Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.
Professor, Dept. of Experimental Radiology, Faculty of Medicine, Kyoto University, JAPAN
In patients with xeroderma pigmentosa there are seven complementation groups. Patients from group A develop many small skin cancers. The cause of this disease is that damage caused by UV light in sunlight cannot be repaired, because they lack the enzymes required to repair DNA damage caused by UV light. Usually patients will develop skin cancer by the age of ten. The frequency of this disease in Japanese is about one in 100,000, so it is a very rare disease. But it is an autosomal recessive disease, so there is higher chance of being heterozygotes. The purpose of our study is to identify those heterozygotes among patients with skin cancer not related to this disease. Skin cancer in Japan is quite rare, so we expect that some of the patients who develop skin cancer may be heterozygotes of this disease, because Dr Mike Swift of North Carolina University, presented epidemiological evidence many years ago that heterozygotes of this disease have a much higher frequency to develop skin cancer than normal control groups.
There are seven complement groups, and these can be identified by cell fusion methods. Among different areas of the world, the frequency of the incidence of this disease caused by these different complement groups vary. In Japan, the most frequent group is group A. While group C is most frequent in North America, Europe or North Africa. Clinically they are very different. The group A patients have neurological abnormalities, while group C patients usually do not. We suspect that those genes may be different. This group A gene was found to be located on chromosome 9, but the group C gene has not yet been identified.
We are searching for heterozygotes among skin cancer patients in Japan. Most of the skin cancer patients were found to have unique mutations at specific sites next to the xeroderma pigmentosa (XPAC) gene which can complement those defective genes. This was discovered by Prof. Tanaka. The possibility of identifying heterozygotes for the defective allele for XPAC is ongoing. Prof. Tanaka found that at the beginning of exon 4 of the gene two bases were deleted. One point mutation was where a G was substituted by C. By this mutation splicing was interrupted so that two bases were deleted. This meant that a stop codon appeared at the second codon and abnormal protein product was formed. Many patients were investigated, and almost all patients in the homozygous state have this mutation. However, Caucasian patients do not have this same mutation, but a mutation occuring at a different site of this gene. Only one patient in Japan who is not related to this mutation has been found. Several patients were found with heterozygous or substituted gene structures. Prof. Tanaka suggested that this may be due to the so-called founder effect, where all these cases originate from one original mutation in a common ancestor. When we irradiate cultured cells from those patients with UV light, we can examine the sensitivity of cells by cell survival. Cells from homozygous and heterozygous patients have essentially the same cell survival, and UV sensitivity. They can be analysed by restriction enzyme analysis because there is a new Lwn1 restriction site in the mutated genes. This can provide easy analysis.
Up to date, we have investigated 40 skin cancer patients, and all 40 are negative. But by our rough estimate, if heterozygotes develop skin cancer with increased chance, we may expect one in 100 skin cancer patients, so this is not so surprising.
We have some collaborative studies with Tunisia and other North African countries. Many Arabic countries have very high frequencies of this disease. One of our workers, Associate Professor Yagi visited Tunisia, and at one hospital 30 patients showed up. In no other part of the world would so many patients be associated with one clinic. Even in Japan, where the number is more than in European and American countries, we still only see two or three patients every month. In Tunisia the population is about 6 million, but there are at least 200 cases of this disease reported there. In Japan we have 120 million people, and only 300 patients are registered with this disease. So the incidence is much greater in Tunisia, maybe 10-20 times more, so such genetic diagnosis may be more important in those countries.
The second topic I want to talk about is genetic counseling and informed consent related to organ transplantation. Genetic counseling in Japan has not been in general practice in most university hospitals. There are some exceptions, for example Prof. Ohkura has said that the situation is greatly improving. In local health offices, genetic counseling is becoming more popular. But still, in Kyoto University and surrounding universities, essentially no genetic counselors are employed as staff members of the university. In a later paper, Dr. Kawashima will explain the situation in Japan.
Recently, as a member of the Medical Ethics Committee of Kyoto University, I encountered several cases which may involve genetic counseling and informed consent. Liver transplantation from one of the parents to children has been performed in Japan during the last two years. The reasons for using living donors for liver transplants in Japan is because of several reasons. One of the parents should have a good chance of being a matching donor. There is also much time for consultation and informed consent because the donor is living with their children. The operations can be performed simultaneously, so there is less chance of complications. The most serious problem, is that we are still discussing whether we accept brain death or not, so we can avoid the brain death issue.
About 28 cases have been performed with good prognosis using partial liver transplantation from a parent, since June 1990. The recipients have been from 7 months to 15 years old. We restrict these operations to children only. Most patients have congenital biliary atresia, and they generally have a good prognosis. However, there are some cases which may need genetic counseling such as Wilson's disease or Refssen's disease or some other unfavourable genetic background. Also we have a few cases with ABO incompatibility. Those cases may require genetic counseling. Among the many causes of liver malfunctions, patients with hereditary diseases make up a considerable proportion of the candidates to be recipients of transplants. However, genetic counseling is not well established in Kyoto. Due to systemic genetic background, prognosis may be worse in patients with heredity defects than in those without them.
The question is how to explain the genetic diseases to the parents or patients, because generally in Japan genetics is avoided in discussions with family members. Genetics has been a sort of taboo subject in the society. The words "hereditary " or "genetics" can be shocking to the members of families of those involved. Also there is a lack of training for medical doctors. I feel quite responsible, because in my course in Kyoto University Medical School on genetics, I always try to emphasise the importance of genetic counseling, but I always feel frustrated at the lack of an established genetic counseling system. As a member of the Medical Ethics Committee, founded by Prof. Hoshino, we are still behind in the practice of genetic counseling. Organ transplantation can involve serious genetic issues. We should improve medical education and training extensively and comprehensively to have a breakthrough in this aspect, and should establish good coordination among doctors, geneticists and counselors.