Cancer Genetics

Author: Robert Nussbaum Medical Geneticist The University of California, San Francisco

2008-07-28

What is Cancer?

Cancer is not a single disease, but rather, is the name used to describe the most dangerous form of neoplasia, a disease process characterized by abnormal, uncontrolled cell division leading to a mass or tumor.  Uncontrolled growth alone, however, does not make a tumor a cancer. For a tumor to be a cancer, it must not only grow inappropriately at the site where it originates (the primary) but must also demonstrate malignant behavior, that is, the capacity to invade normal tissues neighboring the site of the primary tumor and/or to seed new tumors at distant sites in the body (metastases). The surrounding normal tissue is also likely to play an important role, by providing the blood supply that nourishes the tumor, by permitting cancer cells to escape from the tumor and form metastases, and by shielding the tumor from attack by the body’s own defense mechanisms. Thus, cancer is a complex process, both within the tumor and between the tumor and the normal tissues that surround it.

Cancer is a Disease of the Genes

Cancer is fundamentally a genetic disease, that is, the disease starts and progresses because of changes in the DNA sequence of  certain genes, resulting in abnormal genetic information inside the cancer cells that is then passed on to the progeny of these abnormal cells as the cancer cell divides. Most of the time, these abnormalities in the genetic material are the result of what are referred to as somatic mutations (from the Greek word “soma” meaning body and the Latin word “mutare” meaning change). Somatic genetic changes occur in all cancers.  In contrast to somatic mutations, mutations that are inherited through the fertilized egg are passed on to every cell of the body and are referred to as germline mutations.

Most cancer is sporadic, that is, it occurs once in a single individual and not multiple times in the patient and his relatives. In a few percent of cancers, more than one person in a family may develop the same or a related form of cancer. Of course, families in which two or more individuals develop one or more related types of cancers may simply represent a coincidence of two independent sporadic cancers, but there is also the possibility that they have a familial or hereditary form of the disease. In such families, individuals can inherit genetic abnormalities as germline mutations that strongly predispose to cancer and they carry these changes in every cell of their bodies. Regardless of whether a cancer is sporadic or hereditary, or whether the genetic changes are somatic or germline mutations, cancer results from alterations in the genetic material in the cancer cells that cause the cells to become and remain cancerous.

Although mutation in a single gene can initiate a cancer, many more genetic changes must occur to produce a fully malignant cancerous tumor. Rapid and unregulated cell division in the tumor cells leads to additional genetic abnormalities such as an abnormal number or structure of chromosomes, which creates imbalances in the genetic content of the cell, or additional mutations, which damage the structure of important genes. Although some damage kills cells or has no effect on cell survival, genetic changes that increase the growth rate of the tumor and confer the ability to invade surrounding tissue and send metastases to distant sites will cause cells to outgrow other cells in the neoplasia. The cells that experience an enhancement of growth and survival will come to predominate as the cancer evolves and progresses. Genetic damage that occurs in cancer cells sets up a vicious cycle because it reduces the cells’ ability to repair future genetic damage. Thus, the more malignant the cells become, the more their DNA is subject to damage, the more genetic damage accumulates, and the more malignant the cells become. It is in this sense that cancer evolves as a “genetic” disease because alterations in the integrity and functioning of genes are central to its initiation and progression.

Cancer in Families

Many forms of cancer have a higher incidence in relatives of patients than in the general population. For example, a woman’s risk of developing breast cancer is increased up to three-fold if one first-degree relative is affected. A family history of cancer in an individual’s parents, brothers or sisters should arouse suspicion of increased cancer risk in that person. Most of the time, the increased risk of cancer in family members results from the combined effect of changes in many genes, most of which are unknown or poorly understood, that increase cancer susceptibility. There are, however, some families with many relatives with cancer because they have what is referred to as a hereditary cancer syndrome (Figure 1). In a hereditary cancer syndrome, all it takes is for a person to be carrying an alteration in just one of a few dozen currently known hereditary cancer syndrome genes to have a markedly increased risk of cancer. In a hereditary cancer syndrome, the great majority of individuals carrying the gene alteration responsible for the disease will develop cancer. In addition to having multiple relatives affected with the same or related form of cancer, patients with a hereditary cancer syndrome typically develop their disease at an earlier age than what is seen in the general population and can have more than one independent primary tumor occurring at multiple sites or at different times. For example, patients with hereditary breast and ovarian cancer syndrome may have a breast cancer and an ovarian cancer occurring years apart, or breast cancer occurring simultaneously in both breasts.

