Cancer Genetics

The discussion of a genetic predisposition to cancer requires a general knowledge of cancer genetics; however, the molecular genetics of cancer have only recently been understood, and many health professionals may not have a thorough understanding of the meaning of a mutation or the implication of a genetic defect as it relates to cancer risk. This Web site has been developed to help provide an avenue to a greater understanding of cancer genetics by healthcare professionals.

THE CELLULAR AND MOLECULAR BASIS OF INHERITANCE

Every cell in the body contains a nucleus. The nucleus contains chromosomes, each of which are composed primarily of DNA in association with various proteins and some RNA. The DNA located within the nucleus of the cell is composed of genetic information in the form of individual genes that controls and participates in cell growth, division, and normal functioning. Every person should inherit two copies of each chromosome and therefore, two copies of each gene. One copy of each chromosome is of maternal origin, and the other is paternal in origin.

Each somatic cell contains two sets of chromosomes which can be arranged into 23 pairs (46 total). Members of each pair are considered homologues, one of each is inherited from each parent. The first 22 pairs are typically arranged from largest to smallest, and are called autosomes. The twenty-third pair are called sex chromosomes. Females typically inherit two X chromosomes, whereas males inherit one X chromosome and one Y chromosome. Maleness is determined by the presence of a Y chromosome regardless of the number of X chromosomes present in a cell.

DNA or deoxyribonucleic acid is the chemical structure that encodes our hereditary information. DNA is composed of two nucleotide chains arranged in a double helix. The four nucleotide bases that make up the nucleotide chains are adenine (A), guanine (G), cytosine (C), and thymine (T). These four nucleotide bases are arranged sequentially and come in functional units called codons. Each codon consists of three nucleotide bases, and codes for a specific amino acid. The DNA is transcribed into RNA, which is then translated into proteins. Each amino acid in the final protein product is represented by one codon from the DNA strand.

Click here to see a diagram of protein synthesis.

Introns are segments of DNA within genes that are not translated into protein sequences. In most cases the function of introns are not currently known, although sometimes they are involved in gene regulation. Exons are the segments of gene between the introns that contain the actual genetic information that describes the structure of the protein. It is easiest to consider each gene as being associated with one specific protein product. Although this theory has recently been refuted, it is useful for practical education purposes. The main concern for clinical genetics is the presence of genetic mutations, or alterations in the DNA. If a mutation in the DNA sequence leads to a nonfunctional protein product, or stops the protein from being produced at all, this may lead to a symptomatic condition in the individual.

It is believed that the vast majority of mutations occur spontaneously through errors in the replication and repair of DNA. A mutation arising in a somatic cell will not be transmitted to an offspring, however mutations that are present in the gametes can be passed on to the next generation. If left unrepaired, mutations in DNA may have serious implications for an individual, and/or subsequent generations.

A basic knowledge of the stages in the life cycle of the somatic cell (a cell that does not transmit genetic information to the next generation) can significantly contribute to a comprehensive understanding of the development of cancer.

Cancer can develop when the normally precise regulation of the cell cycle is compromised, resulting in a loss of normal cell growth and behavior. Regulation of the cell cycle is a very complex process. Genes control the cell cycle in two very general ways. There are genes that control the production of proteins whose functions are vital for the cell cycle to take place, and there are genes that control the initiation of each phase of the cell cycle. Cdk (cyclin dependent kinase), for example, acts as a control switch for the cell cycle, regulating the passage of the cell through various stages in the cell cycle. Cell cycle activity is dependent on the protein products of many genes (such as the enzymatic activity of Cdk) thus allowing for an elaborate replication system carefully regulated by checkpoints.

The cell cycle is an ordered set of events that results in cell growth and division into two daughter cells. The somatic cell cycle can be considered in two parts; interphase and mitosis. Interphase is composed of three stages: Gap 1 (G1), Synthesis (S), and Gap 2(G2). Interphase is a period of cell growth and synthesis. Mitosis is a period of nuclear division and the separation of cytoplasm into two identical daughter cells (cytokinesis), and is composed of five stages: prophase, prometaphase, metaphase, anaphase, and telophase. Mitosis results in two daughter cells, each with genetic information that is identical to that of the parent cell. There is an exact distribution of genetic information, in the form of chromosomes, to each daughter cell.

