2. Markers of colorectal cancer metastasis
- A. Screening for mutant genes in fecal specimens
- B. Pancreatic cancer genetics
- C. Screening targets of preinvasive neoplasms of the pancreas
4. T-cell targets in pancreatic cancer
- A. Hereditary colorectal cancer genetics
- B. Tumor prevention in MIN mice
- C. Markers of familial pancreatic cancer
JHU's career development research projects include
1. Chromosomal instability
2. Methylation patterns
Dr. Kern explained how genetic mutations occur in the development of cancer. He addressed premutations, which are considered normal polymorphisms yet they increase the mutation rate of neighboring sequences. One specific premutation is common in Ashkenazi Jews. Six percent of healthy Ashkenazi Jews have the premutation, 12 percent of Ashkenazi Jews with colon cancer have the premutation, 17 percent of Ashkenazi Jews with colon cancer under the age of 65 have the mutation, and 28 percent of Ashkenazi Jews with familial colon cancer have this premutation.
Dr. Kern also addressed developing new drugs to test in the MIN mouse model through a translational approach by examining the biochemistry of the adenomatous polyposis coli (APC) pathway. The APC gene--a gene that is essential for normal epithelial cell growth and differentiation--is responsible for the breakdown of beta-catenin, a regulatory protein that acts like a classic oncogene. Because APC is missing in 80-85 percent of colorectal cancer cases, this downregulation of beta-catenin cannot occur. In other cases (about 7-10 percent), beta-catenin mutates in tumors and becomes non-susceptible to APC's degradative abilities. Beta-catenin provides the oncogenic drive in both of these scenarios; therefore, researchers are testing thousands of drugs in an attempt to find those that shut off the beta-catenin.
Dr. Gomez then introduced the next speaker, Dr. Sidney Winawer of Memorial Sloan-Kettering Cancer Center, who presented Colon Cancer Screening to the DDICC members and guests.
Dr. Winawer first presented some common statistics, including that colorectal cancer is one of the four leading cancers in terms of incidence and the second most common cancer killer in the United States. He also said that colorectal cancer is as much a woman's disease as it is a man's, and he presented a dramatic graph in slide format that plotted age-specific incidence rates of breast, colorectal, and cervical cancers per 100,000 women against age.
Dr. Winawer said he co-chaired with Bob Fletcher a multidisciplinary panel at a consortium meeting convened by the Agency for Health Care Policy and Research (AHCPR) to look at the evidence for colorectal cancer screening. Represented on the panel were generalists, surgeons, a radiologist, nurses, an economist, a consumer, a geneticist, an osteopath, gastroenterologists, and oncologists. They developed colorectal cancer screening guidelines, which were published in the February 1997 issue of Gastroenterology. They examined a good deal of evidence that was consistent with a reduction in colorectal cancer mortality with stool blood testing. Preliminary evidence for sigmoidoscopy also shows a reduction in colorectal cancer mortality. Sigmoidoscopy as a colorectal screening tool is being further investigated. Dr. Winawer said that the American Cancer Society's guidelines, as well as the AHCPR's panel's guidelines, recommend that physicians also should discuss colonoscopy and the double contrast barium enema with patients.
Dr. Winawer briefly addressed the cost-effectiveness of colorectal cancer screening. The research has established that all screening methods are comparable and the cost is equivalent to screening mammography.
He then moved on to discuss polypectomy to reduce incidence as another form of secondary prevention of colorectal cancer, as adenomatous polyps are precursors to cancer. Researchers more recently have found that the polyp is preceded by an aberrant crypt. The adenoma develops into carcinoma over a very long period of time, and because the technology allows doctors to detect very small polyps, there is a large window of opportunity for prevention.
The National Polyp Study showed that a good colonoscopy at time zero is extremely effective in clearing out the colon of significant pathology. Patients at higher risk of developing cancer are those with multiple adenomas and a positive family history. Age also is an important factor because people tend to develop more adenomas with age.
To test the hypothesis that the removal of colorectal adenomas results in a reduction of colorectal cancer incidence, Dr. Winawer used data collected prior to the availability of colonoscopy technology and determined that it is beneficial to the patient to have the polyp(s) removed.
Dr. Winawer reported that several trials are either under way or have been completed to study the application of colonoscopy screening to the general population as a viable approach to the ultimate eradication of colorectal cancer in the United States. Currently, the National Colonoscopy Screening Trial is being planned and aims to identify in the general population people at risk for advanced adenomas in order to reduce colon cancer mortality by reducing incidence.
Dr. Frank Hamilton began his presentation with a brief introduction to applicable legislation. Congress enacted the Balanced Budget Amendment that authorized the Health Care Financing Administration (HCFA) for the first time to provide colorectal cancer (CRC) screening to Medicare beneficiaries as of January 1, 1998. This coverage includes fecal occult blood, flexible sigmoidoscopy, and colonoscopy.
Currently, several Federal agencies (Centers for Disease Control and Prevention, HCFA, and NCI) are collaborating on an ongoing national CRC screening initiative, "CRC: Screen for Life," which is a multi-year effort. The objectives are to inform people over the age of 50 about benefits of CRC screening, motivate this group to talk to their health care provider about the CRC screening program, and promote Medicare's new CRC screening benefits.
Dr. Hamilton concluded by mentioning that CRC is the second leading cause of cancer-related deaths; CRC deaths are preventable; and most CRCs begin as polyps, which can be detected and removed. He then distributed an educational handout for attendees to give to family members to inform them of the importance of early detection. [This handout is a printout of the following CDC web page www.cdc.gov/cancer/colorctl/colorect.htm.]
Ms. Rita Yeager of NIDDK reported that the congressional hearings for the National Institutes of Health (NIH) have ended. Each NIH Center and Institute Director had an opportunity to testify, and their statements can be found on their respective agency Web sites. Finally, the President's budget plan for fiscal year 2000 would increase the NIH budget by 2.1 percent.
Dr. Hoofnagle reported on recently released DDDN RFAs, which deal with celiac disease screening in special populations, endoscopy database screening, hepatitis C, and GI motility. He also announced that NIDDK will be hosting a meeting on complementary and alternative medicine and liver disease August 24-26 on the NIH campus. Finally, Dr. Hoofnagle announced that Dr. Thomas Kresina will be leaving DDDN to join the National Institute on Alcohol Abuse and Alcoholism (NIAAA), but he will continue to participate on the DDICC and serve as its Executive Secretary.
Dr. Kresina reported that the next meeting is being moved to June 15 because June 8 conflicts with the international hepatitis C meeting. [Note: This has changed again; the new meeting date is June 10.]
In closing, Dr. Hoofnagle asked attendees to make their agency announcements. Dr. Vishnudutt Purohit reported that NIAAA has put out a program announcement on mechanisms of alcohol-induced fibrosis and an RFA on alcohol and hepatitis C. Dr. Butler reported that the National Naval Medical Center is beginning a study at four military hospitals of screening colonoscopy in women and is in the middle of another study comparing the screening colonoscopy with sigmoidoscopy to see if sigmoidoscopy by itself is missing some cases of polyps. Ms. Diana Berard reported that National Institute of Allergy and Infectious Diseases put out an RFA on animal models of hepatitis C, and they will be putting out another RFA on hepatitis C in the near future.
Dr. Hoofnagle adjourned the meeting.