     

Because the risk of developing cancer is so high in a person carrying a gene alteration responsible for a hereditary cancer syndrome, any relatives of a person with a hereditary cancer syndrome who share this altered gene have a similarly high risk of cancer. Identifying the gene alteration responsible for disease in a hereditary cancer syndrome family allows physicians to identify at-risk family members and provide more intensive screening, more effective prevention, and more successful treatment earlier in the course of the disease.

What Kinds of Mutated Genes Cause Cancer?

Three broad categories of genes are implicated in cancer: oncogenes, tumor-suppressor genes (TSGs) and cell-death genes.  An oncogene is a cancer-causing gene that is an altered (“mutant”) version of a normal gene known as a cellular proto-oncogene. Proto-oncogenes are required for normal development and function. They provide the information, the genetic blueprints, for a large number of different proteins involved in promoting normal cell division. Cell division is a normal process that allows a single fertilized egg to divide and develop into the estimated 100 trillion cells that make up the specialized tissues and organs in an adult. Tissues must also have some cells that are able to divide to repair damage and replace cells that are lost during normal wear and tear. Proto-oncogenes are normally carefully regulated during development, tissue repair, and cell replacement so just the proper number of cell divisions occurs to generate the right number of new cells within a tissue and organ. An oncogene is an “activated” proto-oncogene in which a mutation has destroyed its ability to be regulated, and, as a consequence, it drives excessive cell division and the accumulation of cells that can form a tumor. Mutations in over 50 known proto-oncogenes are capable of causing cancer. Mutation of only one of the two copies of any proto-oncogene that changes it into an oncogene in a cell is sufficient to set that cell on the path to becoming malignant regardless of the presence of the other, normal non-mutated copy of the proto-oncogene.

Activating mutations in proto-oncogenes can explain why certain tumors can occur in both hereditary and sporadic forms. For example, some families have a rare form of cancer of the wall of the stomach, called gastric stromal tumor (GIST), as part of a hereditary cancer syndrome in which a risk for the cancer is inherited from parent to child. In these families, if a parent carrying an activating mutation in a proto-oncogene called KIT passes the mutant gene to a child, that child carries the abnormal form of KIT in all the cells of his body and is at high risk of developing GIST. Because the mutant KIT was present at the beginning in the fertilized egg, having been contributed either by the egg or sperm, DNA obtained from any tissue from anyone who inherited a mutant KIT gene would reveal one normal and one mutant KIT gene. In other individuals with GIST, however, the tumor is sporadic and not familial. These individuals start life as a fertilized egg with two normal copies of the KIT gene, one from each parent, but, later in life, one copy of the KIT gene in a cell in the stomach wall underwent an activating somatic mutation and became cancerous. Because the activating mutation in KIT occurred only in a cell within the stomach wall of an individual with the non-familial form of GIST and not in any other tissues of the body, testing the DNA obtained from the GIST tumor itself would reveal one normal and one mutant KIT gene while DNA from any tissue other than the tumor itself would reveal two normal copies of the KIT gene.

