Cancer cells, the DNA-ransackers

22. July 2011

Whoever studies the DNA of uncontrollably-growing tumor cells finds therein a seemingly wild confusion of mutations: translocations, base pair substitutions and differing sets of chromosomes. The results of the Cancer Genome Project should soon indicate which mutations are critical to the fate of these "cancer clones".

The theory is too simplistic to capture the essence of the story. Why does a normal cell at some point become a cancer cell? In the course of its life, influences from within and without are responsible for ever more points of mutation, areas where the sequence of letters, the sentence structure or even entire chapters in the book of DNA are no longer there in the way that they were written at the beginning. Eventually, it happens – but which mutations are the crucial ones in this transition to the “eternal cell life“ and which determine how fast this cloning proliferates and even migrates into other tissues?

In order to elucidate how, from a rather well-ordered text, a jumble of letters arises, and what meaning errors in individual chapters have, the Cancer Genome Project will sequence the genomes of more than 25,000 cancer patients, among whom are sufferers of about fifty different types of cancer. A mammoth task awaits researchers in Germany, Australia, China, India, Spain, England, the United States and some other participating nations.

Passenger and Driver Mutations

Not all mutations in a cancer cell have the same significance. Most of the changes in the DNA code are known as „passenger mutations”. They arise in the course of many cell divisions of the clone, but are not crucial for survival and rapid growth. Much more rare are the “drivers”. They give the tumor clone a growth advantage over normal cells. They also enable the spread of the clone into other tissues. It is exactly these DNA aberrations that are also the target for new agents acting against the tumor.
So far, researchers have discovered about 400 of these mutated key-genes for individual tumors, which is about two percent of all protein-coding genes. A notorious example is ABL-kinase, which is at the frequent 9:22 translocation constitutively expressed in CML. A matching inhibitor, imatinib, has lead to great successes via treatment. Trastuzumab is an effective antibody in breast cancer treatment, in which it is directed against the constant presence of epidermal growth factor receptor HER2/neu; HER2-positive patients have a rather poor prognosis.

Cancer genes: Few changes suffice for malignant transformation

Thanks to new sequencing methods, we now know that in most types of cancer such as breast, ovarian, colorectal, pancreatic cancers, as well as gliomas, 1000-10000 somatic mutations occured. Cancers with few aberrations, for example, include testicular germ cell tumors and acute leukemias. Very many mutations, by contrast, are found in cancers that have direct contact with harmful environmental influences. This includes lung cancer (tobacco) and melanoma (UV radiation), which collect more than 100,000 mutations in their genomes.

It was long regarded to be true of “cancer genes” that about five of them are altered when a proliferating tumor cell arises from a differentiated somatic cell. Over time, cancer genome specialists have come to doubt that such a rule holds. In hematopoietic neoplasms usually only a few of these genes are mutated. It will probably turn out over the next few years, writes Michael Stratton of The Wellcome Trust Sanger Institute in Cambridge, England in a Science review, that many other DNA segments with aberrations are crucial for tumor development and thus to be previously unknown cancer genes.

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DNA methylation: an indicator of metastases

Many of the previously found driver mutations affect genes that are involved in chromatin modifications and therefore involved in the regulation of DNA expression. Among cancer genes are histon methylases, or methyltransferases, which methylate the DNA. The examples show that not only the sequence of the genes determines tumor development, but also epigenetic mechanisms. One such indication is delivered in a publication in Science Translational Medicine from late-March. Timothy Chan from New York’s Memorial Sloan Kettering Cancer Center therein shows with tissue samples from breast-cancer patients that the methylation status of tumor DNA provides a prediction for whether the cancer cell metastasises. A high degree of methylation signifies a favorable prognosis, whereas unmethylated DNA suggests metastasis and lesser survival. Most of those genes that were previously associated with the migration of tumor cells into other tissues were in the corresponding samples protected by methyl groups.

Few “metastasis genes”

A comparison of data for breast cancer with samples from patients with colon cancer or glioma shows that this principle is universal. In these instances, too, the degree of methylation predicts the development of a tumor.

Whether such interference in the switching on and off of genes is directly associated with mutations of cancer genes is not yet clear at the moment. The results to date of the cancer genome project suggest that the number of “metastasis genes” is readily comprehensible. Epigenetics may therefore play a greater role than mutations which affect the function of the corresponding protein.

Gene profile analysis: tool for oncologists

The immense effort which is the sequencing project should, on its path to personalised cancer medicine, in the coming years lead to both new drugs and to more accurate prognoses for patients. Already at present the FDA (American Food and Drug Administration) has for instrance approved a test for breast cancer taking in a genetic profile of 70 genes. Just as its 21-gene assay competitors do, it allows predictions about the success of chemotherapy and possible recurrence of the tumor. Similar tests are also available for colon cancer and acute myeloid leukemia.

It’s shown in investigations in solid tumors that it will not be so easy, even after the sequencing of cancer genomes of tens of thousands, to simply compare the respective profiles to the database and discern the chance of successful therapy. Unlike many cancer genes in leukemia, fewer than 10 percent of all samples are mutated in any given tumor. The rules which explain unrestrained proliferation of tumor cells seem to be much more complicated than it was initially thought to be.

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