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Journal of Clinical Oncology, Vol 19, No 18S (September 15 Supplement), 2001: 6s-12s
© 2001 American Society for Clinical Oncology

AMERICAN CANCER SOCIETY AWARD LECTURE

A Quarter Century of Colorectal Cancer Screening: Progress and Prospects

By Sidney J. Winawer

From the Gastroenterology and Nutrition Service, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Sidney J. Winawer, MD, Gastroenterology and Nutrition Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; email: winawers{at}mskcc.org


   INTRODUCTION
TOP
 INTRODUCTION
TECHNOLOGY
 REFERENCES
 
IN THE PAST 25 YEARS, considerable progress has been made in our ability to screen patients for colorectal cancer with the introduction of the technology for screening, diagnosis, and removal of the premalignant polyp. During this period, greater insight into the adenoma carcinoma sequence has provided us with an understanding of the benefit of screening by detecting early-stage cancer and the precursor adenomatous polyps. The risk for colorectal cancer in average-risk men and women and in groups that are at increased risk also has been clarified. Strong evidence has accumulated that screening is effective in reducing the incidence and mortality of colorectal cancer. Although tremendous progress has been made in these areas during the past 25 years, we now face the challenging prospects of universal implementation of effective screening methods and integration of new technology and concepts as they develop.

Considerable controversy existed regarding whether screening was effective, but beginning in 1996, a consensus evolved and was reflected in positive guidelines by a number of authoritative bodies,1 including the United States Preventative Task Force, the Agency for Health Care Policy and Research, a Gastrointestinal Consortium, the American Cancer Society, the World Health Organization, the Ontario Expert Panel, the Australian Task Force, and the European Screening Group. It is justifiable to screen people for colorectal cancer in the United States, considering the national burden of this disease: 135,400 new cases in 2001 and 56,700 deaths, representing 11% of all cancer deaths, resulting in 758,000 person-years of life lost, and costing $6 billion annually in treatment. Women do not appreciate that they are at equal risk as men and have a lifetime risk of developing colorectal cancer of 6%, or one in 17.2


   TECHNOLOGY
TOP
 INTRODUCTION
 TECHNOLOGY
REFERENCES
 
In 1967, Greegor3 published in the Journal of the American Medical Association an article that reported that in his office practice of internal medicine, early-stage cancer of the colon could be detected in asymptomatic patients with the use of fecal occult blood guaiac test cards. He postulated that multiple cards over several days were needed because of the intermittent nature of bleeding from cancer. He further recommended dietary control consisting of a high-roughage diet to stimulate bleeding cancers and a meat-free diet to prevent false-positive results. Before this article was published, patients had been asked to bring in a single stool specimen, which then was tested with guaiac reagents, which were unstable and caused many false-positive and false-negative results. This method also was not acceptable to the patient, the physician, or the people who tested the stools. The introduction of the guaiac cards was the first step in conceptualizing the possible strategy of effective colorectal cancer screening.

In the mid-1970s, the flexible sigmoidoscope was introduced.1 For the first time, the entire rectosigmoid and potentially as high as the splenic flexure could be examined comfortably. Before the introduction of the flexible sigmoidoscope, rigid sigmoidoscopes had been used, beginning with its introduction at Johns Hopkins in 1870. Patients did not like this examination because it was uncomfortable, and physicians did not like it because the patients were uncomfortable. It was a failure as a screening instrument. However, these two screening examinations would be of little value without an accurate diagnostic test to examine the entire colon and find early-stage cancers and premalignant polyps. Colonoscopy, which was introduced in 1970,1 provided this examination. Modern-day instruments with 360° deflection and very flexible shafts were introduced into wide clinical practice around 1973. A positive screening test now could be investigated and the reason could be determined with certainty. Before the introduction of colonoscopy, a positive screening test had to be investigated with a double-contrast barium enema, which yielded variable results. A recent study demonstrated that the double-contrast barium enema, even in the best of hands, will miss approximately 50% of all adenomas of the colon, including adenomas that are larger than 1 cm.4

