Cancer Genetics | Research & Encyclopedia Articles

Cancer Genetics

The hallmark of a malignant cancer is the uncontrolled clonal proliferation and spread of abnormal cancer cells.

Cancer is thus our most common genetic disease but only rarely is it inherited. Most cancers are sporadic and arise in a particular tissue such as the colon, breast, lung, or skin when normal cells acquire mutations in one or more oncogenes or tumor suppressor genes. The acquisition of multiple new genetic changes is what sets the cancer cell apart from the normal cells in its surrounding tissues.

The cancer cell develops when a normal cell in an organ or tissue acquires the capacity to divide in an uncontrolled fashion. Over time the developing cancer cell starts to multiply in a clonal fashion, begins to appear different (anaplastic or undifferentiated), and progressively acquires other characteristics, such as the capacity metastasise while losing cell-to-cell adhesion. The continued acquisition of new biologic characteristics is the key to many aggressive cancers evading the host defenses, and to the resisting some treatments such chemotherapy and radiotherapy. Cancer biology can be likened to a rapid evolutionary sequence whereby cancer cells undergo a progressive selection for survival of the fittest. In Darwinian terms, the evolution of a species occurs by slow but spontaneous genetic change which provides a survival advantage to individuals who can go on to reproduce. In the evolution of a cancer, some cells become genetically unstable and this permits the rapid development of multiple genetic changes that equip cells with a survival advantage, the ability to multiply rapidly, spread to other tissues and evade the hosts defenses.

The term cancer derives from the observation by Hippocrates in 400 B.C. that the veins radiating from a breast cancer resembled the legs of a crab, hence karkinoma in Greek and cancer in Latin. Cancer is not a single disease, but is many different diseases that all share common biological and pathological characteristics. In most western societies, cancer is a leading cause of death. The disease may develop in any body tissue or organ and over one hundred different types of cancer can occur in adults. Cancer also occurs in children and may even be present at birth.

The first clues to the cause of cancer came over two hundred years ago from an observation by Percivall Pott, a London doctor, who in 1775 found a high incidence of scrotal cancer in men who had worked as chimney sweeps. Later, radiation was found to cause skin cancer and tragically Marie Curie (1867-1934) the discoverer of x-rays, died of a cancer caused by prolonged exposure to radiation. During the second half of the twentieth century, epidemiologists (those who study disease in populations) linked exposure to certain environmental toxins and particular types of cancer. Most notably, cigarette smoking and lung cancer, sunlight and skin cancer, and certain industrial chemicals to the cause of bladder and liver cancer. Finally several viruses were also been implicated in causing cancer, such as the hepatitis B virus and cancer of the liver, the Epstein Barr virus and lymphoma, and the human papilloma virus and cancer of the cervix. These important observations all suggested that specific external environmental agents could cause specific cancers.

How then could a diverse range of external agents such as chemicals, radiation and viruses, all lead to the development of cancer?. The answer to this question has come over the last 25 years from two different lines of investigation; studies on cancer causing viruses and research into the genetics of some rare cancers in children.

In 1910, Frances Peyton Rous (1978-1970) isolated a virus from a cancer in chickens (a sarcoma) that caused new sarcomas to develop when infected into healthy chickens. Rous's work languished for over 50 years until he was awarded a Nobel Prize in 1966. By this time, methods for the study of viruses and cancer had improved considerably and many new animal derived viruses were found to cause cancer in a range of species. These viruses could also induce cancer-like changes when introduced into normal cells grown in the laboratory. A genetic study of these cancer causing viruses identified a small number of genes termed viral oncogenes (v-oncogenes) which, when introduced into cells, could transform the normal cells into malignant cells.

The presence of viral oncogenes led to the search for endogenous cellular oncogenes, which might cause cancer. In a crucial experiment in the late 1970s, DNA from mouse cells which had been transformed by a chemical carcinogen, was transfected into normal mouse cells. The normal mouse cells became malignant suggesting that a gene within the cancer (a proto-oncogene) had been mutated by exposure to the chemical and was able to induce cancer. Surprisingly, when these endogenous cellular oncogenes were eventually isolated they were found to be homologous to virally derived oncogenes.

In the early 1970s the American paediatrician and scientist, Alfred Knudson at the Fox Chase Cancer Center studied retinoblastoma, a rare childhood eye cancer that is sometimes inherited but is most often sporadic. He observed that children who had inherited retinoblastoma often had the cancer at birth, and were at high risk of developing multiple cancers in both eyes. Children with later onset retinoblastoma usually had no family history and developed isolated tumors. Knudson reasoned that children with inherited retinoblastoma had a germline mutation in one allele of a recessive cancer gene. The germline mutation was the first of two hits in knocking out a recessive cancer gene. This is known as Knudson's two hit hypothesis. Later genetic studies found the first hit in children with inherited retinoblastoma to be a partial deletion of the long arm of chromosome 13 causing loss of the tumor suppressor gene, RB1.

