New technology makes it possible to build a genetic profile for cancer patients
By Marit Selvin
In the last twenty years, there has been a great momentum in the study of the genetic basis of cancer. Many genes have been found whose disruption may cause the disease, and knowledge has been accumulated about the activity of the mechanisms that turn a normal cell into a cancerous cell. To these is now added a new technology that was developed in recent years, called "DNA chips", and helps to diagnose the genetic characteristics of the cancer in question.
The term "cancer" does not refer to one specific disease, but to a huge number of pathological conditions. There are hundreds of types of cancer, each of which has unique characteristics. It so happens that a certain type of cancer may respond to treatment that will not help another type of cancer. Furthermore, even tumors of the same type may respond differently to a certain treatment. The reason for this is the activity that takes place inside the cancer cell according to the commands coming from the active genes in it.
The DNA chip method makes it possible to locate the active genes in the cancer cell. In the cancer cell, unlike the normal cell, genes are activated that help the cancer process and shape its various characteristics. It turns out that different types of cancer, and even cancerous tumors belonging to the same type, are characterized by a unique genetic profile. This profile can explain the differences in the degree of violence of the different tumors and their response to different treatments. Locating these genes will shed light on the mechanism of the cancer process and allow the development of substances that will stop it.
"Such information will lead to the rewriting of textbooks dealing with cancer in the next three to four years," said Louis Stout from the National Cancer Research Institute to the journal "Science", which published an article on the matter.
DNA chips are small chips the size of a coin, divided into tiny boxes where thousands of known genes are placed side by side. This arrangement of genes is intended for the purpose of making a sort of comparison between them and genes from living tissue. Using a special method, molecules are extracted from the tissue that represent the genes active in it and turn them into DNA molecules, known as "complementary DNA". This DNA is labeled with a fluorescent substance. When these molecules come into contact with the chip, genes in the complementary DNA bind to their corresponding genes in the chip and light spots are obtained. According to the location of the illuminated points, it is possible, through a computerized scan, to determine the identity of the active genes in the tissue.
Louis Stout, with a group of researchers from Stanford University, tried to use this method to test why in the case of lymphoma (a type of blood cancer) 40% of patients respond to treatment while 60% succumb to the disease. In the first step, they built a chip containing about 18,000 known genes, most of which are active in normal and cancerous blood cells. Later, they prepared complementary DNA from biopsies of 40 lymphoma patients, and added them to the chip. To their surprise, they found great variation in the active genes in the patients, even though they all have the same disease.
Analysis of the results on the computer revealed that it is possible to divide the patients into two groups according to the degree of activity of certain genes. It turned out that this division created two groups, which also differ from each other in their clinical characteristics. One group included patients who responded to chemotherapy treatments, compared to the patients in the second group who did not respond to this treatment. The difference between the groups was also expressed in the patients' ability to survive.
These findings also have practical implications. Lymphoma patients currently receive chemotherapy treatments, and when they fail to improve their condition, a bone marrow transplant is performed. In the future it will be possible, depending on their genetic profile, to refer them directly to transplantation and thus save them the damage of the treatments and unnecessary suffering.
Different activity patterns of genes have also been found in melanoma (the most aggressive skin cancer). It turned out that these tumors can also be divided into two groups, according to the pattern of the genes active in them: it was found that the level of activity of the genes involved in the movement of cancer cells in one group is lower than that of the malignant one. Lower activity means slower movement of the cancer cells, and hence also a smaller degree of invasiveness. In this group - out of 31 melanoma patients examined - few patients died compared to the other group - in which the genes involved in movement were more active.
In other studies, two groups of researchers tried to identify the genes responsible for changes in cell movement in melanoma. The researchers wanted to check if there is a connection between the changes in their activity and the degree of violence of the disease. Using DNA chips, they compared the active genes in aggressive melanoma tumors, which form metastases with a high frequency, with genes in less aggressive tumors. The comparison revealed that in cases where the melanoma cells began to produce metastases, the level of activity of certain genes also increased. Most of these genes have something to do with the cells' ability to move and penetrate new tissues.
A different activity pattern of genes was also found in tumors with a similar pathology of breast cancer. The test showed that breast tumors can be divided into two groups according to the degree of activity of the gene encoding the estrogen hormone receptor. Differences were found in the activity level of the gene between the two groups, which probably affects the degree of violence of the tumor. From this study, published in August in "Nature", it appears that this is not the only difference.
These studies are the first in a growing field of studying the genetic activity that leads to the development of cancerous conditions. "There is no doubt that this is the way to take advantage of the huge investment made in deciphering the human genetic code not only for the purpose of knowledge, but for immediate use in medicine," says Prof. Avraham Hochberg from the Institute of Life Sciences at the Hebrew University. "These methods will in the future lead to the development of an approach to treatment adapted to the patient, which will provide an accurate genetic analysis of the patients and offer a treatment 'tailored' to the unique genetic profile of the disease."
{Appeared in Haaretz newspaper, 5/10/2000}
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