Diagram: The Cell Cycle

CANCER-CAUSING GENES

There are three general types of genes that are associated with causing cancer:

Tumor suppressor genes function in growth, development, and cell signaling pathways. They normally produce certain proteins that regulate cell division, and can therefore inhibit tumor formation in normal cells (by restricting mitosis). The absence or malfunction of tumor suppressor genes can lead to deregulation of the cell cycle, causing unchecked growth and replication of the cell, resulting in the development of cancer. Individuals who inherit an increased risk to develop cancer may be born with one inactivated copy of a particular tumor suppressor gene in every cell. However since genes come in pairs, an inherited defect in one copy will not cause cancer if the other copy of the pair is still functioning. If the second copy of the tumor suppressor gene undergoes mutation in a single cell, then that cell is at risk to develop into a cancer since there is no longer a functional copy of that tumor suppressor gene present (resulting in a loss of mitotic inhibition).

p53 is a well-known tumor-suppressor gene. In 1993 it was named "Molecule of the Year" by Science magazine. p53 has been found to be the most common mutation in cancers, suggesting that it is of great importance in the suppression of cancer. Normally p53 exists in an inactive state. When there is damage to the DNA, p53 is activated and halts the cell cycle. When activated, p53 forms a transcription factor as a tetramer, and binds to several gene promoters. These genes cause disruption of the cell cycle to allow time for DNA repair, or if the damage is too severe, trigger the steps leading to apoptosis (programmed cell death). If p53 is damaged or mutated, it will remain in the inactive state allowing DNA damage to accumulate within a cell, thus increasing the risk for cancer formation. p53 has been called the "gatekeeper" to the cell cycle because of its critical role in cell regulation.

Dr. Alfred Knudson predicted the existence of tumor suppressor genes in 1971. Dr. Knudson came up with the two-hit hypothesis based on the disease history of Retinoblastoma. Retinoblastoma is more common in childhood because the retinoblast cells are precursors to the cone cells in the retina of the eye. The retinoblast cells no longer divide after the cells differentiate in childhood. Dr. Knudson noted that some children would develop only one tumor of the eye, whereas other children who inherited a retinoblastoma gene (assumed to have one mutation, or "hit") would develop multiple tumors of the eye. This prompted Dr. Knudson to suggest that a second mutation, or "hit" occurred after conception and was necessary for tumor formation. Children who have the sporadic, non-inherited, form of retinoblastoma require the same two "hits," but they both occur after conception, thus making it much less likely to develop several tumors in the eye. The retinoblastoma gene, RB1, is now known to be a tumor suppressor gene that normally functions to regulate cell division. Two "hits" in the RB1 gene in a cell result in a loss of function as a tumor suppressor, resulting in the tumor formation characteristic of Retinoblastoma. Although the theory for tumor suppressor genes was originally developed as a model for retinoblastoma, it is now apparent that the two-hit hypothesis explains the etiology of many forms of cancer.

Proto-oncogenes are normal genes that promote the specialization and division of healthy cells. Oncogenes are a mutated form of these genes that can cause uncontrolled cell growth, and may lead to cancer development. Oncogenes were first discovered in retroviruses and were then found in association with tumors in animals. Oncogenes act in a dominant fashion. Even if a cell has one normal gene, and only one mutated ("hit") gene, the mutated gene takes precedence and results in enhanced cell growth by increasing the rate of mitosis in the cell. Thus two separate "hits" are not necessary for tumor formation if the mutated gene functions as an oncogene.

Click here to see an illustration of mutation in oncogene

DNA Repair Genes

DNA repair genes typically function to repair mutations in cellular DNA before a cell enters mitosis. They prevent the replication of a cell with damaged DNA by identifying and repairing damaged DNA during Interphase. However a mutation or mistake within the DNA repair genes themselves may lead to continued transcription of mutated DNA sequences and compromise the normal functioning of a cell. In addition, these genes play a role in maintaining genetic stability. Most instances of tumor development are a result of a multi-step process involving multiple chances in cell genotype. Vogelstein's model of colon cancer describes a series of mutations occurring in both oncogenes and tumor suppressor genes. When explaining inherited susceptibility to patients, it is important to note that a single gene mutation only predisposes to cancer and other somatic (acquired) events are needed for malignancy to develop.

CANCER AND THE ENVIRONMENT

Recent research has given us a better understanding of the genetic factors involved in cancer, however it is important to recognize the environmental component involved in the development of cancer.

Environmental factors are easily evident in some forms of cancer, such as lung cancer in individuals who smoke or work near asbestos. DNA viruses can occasionally also be associated with an increased risk for cancer, such as in individuals with certain strains of HPV having an increased risk for cervical cancer. Other types of environmental exposures such as radiation, diet, etc have also been suggested to have an association with increased risk for certain types of cancer. However in the majority of cancers, environmental and genetic components are both involved in a complex, multifactorial interaction which is yet to be fully understood. Evidence to help sort out these factors will ultimately come from combinations of studies, including epidemiological, family, animal, and twin studies, as well as from disease associations and examination of biochemical factors.

PATTERNS OF INHERITANCE

Autosomal Dominant Inheritance

Although in theory autosomal dominant inheritance appears to be the simplest mode of inheritance, in clinical practice autosomal dominant inheritance can be confusing and unclear, and thus warrants thorough commentary.