The learning curve had to be overcome with the introduction of colonoscopy. Many courses were organized by local gastroenterology societies and the American Society for Gastrointestinal Endoscopy. One such course, "A Day in the Colon," was held at Memorial Sloan-Kettering Cancer Center in 1973. The title of the course had a dual meaning indicating that the course would be for 1 day but also suggesting (tongue in cheek) that many endoscopists literally were spending a full day in the colon with a single colonoscopy. The procedure initially was not very comfortable for the patient because we did not know how to do the examination well, overinsufflated air into the colon, and used a considerable amount of fluoroscopy to negotiate the colonoscope from the rectum to the cecum. A sequel to this course was a "Night in the Cecum." This also had a dual meaning reflecting the initial uncertainty of the endoscopists with the landmarks in the cecum. After many courses and instructions by pioneer mentors, colonoscopy became an efficient examination, done in 15 to 20 minutes with a very low complication rate and with patient comfort. The entire colon could be examined well, and suspicious lesions could be biopsied.

ADENOMA-CARCINOMA SEQUENCE
The concept that colorectal cancer evolves from a precursor lesion, the adenomatous polyp, was based on the eloquent pathology studies from the St Marks Hospital in London, published by Lockhart-Mummery and Dukes in 1928,5 and culminated in the concept of the polyp-cancer sequence published in 1977 by Muto et al.6 This concept was challenged quickly on the basis of the lack of the finding of adenomatous tissue in many cancers. However, it was demonstrated later that the reason for this was that as a cancer grows and invades surrounding tissues, it destroys the underlying adenoma from which it arose. An inverse correlation was demonstrated between the finding of residual adenomatous tissue and the size and stage of the cancer. In 1987, Stryker et al7 at the Mayo Clinic published a study of the natural history of colorectal cancer as it evolved from the polyp (Table 1). This was in the precolonoscopy era. For polyps to be removed, patients had to have an exploratory laparotomy and multiple colotomies to examine the entire colon, with an associated high morbidity. Many patients refused this approach. In the study by Stryker et al, a group of patients who refused to be operated on and who had a polyp larger than 1 cm demonstrated on barium enema were followed for up to 20 years with a progressive increase in the percentage of polyps with cancer. More recently, the progression from normal mucosa to carcinoma through the adenoma stage has been shown to be associated with an accumulation of acquired somatic mutations within the tissues.8


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  		Table 1.  Cancer Risk of Polyps
 
The National Polyp Study was organized in 1978 and began to enroll patients in 1980 in a multicenter trial to study various aspects of the clinical management and biology of the adenoma-carcinoma progression. One of the findings of the National Polyps Study was the 10-year difference in the mean age distribution of National Polyp Study patients with adenomas as compared with Surveillance, Epidemiology, and End-Results cancer patients9 (Fig 1). This demonstration supported the concept that a long period of time elapses between the appearance of polyps in the colon and their progression to cancer. It is now widely known that only a small percentage of adenomas progress to cancer, perhaps as few as 1%, although most if not all colorectal cancers arise from the precursor adenomatous polyp. The 10-year "polyp dwell time" is critical because it provides a long window of opportunity for effective screening.1



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  		Fig 1. National Polyp Study data shows age distribution of 1,622 patients with adenomas compared with 47,669 Surveillance, Epidemiology, and End-Results cancer patients.

 
RISK GROUPS
The majority of patients who will develop colorectal cancer are considered to be at average risk (75%) with no special risk factors. People who are at increased risk include those who have inflammatory bowel disease, which is associated with 1% of the colorectal cancers each year; familial adenomatous polyposis (FAP) (1%); hereditary nonpolyposis colorectal cancer (HNPCC) (5%); and a family history consisting of one or two close relatives with cancer (15% to 20%; Fig 2). Today, we have a much better understanding of the magnitude and clinical patterns in these increased-risk groups. People who have one first-degree relative with either a colorectal or an adenomatous polyp have approximately a two-fold increased risk of colorectal cancer, and the risk begins approximately 10 years sooner than in people of average risk. The risk in close relatives increases inversely with the age at which the proband had either an adenomatous polyp or colorectal cancer: the younger the age of the proband, the greater the risk in the first-degree relatives.1



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  		Fig 2. Colorectal cancer risk groups (IBD, inflammatory bowel disease; FAP, familial adenomatous polyposis; HNPCC, hereditary nonpolyposis colorectal cancer; FH, family history). Percentage of new cases each year for associated risk factor.