Tumor Suppressor Genes (TSGs)

A second category of gene implicated in cancer is the tumor suppressor gene (TSG). TSGs provide the genetic information for a large number of different proteins involved primarily in preventing cancer. Some are referred to as "gatekeepers" because they normally regulate and control cell division and, therefore, block the growth of the cancer. Loss of function of both copies of a TSG in a cell leads to uncontrolled cell division. Loss of function of a TSG usually comes about through a genetic change ("mutation") in the gene sequence itself. However, another mechanism for loss of function of a TSG is gene silencing that results from modification of the DNA or the proteins in which the DNA is packaged, thereby rendering the gene inaccessible to  the cellular machinery that reads gene sequences.  This type of gene silencing  is referred to as "epigenetic" silencing because no mutation in the sequence of the gene occurs. Other TSGs, referred to as "caretakers", are involved in maintaining normal structure and number of chromosomes, repairing DNA damage, and preventing mutations. Loss of function of both copies of a caretaker TSG leads to cancer indirectly by allowing additional secondary mutations to accumulate that either activate proto-oncogenes or inactivate gatekeeper TSGs. These secondary mutations fuel the vicious cycle of genetic change in cancer since malignancy increases genetic damage and instability, which in turn leads to increased malignancy. As with the gatekeeper TSGs, both copies of a caretaker TSG must be inactivated in order for a cell to completely lose the caretaker function of that gene.

Inherited Gatekeeper Gene Mutations in Hereditary cancer syndromes: Retinoblastoma and the Two-Hit Model for Cancer

If a cell must lose both functioning copies of a TSG to lose the gatekeeper or caretaker function of the protein encoded by that TSG, how is it then that individuals affected with most hereditary cancer syndromes need only inherit one defective copy of a TSG to develop the cancer? Why doesn’t the other, normal copy make enough of the protein to prevent complete loss of the gatekeeper or caretaker functions? The explanation is best demonstrated with the example of retinoblastoma, a cancer of the retinoblast, the cells in the embryo that develop into the retina at the back of the eye. Retinoblastoma occurs in 1 in 20,000 infants and small children and is part of a hereditary cancer syndrome 40% of the time, and occurs as a sporadic cancer 60% of the time. In familial retinoblastoma, a person starts life as a fertilized egg with one inherited, defective copy of the RB1 gene, a well-known gatekeeper TSG. As a result, every cell in his body that develops from that fertilized egg also has one defective copy of the RB1 gene (Figure 2). In a small number of retinoblasts, a second “hit” occurs during cell division and development that inactivates the other, normal copy of RB1. As a consequence of this second hit, the cell loses the function of both copies of RB1, giving rise to a tumor. The second hit is most often a mutation, although loss of function without mutation, such as occurs when a gene is shut off inappropriately can also occur. Although  a second hit is a rare event, all it takes is one second hit in any of the approximately one million retina cells already carrying one dysfunctional RB1 gene for a tumor to develop from that cell. In fact, because these second hits are rare, but not vanishingly so, they can occur in more than one retinoblast. As a result, patients with familial retinoblastoma are frequently young infants who develop more than one independent primary retinoblastoma tumor, either within one eye or in both eyes. Furthermore, because every cell of the body already carries one defective RB1 gene, a second hit later in life also results in a cell lacking function of the RB1 gatekeeper. In fact, children who survive retinoblastoma as part of a hereditary cancer syndrome have an 80-90% risk of developing cancers of bone, muscle, and connective tissues over their adult lifetimes.

In the sporadic, non-familial form of retinoblastoma, both copies of RB1 in a cell are also inactivated, but the inactivation results from two independent events occurring in the same cell. The loss of both copies of RB1 independently of one another in the same cell is a very rare event, equivalent to “lightening striking twice” in the same cell. As a result, the sporadic form of retinoblastoma occurs at only one location, in one eye, and generally when children are toddlers. As one might also predict, because survivors of the non-familial form of retinoblastoma are not carrying a defective RB1 gene in their other cells, they are not at greatly increased risk for cancers of bone, muscle, and connective tissues later in adulthood.