These two directions of study independently identified two different classes of cancer gene, the oncogene and tumor suppressor gene, that when mutated in a given cell can set in train the sequence of events leading to the development of a cancer.

It is important to appreciate that oncogenes and tumor suppressor genes are in fact normal cellular genes with vital functions within normal cells. It is only when they are mutated in some way that these genes become cancer causing.

The Ha-ras gene is a good example of an oncogene. Located on chromosome 11 at the normal cellular Ha-ras gene is one of a family of ras genes and encodes a small protein that is involved in intracellular signaling. Mutations in the ras oncogenes disrupt processing of cell signals and contribute to cell transformation. Mutations in ras oncogenes are found in approximately 10% of cancers especially cancer of the colon and lung.

The most important tumor suppressor gene is the p53 gene. This gene which is known as the guardian of the genome encodes for a protein with multiple intracellular functions related to the detection of DNA damage. When DNA is damaged by exposure to a mutagen such as UV irradiation the p53 gene is expressed. The p53 protein causes the cell to stop dividing so DNA mismatch repair genes can repair the DNA. If the DNA is successfully repaired, the cell resumes normal cell functions and the p53 gene is down regulated. However, if the DNA damage is beyond repair the p53 protein switches on a process called apoptosis (programmed cell death) leading to the death of the cell. For example, sunburn to the skin causes UV induced DNA damage, which often cannot be repaired. Expression of the p53 gene induces apoptosis the skin cells die and peel off.

Mutations in the p53 gene occur in approximately 50% of all cancers - particularly cancer of the breast, colon, lung, and brain. The mutant p53 protein is unable to stop uncontrolled cell division or switch on apoptosis, and can no longer protect the cell from acquiring additional mutation in other genes. The result is an unstable cell genome liable to further progressive DNA damage. The inherited cancer condition, Li-Fraumeni syndrome, is an autosomal dominant disorder caused by inherited mutations in the p53 gene. Individuals affected with Li-Fraumeni syndrome may develop breast cancer, brain tumors, leukemia, prostate cancer and various sarcomas at a young age.

Mismatch repair genes are another class of cancer gene contributing to instability of the cancer cell genome. Damaged DNA is repaired by an active DNA mismatch repair mechanism that identifies damaged DNA, then cuts out and repairs the the damaged DNA bases. Mutations in these repair genes are common in cancer cancers of the colon.

Oncogenes, tumor suppressor genes and other cancer causing genes can become mutated in any number of different ways. Most oncogenes become activated by specific mutations within their DNA sequence that causes the gene protein to function abnormally. Some oncogenes such MYCN are activated by DNA amplification. Oncogene amplification occurs commonly in neuroblastoma an aggressive cancer in children. These tumors can acquire hundreds of copies of this gene by DNA amplification making the cancer very resistant to treatment. Another means of oncogene activation is by its translocation from one chromosome to another. In the Burkitt lymphoma the c-myc oncogene is translocated from chromosome 8 to chromosome 14 where it becomes activated by an immunoglobulin gene. Only one allele of an oncogenes need to be activated for it to participate in cell transformation.

Tumor suppressor genes on the other hand are recessive and normally act to suppress cell replication. Cell transformation occurs when both gene alleles are inactivated (knocked out). Most commonly, inactivation of one gene allele occurs by a chromosome deletion. The second event may be an inactivating gene mutation, a second deletion or methylation of the genes promoter.

Regardless of the actual mutations involved a crucial concept in the development of most cancer is that more than one gene is usually involved in the process. Indeed in the development of cancer of the colon at least six or more separate oncogenes and tumor suppressor genes are involved in a progressive multi-step process to transform a normal colon cell into an aggressive, self replicating and invading cancer.

More recently, the application of gene expression arrays (microarrays) to the study of cancer has found that in addition to multiple gene mutations, the expression of many hundreds of non-mutant genes is affected in the process of cell transformation.

Microarray analysis of cancers of the breast and soft tissues has also identified distinctive patterns of gene expression which can be used to aid diagnosis and predict the clinical behavior of individual tumors.

This type of genetic analysis will also aid the development of new cancer therapies directed specifically at the molecular biology of the cancer.

This is the complete article, containing 1,733 words (approx. 6 pages at 300 words per page).