 
The clinical features of FAP have been well delineated during the past few years.1 It is an autosomal dominant disease with penetrance over 90%; colorectal adenomas appear at puberty and colorectal cancer appears in the 30s. It has associated extracolonic tumors, including upper gastrointestinal tumors, desmoids, osteomas, thyroid tumors, and brain tumors. There has been great interest in HNPCC during the past few years.1 It also is an autosomal dominant disease but has a penetrance of only 70%; colorectal adenomas appear in the 20s, and colorectal cancer appears in the 40s. It has many extracolonic cancers, including cancers of the endometrium, ovaries, stomach, urinary tract, small bowel, and biliary tract. The following criteria for identifying families with HNPCC was set forth in Amsterdam at an international conference and were called the Amsterdam criteria: three relatives with HNPCC cancers, one a first-degree relative of the other two; two or more generations affected; and one cancer in a family member who is younger than 50 years.1 Patients with a family history of HNPCC not only are at risk for adenomas and cancers at a young age but also have an accelerated adenoma-carcinoma sequence, which means that they will have to be screened directly with colonoscopy every year.

EVIDENCE
The early evidence of the benefit of colorectal cancer screening demonstrated a shift in screen-detected cancers to an earlier stage with fewer Dukes’ D screen-detected cancers as compared with control subjects. However, this stage shift was challenged quickly as possibly being due to length bias and lead-time bias. Length bias suggests that screening would detect cancers that are slow growing more often than it would detect cancers that are more aggressive, and lead-time bias suggests that screening merely detects the cancers earlier in their natural history but with no changes in their outcome.1 However, more recently, results of three major randomized, controlled trials demonstrated a mortality reduction in colorectal cancer of the entire screened cohort10-12 (Table 2). The largest reduction in mortality was in the University of Minnesota program in which one group of patients was screened annually with a sensitive slide test. That group demonstrated a 33% reduction in mortality. The compliers of the test demonstrated a 45% reduction in mortality. All of the trials in the United States and Europe are consistent with one another in terms of the magnitude of the mortality reduction as a function of the type of slide test used and the frequency of screening. This put to rest questions of screening bias and for the first time convincingly demonstrated that screening for colorectal cancer with fecal occult blood testing is effective. More recently, a favorable relationship of benefits to harms in screening has been reported.13


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  		Table 2.  Fecal Occult Blood Test Screening Randomized Controlled Trials
 
Colorectal cancer mortality also was shown to be reduced by sigmoidoscopy in two case-control studies with a mortality reduction of 30% to 40%14,15 (Table 3). The combination of fecal occult blood testing added to sigmoidoscopy also has been associated with a mortality reduction in a study conducted by us.16 As a result of these studies, colorectal cancer screening guidelines recommend that average-risk men and women who are 50 of age (or 40 years of age with a family history) be offered options for screening, which include either fecal occult blood testing annually or flexible sigmoidoscopy every 5 years or a combination of the two1 (Table 4).


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  		Table 3.  Colorectal Cancer Mortality Reduction by Sigmoidoscopy
 

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  		Table 4.  Colorectal Cancer Screening Guidelines
 
The most frequent finding of screening is not cancer but an adenomatous polyp. These polyps can be removed expeditiously by colonoscopy as an outpatient procedure, with the entire colon being examined, including the polypectomy in 15 to 20 minutes. This was a major advance compared with the exploratory laparotomy and multiple colotomies that were done in the past. The feasibility of removing polyps through the colonoscope was reported in the mid-1970s,16 and shortly thereafter, the National Polyp Study was organized9 as a randomized, multicenter, controlled trial to examine surveillance intervals and methods after polypectomy, to examine the potential incidence reduction of colorectal cancer after polypectomy, and to study the adenoma-carcinoma natural history and biology. The National Polyp Study demonstrated that although follow-up colonoscopy found many polyps, it was successful in clearing the colon of advanced adenomas. Advanced adenomas are defined as those that are 1 cm or larger or with high-grade dysplasia or invasive cancer, and some investigators also include in the definition a high degree of villous component. In the National Polyp Study, it was demonstrated that at a 3-year follow-up examination, only 3% of the patients had advanced adenomas after they had their colons cleared of all polyps at baseline. An examination at 1 year before the 3-year examination provided no additional benefit18 (Fig 3). This resulted in guidelines that now recommend omitting the 1-year examination after polypectomy and going to a 3-year examination for the first follow-up.



