Dr. Richard A. Gatti
UCLA School of Medicine
Department of Pathololgy
Los Angeles, CA 90095-1732
Phone: 310-825-7618
Fax: 310-825-7618
Email: rgatti@pathology.medsch.ucla.edu
Projects are approved by an IRB located at: University of California, Los Angeles - School of Medicine.
The approving IRB operates under a Multiple Project Assurance (MPA) recognized by DOE or by the Department of Health and Human Services (HHS).
MPA number of the IRB: M-1127
Number of Human Subjects Projects reported: 1
Project Identifier: UCLA-87-ER60548
Project Title:
Human Gene for Radiation Hypersensitivity
Principal Investigator:
Dr. Richard A. Gatti
Principal Investigator's Institution: UCLA School of Medicine
Project started in: 1987
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
Total Funding: $310,000
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 19, 1996
IRB Approval Number: 93-07-260-03
Number of Human Subjects who participated in this project/protocol during
03/19/95 - 03/19/96: 40
Type of Human Subjects Involvement:
This project has attempted to map and isolate a gene for ataxia-telangiectasia (A-T), a progressive neurological disorder that is also associated with radiation sensitivity, immunodeficiency and cancer susceptibility. The frequency of A-T carriers is 0.5-3%. A-T carriers may account for 5% of cancer patients in the United States and 1 in 5 women with breast cancer. A-T carriers are also radiosensitive in vitro and MAY need less than conventional doses of radiotherapy in the event of developing cancer.
Our laboratory mapped the gene to chromosome 11q22-23 in 1988, sublocalized it by linkage analyses to a 500-kilobase region in 1994, and participated in its cloning and analysis of mutations in A-T patients in 1995. The earlier linkage analyses involved DNA from blood specimens of more than 250 families from many countries; the results of this genotyping were then correlated with the phenotypes of family members. The major laboratory work of the past few years has not involved human subjects directly, but has involved the study of anonymous DNA samples from genomic and expression libraries. Now that the gene has been isolated, we are attempting to characterize each family's mutations and then to correlate the mutation sites with variations in the phenotypes. The latter will certainly involve returning to the referring physicians for further clinical details.
Most bloods (5-20 milliliters) from A-T families are sent to our laboratory by physicians in various countries, including the U.S., for genetic analyses. The mutation analyses are provided at no cost to the families or to their insurance. We analyze the DNA or RNA extracted from this blood, or from cell lines derived from these bloods on approximately 30 new families each year. We are also analyzing the radiation sensitivity of suspected A-T patients, to assist in the clinical diagnosis, by an in vitro assay performed on the patients' lymphoblastoid cell lines.
When samples are sent to our laboratory for research analyses, the Principal Investigator immediately assigns a family number and individual family member numbers. From that time on, all references to that family, data analyses, etc., use only those numbers. The individual identification names are included in the computer database for cross-checking errors. However, only the PI and the biomath data processors have access to that information. The original names are only used when information is sent back to the referring physicians. No reference is made to these names in the event of publication or transfer of data to a collaborating laboratory. Cell lines are also coded.
From these and from previously studied families in our databases, we can also identify many individuals who are heterozygotes or carriers. Most of these individuals know that they are carriers, such as the mothers and fathers of patients, many having requested further information about their cancer risk and radiation sensitivity, which they learn from various brochures and newsletters circulated by the families themselves. In some families, members of additional branches have requested that they be tested as well. At no cost to them, we try to meet these requests whenever possible and feasible.
One risk to members of families might be the psychological burden of learning specifically that they are A-T carriers, since it already seems clear that such individuals are at an increased cancer and radiation exposure risk. On the other hand, the benefit of knowing would be that these individuals would be more closely monitored in the future for cancer and for radiation exposure. They would also be alerted for child-bearing purposes. Conversely, family members who are identified as non-carriers are relieved to learn that they no longer need to worry about the adverse effects of being an A-T carrier.
At risk pregnancies can now be monitored for prenatal diagnosis. Our laboratory was the first to report prenatal testing for A-T by genetic haplotyping in 1993. This is now being performed in several laboratories around the world. We no longer need blood from A-T families in order to perform genotyping; we have the capability to perform these studies on mouth washings. However, since this procedure for DNA isolation has not yet been approved by the Food and Drug Administration, we have not yet incorporated it into our testing. In some families in whom the mutation is actually known, simple assays have recently been developed which allow for rapid pre-natal diagnosis.
Another potential risk is insurance risk assessment. So far this has not been a problem. Besides, an argument could be made that within the same families, non-carriers will be at a lesser cancer risk than the general untested population. So, if individual data were not provided to insurance companies, the summed risk for the family might not be significantly different from that of the general population. However, on an individual basis, this could later become a problem. Hopefully, with further understanding of the functions of the A-T gene and the health status of A-T carriers, medical care for carriers and affecteds will improve. That is the potential benefit to all A-T families from this research effort.
Once a family member has been identified as a carrier, we routinely provide free advice, if requested, to these individuals and to their primary physicians regarding their carrier status. For example, a primary care physician or family member may call to ask whether a planned tomogram is "safe". The PI offers to discuss the pros and cons of this with the carrier's physician. A second radiological opinion may be sought. The indications for the radiological procedure are reviewed with the physician. In several actual cases, the physicians recognized that the recommended procedure was not absolutely necessary and, when they were alerted to the moderately increased radiosensitivity of A-T carriers, they chose to use alternative procedures, with the option to return to their original plan if needed. The PI also provides advice or referrals for second opinions at times of biopsies and genetic counseling, all at no cost. The families have been very appreciative - in the U.S., Norway, Poland, Israel, England, Italy, Germany, Costa Rica, Kenya, and Australia.