that many patients present with large tumours or with advanced disease that has already metastasized to distant organ sites at the time of diagnosis. This is a disappointing fact because the majority of tumours take years to develop, during which time there may be the opportunity for early detection and possible prevention. Early detection by screening is generally the best means of detecting this disease in a curable stage. The concept of screening to reduce cancer mortality has gained signicant favour in the management of breast cancer, where routine screening mammography has shifted the identication of the majority of breast cancers to earlier stages than was previously possible. While in the past colon cancer

ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Macmillan Publishers Ltd, Nature Publishing Group / www.els.net

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screening was limited to the use of an uncomfortable aircontrast barium enema, current breoptic technology has permitted development of exible sigmoidoscopes and colonoscopes, which can be used to inspect the entire mucosal surface of the large intestine without signicant discomfort. Current screening recommendations from the American Cancer Society (Table 1) recommend an annual faecal occult blood test, and sigmoidoscopy every 5 years, starting at age 50, for low-risk adults. For those with a rstdegree relative diagnosed with colon cancer, a total colonoscopic examination is recommended, starting at age 40 or 10 years before the age at which the youngest rstdegree relative developed cancer. Tumour markers are generally ineective in detecting carcinoma of large intestine and are therefore not recommended for screening purposes. Once diagnosed with colon cancer, however, measurements of carcinoembryonic antigen (CEA) may be useful in predicting the presence of distant metastatic disease (serum levels 4 10 ng ml 2 1) for determining the eectiveness of a surgical resection. Computed tomography is generally not useful for screening purposes but is quite eective in determining the extent of local or metastatic disease.

Treatment
The treatment plan for colon cancer is generally based on the state of the disease, the location of the disease and the functional status of the patient. Thus, attempts at preoperative staging can be useful in the proper management of the colon cancer patient. The primary treatment modality for colon cancer is surgery. Most surgical
Table 1 American Cancer Society guidelines for the early detection of colon or rectal cancer Starting at age 50, both men and women should have: . yearly faecal occult blood test, and exible sigmoidoscopy and digital rectal examination every 5 years or . colonoscopy and digital rectal examination every 10 years or . double-contrast barium enema and digital rectal examination every 510 years People should begin screening earlier and have it more often if they have any of these risk factors: . a strong family history of colon or rectal cancer or polyps (mother, father, sisters or brothers) . a family history of hereditary colorectal cancer syndromes . a personal history of colon or rectal cancer or chronic inammatory bowel disease (having already had colorectal cancer)

procedures are performed via an exploratory laparotomy, although laparoscopic procedures conducted without large systems are also being performed on an experimental basis. Surgical extirpation of the disease is frequently the most important component of treatment and may be the only form of treatment required. These operations are nearly always accomplished without the use of a permanent colostomy, and only rarely are temporary colostomies needed. Wide local excision with resection of associated regional lymphatics and lymph nodes is the underlying principle of all surgical treatment of the colon. In most circumstances, the risk of local recurrence is not related to the extent of a mucosal margin (proximal or distal) but rather it is often related to the extent of a radial margin. This status is justied by the fact that the anastomotic occurrences are actually uncommon. On the other hand, local recurrences and local metastatic spread to the peritoneum and the omentum (termed carcinomatosis) are more common. This problem relates to the frequent full-thickness penetration of the bowel wall by colon cancers. Cancers that invade all layers of the bowel wall may continue to invade adjacent organs and local tissues or spread throughout the abdomen, much like the seeds of a dandelion in the wind. The surgeon faced with local disease will generally attempt to resect it all en bloc; even adjacent organs, such as the uterus, ovaries or bladder, may be completely or partially removed. Once the disease has metastasized to lymph nodes beyond the local basin, or to distant organ sites such as the liver or the lungs, it is rarely curable by surgical intervention alone. Exceptions include limited metastatic disease (fewer than four lesions) to the liver or lungs without extrahepatic or extrapulmonary disease. Once the disease has spread to lymph nodes or to distant organ sites, chemotherapy is generally incorporated into treatment plans. Adjuvant chemotherapy is generally recommended for patients with nodal disease (Dukes stage C). Current regimens generally utilize 6 months of adjuvant chemotherapy with S-phase-specic cytotoxic drugs, including 5-uorouracil and leucovorin. While patients with full-thickness tumours but without evidence of total disease (Dukes B) carry the risk of distant metastasis, chemotherapy has not been proven to be eective. Recently, however, immune modulation has been demonstrated to have potentially benecial eects in this subgroup of patients. Modulation may take the form of vaccination with radiated, autologous tumour cells in combination with the immune adjuvant bacillus Calmette rin (BCG). Recent trials are also underway with an Gue antibody called 17-1A directed against tumour cells, which may have some benet in these stages of disease (Dukes B and C). For patients with metastatic disease to distant sites, such as the liver or lungs, systemic chemotherapy is generally indicated and includes drugs such as 5-uorouracil, leucovorin and ironotecan. While 5-uorouracil has been
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the mainstay of colon cancer chemotherapy for 30 years, novel therapeutic interventions are currently in clinical trials. These agents include drugs to inhibit blood vessel formation (antiangiogenesis) and drugs to target specic abnormal proteins within the colon cancer cell, such as Ras.

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