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  		Fig 3. National Polyp Study data shows cumulative percentage of people with advanced adenomas after colonoscopic polypectomy (advanced adenoma >= 1 cm or with high-grade dysplasia or with invasive cancer).18

 
It was long believed that the adenoma was the precursor of colorectal cancer and that its removal would result in the prevention of colorectal cancer. This belief was substantiated by data from the National Polyp Study, which demonstrated a sharp reduction in observed cancers as compared with expected cancers in the National Polyp Study cohort after the baseline clearing colonoscopy.19 The prevention of colorectal cancer by polypectomy is one of the best-kept secrets from the public. It is one of the most powerful prevention strategies that is available and yet is not widely known. In the National Polyp Study, we demonstrated further that one could stratify patients into those who are at high risk for advanced adenomas in the future and those who are at low risk for advanced adenomas. The low-risk patients constituted 70% of the cohort and probably could have their first follow-up colonoscopy 10 years after their clearing colonoscopy, but this needs to be studied further.20 It is reasonable to do the first follow-up colonoscopy at 3 years for only high-risk patients. This group is defined as those who have multiple adenomas at baseline or have a positive family history and are older than 60 years at their first polypectomy. This stratification would reduce complications and costs and conserve resources, which could be directed toward the initial screening of patients. The surveillance of patients after cancer surgery is the same as for those after polypectomy, because the reason for the colonoscopies after cancer surgery primarily is to detect polyps. However, these patients do need a preoperative or postoperative clearing colonoscopy to be sure that all synchronous polyps have been removed. Because of the striking effectiveness of colonoscopy in preventing cancer, screening guidelines now incorporate colonoscopy every 10 years for average-risk men and women as an additional option for screening. Two major studies have reported results of screening colonoscopy, one a Veterans Affairs collaborative study and another conducted on employees of Eli Lilly. The total number of patients examined in both studies was more than 5,000, and the studies are similar in outcome, demonstrating that approximately 10% of asymptomatic patients who are older than 50 years, both men and women, have either a cancer or an advanced adenoma.20,21

IMPLEMENTATION
Screening rates for colorectal cancer are low and well below those for mammography. National Health Interview Surveys have consistently demonstrated this fact. One of the most frequent reasons for not getting screened is that "it was not recommended by my doctor," according to an American Cancer Society Survey. The health care provider plays a very important role in motivating patients to be screened. Health care providers may be more motivated today because of the litigation that is occurring in colorectal cancer; the most frequent reasons for litigation are failure to screen, failure to diagnose, and deviation from standard of care. Standard of care now is based on published guidelines rather than on practice in the community. Many active screening campaigns in the United States are bringing to the attention of the public the prominence of colorectal cancer as a major disease and killer and the benefits that screening can provide. We have had the benefit of Katie Couric’s strong interest in keeping colorectal cancer awareness at the media forefront and recommending that people get screened.

The American Cancer Society’s objectives for colorectal cancer are as follows: (1) by 2005, 75% of people will be aware of colorectal cancer screening and 60% will get screened; and (2) by 2015, there will be a 40% incidence reduction in colorectal cancer and 50% mortality reduction. These goals have been enhanced recently by legislation from the United States Congress, which in 2000 provided Medicare reimbursement for screening fecal occult blood testing and flexible sigmoidoscopy and in July 2001 provided Medicare reimbursement for screening colonoscopy. This legislation was based on the demonstration in recent years by many cost-effectiveness models that colorectal cancer screening is cost-effective, costing less than $20,000 per life-year saved, and is equivalent to screening mammography. Colorectal cancer screening has been enhanced further by designation of March as National Colorectal Cancer Awareness Month by former President Bill Clinton. This has provided a basis for many organizations to focus efforts on public education. All of the campaigns are a call to action for the public to get screened. There has been great debate as to which screening test is the best, but the best screening test is the one that gets done.