Autosomal dominant inheritance is associated with a variety of different conditions. The word autosomal refers to the fact that the condition is caused by a gene that is on an autosome (an autosome is any chromosome that is not a sex chromosome, i.e. Chromosomes numbered 1-22). Autosomes are inherited from both our mothers and our fathers, and are passed on to both sons and daughters. Thus, in a family with an autosomal condition, we would expect to see (approximately) equal numbers of males and females with the condition. Dominant inheritance refers to the fact that only one mutation in one pair of genes is necessary to cause the condition associated with the genetic alteration. Since we have two copies of every gene, any individual who has an autosomal dominant condition has a 50% chance of having a child (male or female) who will also have the condition.

Reduced penetrance refers to a situation in which an individual known to carry the dominantly inherited mutated gene may show no clinical evidence of the condition. For some specific diseases, the different mechanisms behind the lack of penetrance are becoming clearer. For many of the familial cancer syndromes, the etiology of reduced penetrance is not well understood, although theories include the modifying effects of other genes, as well as possible interactions of the gene with environmental factors. For example, in families with a hereditary predisposition to breast and ovarian cancer, although carrying a mutation in either BRCA 1 or BRCA 2 confers a high risk for cancer, it does not necessarily mean that each individual will develop a cancer in his or her lifetime.

-Variable Expressivity

Variable expressivity refers to the degree to which a condition or disorder is expressed in an individual. Expressivity differs from penetrance. Think of penetrance as a light switch that can only be on or off, and expressivity as a dimmer on that light switch. Though some disorders are expressed with little variation, it is worthwhile to note that the majority of autosomal dominant conditions do appear to exhibit some variation in expressivity. It is useful to consider the possibility of variable expressivity when considering apparent inconsistencies in a family history, such as "skipped generations." For example, a young woman with an early onset breast cancer diagnosis may report a family history that is negative for ovarian cancer. However, if genetic testing demonstrates that she carries a mutation in the BRCA1 gene, she does have a significantly increased risk to develop ovarian cancer, as do other women in the family who carry the same genetic abnormality, regardless of family history.

-Variable Age of Onset

In regard to cancer genetic counseling, it is important to keep in mind the ages of unaffected relatives in the family tree. Consideration must be given to the question of how old a family member needs to be before they would have probably developed a cancer if they had a susceptibility gene. A complete and thorough family history helps in assessing risk since an unaffected relative may not actually provide reassurance, but may instead be uninformative based either on current age, or age at death.

-Sex-Specific Expression

Some traits or conditions are only expressed in one sex even though both sexes can carry the genes that are associated with the trait or condition. Although both males and females can carry mutated BRCA genes, men do not have ovaries and therefore are not at risk for developing ovarian cancer even though a woman carrying the exact same genetic alteration could have as high as a 50% lifetime risk of developing ovarian cancer. Sex-specific expression can alter the presentation of a genetic mutation in a family. For example, a woman with an early-onset breast cancer may report that she has no family history of ovarian cancer. However, if her father is an only child, and her paternal grandmother (who was also diagnosed with early onset breast cancer) had four brothers, her "negative" family history must be interpreted cautiously taking into account the phenomenon of sex-specific expression.

Autosomal Recessive Inheritance

Autosomal recessive inheritance is associated with a variety of different conditions. The word autosomal refers to the fact that the disease causing gene is on an autosome (an autosome is any chromosome that is not a sex chromosome, i.e. Chromosomes numbered 1-22). Autosomes are inherited from both our mothers and our fathers, and are passed on to both sons and daughters. Thus, in a family with an autosomal condition, we would expect to see (approximately) equal numbers of males and females with the condition. Recessive inheritance occurs when the condition is produced only if BOTH genes of a pair are non-functioning. If only one gene in the pair is non-functioning, the condition is not manifested or is only mildly manifested. However, a person with a single non-functioning gene is called a carrier, and may have a child affected with the condition if the other parent is also a carrier of the same condition.

X-Linked Recessive Inheritance

X-linked recessive inheritance is associated with a variety of different conditions. The word X-linked refers to the fact that the condition causing gene is on the X chromosome. The 23rd chromosome pair consists of the X and the Y chromosomes. Females inherit two X chromosomes, one each from the mother and father. Males inherit one X chromosome (from the mother) and one Y chromosome (from the father). Since a male has only one X chromosome, all the genes on his X chromosome, whether dominant or recessive, will be expressed because there are no corresponding genes on the Y chromosome. Thus a male with a mutation on his X chromosome will express whatever condition is associated with that mutation. Since a female has two X chromosomes, if she has a mutation on one of her X chromosomes, but a functioning gene on her other X chromosome, she will be a carrier of the condition, but unaffected.

Multifactorial Inheritance

Multifactorial inheritance is an interaction between many genes with potentially additive effects and environmental components. Multifactorial inheritance may be caused by the expression of many genes, the interaction of several genes, or the interaction of a gene or genes with other environmental factors. With multifactorial inheritance it is difficult to determine the precise etiology of the condition because it is a net effect of genetic, environmental and lifestyle factors that may impact an individual's susceptibility to develop the condition.