Inherited Caretaker Gene Mutations in Hereditary Cancer Syndromes: the Example of Familial Breast Cancer

Breast cancer is common. Up to 10% of all women in North America and Western Europe will develop breast cancer in their lifetime. In approximately 3% of cases, the cancer is due to an inherited mutation in one of two caretaker TSGs, known as BRCA1 and BRCA2. Women carrying a disease-causing mutation in BRCA1 or BRCA2 have a 60-90% risk lifetime risk of developing breast cancer and a 30-50% risk of ovarian cancer. In males, mutations in BRCA1 and BRCA2 account for 10-20% of all male breast cancer, which affects nearly 0.1% of males in the population, and increase the risk of prostate cancer. BRCA1 and BRCA2 families demonstrate features characteristic of other hereditary cancer syndromes: there are multiple affected individuals in a family with more than one type of cancer, the age at onset is earlier compared with the average in the population at large, and cancer in both breasts is frequent.

Inherited Caretaker Gene Mutations in Hereditary Cancer Syndromes: Familial Colon Cancer

Approximately 2-4% of cases of colon cancer are attributable to a group of hereditary cancer syndromes known as hereditary nonpolyposis colon cancer (HNPCC). HNPCC is characterized by inheritance of colon cancer occurring during adulthood, but at a relatively young age. Males carrying a mutant HNPCC gene have an approximately 90% lifetime risk of developing cancer of the colon; females have a somewhat smaller risk, approximately 70%, but have an approximately 40% risk for endometrial cancer. There are also additional risks of 10-20% for cancer of the bile ducts, the urinary tract, and the ovary.    

HNPCC is a group of five similar hereditary cancer syndromes caused by mutations in one of five distinct genes that contain the blueprints for five DNA enzymes responsible for repairing certain kinds of DNA damage. As such, the HNPCC genes are prototypical caretaker TSGs. Although all five of these genes have been implicated in HNPCC in different families, two of these genes, MLH1 and MSH2, are together responsible for the most cases of HNPCC.

Tumor Suppressor Genes in Sporadic Cancers

The “two-hit” model of loss of function of a TSG is now widely accepted as the explanation for hereditary cancer syndromes besides retinoblastoma, including in familial breast cancer and HNPCC. The importance of TSGs and the two-hit model for explaining many features of the hereditary cancer syndromes goes way beyond these relatively rare syndromes. As with the example of retinoblastoma, the two-hit model also explains how loss of function of a TSG occurs in the more common sporadic forms of cancer. For example, there is a rare hereditary cancer syndrome known as Li-Fraumeni syndrome in which multiple family members in early- to mid-adulthood develop one or more cancers of bone or muscle, breast, and adrenal gland, as well as brain tumors and leukemia. Li-Fraumeni syndrome is usually caused by the inheritance of mutations in an important TSG known as TP53, a critical regulator of a cell’s response to DNA damage. Although the Li-Fraumeni syndrome is rare, mutations causing a loss of function of both copies of TP53 turn out to be one of the most common genetic alterations in all sporadic cancers. Mutations or deletion of both copies of the TP53 gene are frequent in a wide range of sporadic cancers, including breast, ovarian, bladder, cervical, esophageal, colon and rectal, skin, liver, and lung cancers, glioblastoma of the brain, and  cancer of the bone.  

Other TSGs have also been implicated in sporadic cancer. There is mutation or loss of expression of both copies of one or more of these DNA repair genes in up to 12% of sporadic colon cancer. BRCA1 and BRCA2 in sporadic breast cancer present a somewhat more complex situation. A mutation of one copy of BRCA1 or BRCA2 occurs in approximately half of sporadic breast cancer but the other copy of BRCA1 or BRCA2 is generally not lost or mutated. What has been found, however, particularly in more malignant forms of breast cancer, is a marked reduction in the amount of protein product made from what appears to be unaltered copies of BRCA1 or BRCA2. This reduction may be associated with changes in the way the genetic information is extracted from the genetic blueprint contained in the gene rather than with the gene itself.

Cell-Death Genes

During the normal processes of development, certain cells are supposed to be eliminated by a natural program of cell death, most commonly known as apoptosis. If cells fail to undergo programmed cell death normally, they will accumulate and ultimately result in cancer. The best-known example of a failure of programmed cell death in cancer is in a sporadic form of cancer of the white blood cells known as B-cell leukemia. Certain B-cell leukemias carry a major alteration in the genetic material such that a gene that suppresses cell death, called BCL2, continues to function when it was supposed to be shut off. As a result, white blood cells that were supposed to die and be eliminated remain alive and accumulate, ultimately leading to cancer.