FUTURE
Universal implementation of screening is a major challenge. In the United States, the target population is 80 million men and women who are 50 years of age and older. The question is whether we have the resources to accomplish screening in such a large population. There are alternatives that can be considered. Once-in-a-lifetime screening colonoscopy is one alternative. We can identify people who have adenomas, who then can be stratified further as low risk and high risk for subsequent advanced adenomas, with less intense or more intense follow-up surveillance, respectively. Patients with no neoplastic disease may require no further screening. This concept is under examination. Another approach is to try to identify individuals who would be most likely to benefit from screening. One such approach is genetic testing. However, genetic testing can identify only 5% to 6% of people who are destined to get colorectal cancer, and these individuals first must be identified by their family history of either FAP or HNPCC.1 There is room for discovery of additional genes in HNPCC because 30% to 50% of individuals who have a family history consistent with Amsterdam criteria will not have mutations detected. New genetic mutations in colorectal cancer have been demonstrated in the general population, two in Ashkenazi Jews and one in non-Jewish people.23-25 These require further study. The genetic mutations in Ashkenazi Jews have a very low penetrance and by themselves do not confer a striking increase in risk. They probably require additional polymorphisms to increase substantially the risk for colorectal cancer in those individuals. There has been recent interest in studying genetic mutations in the stool; a recent report suggested that a panel of DNA mutations in stool could result in the detection of cancers and adenomas with a high degree of sensitivity and specificity26 (Table 5). This was a small study and will require further investigation. The best stool marker that is available now is the fecal occult blood test, which can reduce mortality strikingly if done annually.


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  		Table 5.  Colorectal Cancer Screening Detection of Altered Stool DNA (APC, p53, BAT-26, L-DNA)
 
Another approach is to use two-stage screening with virtual colonoscopy first.27 Only individuals who have a significant lesion found on virtual colonoscopy would be referred for fiberoptic colonoscopy with biopsy and polypectomy. The accuracy of virtual colonoscopy has not yet been well established, and it is not totally noninvasive; patients require a preparation for 1 day before the examination and have air instilled in the bowel. This is promising, however, and needs further study. There have been many advances recently in diagnostic endoscopy with magnification lenses, dye staining, spectroscopy, and optical coherence tomography, which would greatly enhance our ability to make tissue diagnosis more accurately and perhaps separate out endoscopically those patients who do not need biopsy or polypectomy, especially in the case of very small polyps.

Screening has provided great opportunities. Screening can prevent colorectal cancer by polypectomy and find early-stage cancers for treatment with less morbidity. Screening can reduce the burden of treating advanced cancer and can identify families that are at increased risk. Screening also has provided a better understanding of the biology of colorectal cancer. We have learned about the long natural history of the adenoma-carcinoma sequence and about the steps in the pathology along this progression, particularly the importance of the advanced adenoma. The advent of colonoscopy and polypectomy and our understanding of the adenoma carcinoma sequence have permitted correlations of somatic mutations in this progression and phenotype-genotype correlations, especially in HNPCC and FAP. We also have learned about risk stratification. The adenoma-carcinoma sequence provides a wonderful model of carcinogenesis that can help us understand the evolution of other cancers. We also have learned about the importance of the neoplastic targets for chemoprevention and nutrition studies. The advanced adenoma must be the lesion that is the target of screening and must be the neoplastic stage by which we evaluate new technology and the results of chemoprevention and nutrition studies. It is no longer acceptable to detect only early-stage cancer.

Screening for colorectal cancer should be part of a complete prevention program that includes a healthy lifestyle and familial risk assessment (Fig 4). Individuals who have increased familial risk require special screening approaches, whereas those who are at average risk can have more standard screening. Those who are at average risk can be stratified further into those who require intensive follow-up and those who require less intensive or no follow-up. We are beginning to learn how to apply screening and surveillance approaches on the basis of risk stratification for a more cost-effective approach. Chemoprevention can be added to the program when substantial benefit of agents has been demonstrated. We now have a better understanding of the biology of colorectal cancer and the technology to intervene in that biology to make a difference in the lives of many people. Although there are many promising future developments, we must not encourage people to wait for new developments. We have the concepts and technology today to reduce substantially the mortality of colorectal cancer and even prevent it.16, 17



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  		Fig 4. Colorectal cancer prevention program. F/U, follow-up.