Genetic Testing in Cancer Patients

There are two major reasons to test a cancer patient for gene mutations causing a hereditary cancer syndrome. First, finding such a genetic alteration affects patient care. Individuals known to have a hereditary cancer syndrome are at much higher risk for additional tumors later in life and, therefore, prophylactic surgery or heightened surveillance is often necessary to prevent additional cancers or to find these cancers early when they are more treatable. Secondly, knowing the specific mutation allows the identification of those relatives who either are or are not at the same increased risk for cancer as their affected relatives, so they can receive appropriate counseling and care.

Not all patients with cancer need genetic testing, however. Whether to do genetic testing depends on a number of factors including (1) the type of cancer, (2) other features of the cancer such as the age of onset and whether it was bilateral or arose at more than one primary site, (3) other physical features besides the cancer itself that are known to be associated with a hereditary cancer syndrome, and (4) the patient’s family history and ethnicity.  At one end of the spectrum is a patient whose cancer is of a kind that is recognized as frequently the result of inherited mutations in a known gene, especially when the patient’s relatives have cancers that are known to be related to the kind of cancer the patient has. For example, in retinoblastoma, there is only one gene, RB1, in which mutations cause the disease. A patient with bilateral retinoblastoma whose parent, uncles or siblings have also had the disease, is very likely to have inherited a mutation in the RB1 gene and to be carrying the mutation in all the cells of his body. Genetic testing to find the specific mutation in RB1 is often done in this situation.

 At the other end of the spectrum is a patient with little or no family history of cancer whose own cancer is of a type that is rarely part of a hereditary cancer syndrome and for which no gene mutation is known.  For example, no genetic testing is currently recommended for a patient with lung cancer and no family history.
Between these two ends of the spectrum are cancers of the breast, kidney, and colon, among others, in which less than 5% of all such cancers occur as part of a hereditary cancer syndrome. In these situations, the genetic counselor collects a lot of information about the cancer and the family history to assess whether the cancer in this particular patient is more or less likely to be part of a hereditary cancer syndrome for which testing is available.  In some cases, there are a variety of software tools that aid in this assessment. In general, if the characteristics of the cancer and the family history together raise the chance there is a hereditary cancer syndrome from less than 5% to 10% or greater, genetic testing of the appropriate gene or genes is performed. Once again, knowing there is a mutation in a particular gene associated with a hereditary cancer syndrome can be extremely important for managing the patient’s disease, designing further surveillance measures, and testing relatives for their risk. In contrast, an individual who tests negative for a gene mutation responsible for cancer in a relative could forgo any special medical interventions or surveillance. However, it is important to stress that this does not mean the individual is at no risk for his relative’s cancer. It only means his or her risk drops down closer to the population risk. So, for example, a woman with a BRCA1 mutation has a 60-80% lifetime risk of developing breast cancer. A sister who tests negative for this BRCA1 mutation still has an approximately 10-15% lifetime risk of breast cancer, slightly above the risk of any woman in the general population.

References

Vogelstein B, Kinzler KW (2002) The Genetic Basis of Human Cancer. McGraw Hill, New York, 2nd edition.

Vogelstein B & Kenneth W Kinzler KW (2004) Cancer genes and the pathways they control. Nature Medicine  10:789–799.

Barnetson RA, Tenesa A, Farrington SM et al. (2006) Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. New Engl J Med 354:2715-2763.

Croce CM. (2008) Oncogenes and cancer. N Engl J Med. 358:502-11.
  
Esteller M (2003) Cancer epigenetics: DNA methylation and chromatin alterations in human cancer. Adv Exp Med Biol. 532:39-49.

Knudson AG (1996) Hereditary cancer: Two hits revisited. J Cancer Res Clin Oncol 122:135–140.

Michor F, Iwasa Y and Nowak MA (2004) Dynamics of cancer progression. Nature Reviews Cancer 4:197-205.