 

   REFERENCES
TOP
 INTRODUCTION
 TECHNOLOGY
 REFERENCES
 
1. Winawer SJ, Fletcher RH, Miller L, et al: Colorectal cancer screening: Clinical guidelines and rationale. Gastroenterology 112: 594-642, 1997[Medline]

2. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51: 15-36, 2001[Abstract/Free Full Text]

3. Greegor DH: Diagnosis of large-bowel cancer in the asymptomatic patient. JAMA 201: 123-125, 1967[Medline]

4. Winawer SJ, Stewart ET, Zauber AG, et al: A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy. N Engl J Med 342: 1766-1824, 2000[Abstract/Free Full Text]

5. Lockhart-Mummery Ducks C: The pre-cancerous changes in the rectum and colon. Surg Gynecol Obstet 5: 46 1928

6. Muto T, Bussey HJR, Morson BC: The evolution of cancer of the colon and rectum. Cancer 36: 2251-2270, 1975[Medline]

7. Stryker SJ, Wolff BG, Culp CE, et al: Natural history of untreated colonic polyps. Gastroenterology 93: 1009-1013, 1987[Medline]

8. Kinzler KW, Volgelstein B: Lessons for hereditary colorectal cancer. Cell 87: 159-170, 1996[Medline]

9. Winawer SJ, Zauber AG, O’Brien MJ, et al: The National Polyp Study: Design, methods, and characteristics of patients with newly diagnosed polyps. Cancer 70: 1236-1245, 1992[Medline]

10. Mandel JS, Bond JH, Church TR, et al: Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 328: 1365-1371, 1993[Abstract/Free Full Text]

11. Hardcastle JD, Chamberlain JO, Robinson MHE, et al: Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 348: 1472-1477, 1996[Medline]

12. Kronborg O, Fenger C, Olsen J, et al: Randomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet 348: 1467-1471, 1996[Medline]

13. Robinson MHE, Hardcastle JD, Moss SM, et al: The risks of screening: Data from the Nottingham randomised controlled trial of faecal occult blood screening for colorectal cancer. Gut 45: 588-592, 1999[Abstract/Free Full Text]

14. Selby J, Friedman GD, Quesenberry CP, et al: A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 326: 653-657, 1992[Abstract]

15. Newcomb PA, Norfleet RG, Storer BE, et al: Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 84: 1572-1575, 1992[Abstract/Free Full Text]

16. Winawer SJ, Flehinger BH, Schottenfeld D, et al: Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst 85: 1311-1318, 1993[Abstract/Free Full Text]

17. Wolf WI, Shinya H: Polypectomy via the fiberoptic colonoscope: Removal of neoplasm beyond the reach of the sigmoidoscope. N Engl J Med 288: 329-332, 1973

18. Winawer SJ, Zauber AG, Ho MN, et al: Prevention of colorectal cancer by colonoscopic polypectomy: The National Polyp Study Workgroup. N Engl J Med 329: 1977-1981, 1993[Abstract/Free Full Text]

19. Winawer SJ, Zauber AG, O’Brien MJ, et al: Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps. N Engl J Med 238: 901-906, 1993

20. Zauber AG, Winawer SJ, Bond JH, et al: Can surveillance intervals be lengthened following colonoscopic polypectomy? Gastroenterology 112: A50, 1997 (abstr)

21. Lieberman DA, Weiss DG, Bond J, et al: Use of colonoscopy to screen asymptomatic adults for colorectal cancer. N Engl J Med 343: 162-169, 2000[Abstract/Free Full Text]

22. Imperiale TF, Wagner DR, Lin CY, et al: Risk of advanced proximal neoplasms in asymptomatic adults according to the distal colorectal finding. N Engl J Med 343: 169-174, 2000[Abstract/Free Full Text]

23. Rozen P, Shomrat R, Strul H, et al: Prevalence of the I1307K APC gene variant in Israeli Jews of differing ethnic origin and risk for colorectal cancer. Gastroenterology 116: 54-57, 1999[Medline]

24. Prior TW, Chadwick RB, Papp AC, et al: The I1307K polymorphism of the APC gene in colorectal cancer. Gastroenterology 116: 58-63, 1999[Medline]

25. Pasch B, Kolachana P, Nafa K, et al: TßR-I(6A) is a candidate tumor susceptibility allele. Cancer Res 59: 5678-5682, 1999[Abstract/Free Full Text]

26. Ahlquist DA, Skoletsky JE, Boynton KA, et al: Colorectal cancer screening by detection of altered human DNA in stool: Feasibility of a multi-target assay system. Gastroenterology 119: 1219-1227, 2000[Medline]

27. Fenlon HM, Nunes DP, Schroy PC III, et al: A comparison of virtual and conventional colonoscopy for the detection of colorectal polyps. N Engl J Med 341: 1496-1503, 1999[Abstract/Free Full Text]




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