Understanding Gene Testing

Genes are working subunits of DNA. DNA is a vast chemical information database that carries the complete set of instructions for making all the proteins a cell will ever need. Each gene contains a particular set of instructions, usually coding for a particular protein.
DNA exists as two long, paired strands spiraled into the famous double helix. Each strand is made up of millions of chemical building blocks called bases. While there are only four different chemical bases in DNA (adenine, thymine, cytosine, and guanine), the order in which the bases occur determines the information available, much as specific letters of the alphabet combine to form words and sentences.
DNA resides in the core, or nucleus, of each of the body's trillions of cells. Every human cell (with the exception of mature red blood cells, which have no nucleus) contains the same DNA. Each cell has 46 molecules of double-stranded DNA. Each molecule is made up of 50 to 250 million bases housed in a chromosome.
The DNA in each chromosome constitutes many genes (as well as vast stretches of noncoding DNA, the function of which is unknown). A gene is any given segment along the DNA that encodes instructions that allow a cell to produce a specific product - typically, a protein such as an enzyme - that initiates one specific action. There are between 50,000 and 100,000 genes, and every gene is made up of thousands, even hundreds of thousands, of chemical bases.
Human cells contain two sets of chromosomes, one set inherited from the mother and one from the father. (Mature sperm and egg cells carry a single set of chromosomes.) Each set has 23 single chromosomes - 22 autosomes and an X or Y sex chromosome. (Females inherit an X from each parent, while males get an X from the mother and a Y from the father.)

For a cell to make protein, the information from a gene is copied, base by base, from DNA into new strands of messenger RNA (mRNA). Then mRNA travels out of the nucleus into the cytoplasm, to cell organelles called ribosomes. There, mRNA directs the assembly of amino acids that fold into completed protein molecule.

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Each human cell contains 23 pairs of chromosomes, which can be distinguished by size and by unique banding patterns. This set is from a male, since it contains a Y chromosome. Females have two X chromosomes.

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Different genes are activated in different cells, creating the specific proteins that give a particular cell type its character.

Acquired mutations:

gene changes that arise within individual cells and accumulate throughout a person's lifetime; also called somatic mutations. (See Hereditary mutation.)

Alleles:

variant forms of the same gene. Different alleles produce variations in inherited characteristics such as eye color or blood type.

Alzheimer's disease:

a disease that causes memory loss, personality changes, dementia and, ultimately, death. Not all cases are inherited, but genes have been found for familial forms of Alzheimer's disease.

Amino acid:

any of a class of 20 molecules that combine to form proteins in living things.

Amyotrophic lateral sclerosis:

an inherited, fatal degenerative nerve disorder; also known as Lou Gehrig's disease.

Autosome:

any of the non-sex-determining chromosomes. Human cells have 22 pairs of autosomes.

Base pairs:

the two complementary, nitrogen-rich molecules held together by weak chemical bonds. Two strands of DNA are held together in the shape of a double helix by the bonds between their base pairs. (See Chemical base.)

BRCA1:

a gene that normally helps to restrain cell growth.

BRCA1 breast cancer susceptibility gene:

a mutated version of BRCA1, which predisposes a person toward developing breast cancer.

Carrier:

a person who has a recessive mutated gene, together with its normal allele. Carriers do not usually develop disease but can pass the mutated gene on to their children.

Carrier testing:

testing to identify individuals who carry disease-causing recessive genes that could be inherited by their children. Carrier testing is designed for healthy people who have no symptoms of disease, but who are known to be at high risk because of family history.

Cell:

small, watery, membrane-bound compartment filled with chemicals; the basic subunit of any living thing.

Chemical base:

an essential building block. DNA contains four complementary bases: adenine, which pairs with thymine, and cytosine, which pairs with guanine. In RNA, thymine is replaced by uracil.

Chromosomes:

structures found in the nucleus of a cell, which contain the genes. Chromosomes come in pairs, and a normal human cell contains 46 chromosomes, 22 pairs of autosomes and two sex chromosomes.

Clone:

a group of identical genes, cells, or organisms derived from a single ancestor.

Cloning:

the process of making genetically identical copies.

Contig maps:

types of physical DNA maps that consist of overlapping segments of DNA (contigs) that, taken together, completely represent that section of the genome. (See Physical maps.)

Colonoscopy:

examination of the colon through a flexible, lighted instrument called a colonoscope.

Crossing over:

a phenomenon, also known as recombination, that sometimes occurs during the formation of sperm and egg cells (meiosis); a pair of chromosomes (one from the mother and the other from the father) break and trade segments with one another.

Cystic fibrosis:

an inherited disease in which a thick mucus clogs the lungs and blocks the ducts of the pancreas.

Cytoplasm:

the cellular substance outside the nucleus in which the cell's organelles are suspended.

Dementia:

severe impairment of mental functioning.

DNA:

the substance of heredity; a large molecule that carries the genetic information that cells need to replicate and to produce proteins.

DNA repair genes:

certain genes that are part of a DNA repair pathway; when altered, they permit mutations to pile up throughout the DNA.

DNA sequencing:

determining the exact order of the base pairs in a segment of DNA.

Dominant allele:

a gene that is expressed, regardless of whether its counterpart allele on the other chromosome is dominant or recessive. Autosomal dominant disorders are produced by a single mutated dominant allele, even though its corresponding allele is normal. (See Recessive allele.)

Enzyme:

a protein that facilitates a specific chemical reaction.

Familial adenomatous polyposis:

an inherited condition in which hundreds of potentially cancerous polyps develop in the colon and rectum.

Familial cancer:

cancer, or a predisposition toward cancer, that runs in families.

Functional gene tests:

biochemical assays for a specific protein, which indicates that a specific gene is not merely present but active.

Gene:

a unit of inheritance; a working subunit of DNA. Each of the body's 20,000 to 25,000 genes contains the code for a specific product, typically, a protein such as an enzyme. (Revised: October 2004)

Gene deletion:

the total loss or absence of a gene.

Gene expression:

the process by which a gene's coded information is translated into the structures present and operating in the cell (either proteins or RNAs).

Gene markers:

landmarks for a target gene, either detectable traits that are inherited along with the gene, or distinctive segments of DNA.

Gene mapping:

determining the relative positions of genes on a chromosome and the distance between them.

Gene testing:

examining a sample of blood or other body fluid or tissue for biochemical, chromosomal, or genetic markers that indicate the presence or absence of genetic disease.

Gene therapy:

treating disease by replacing, manipulating, or supplementing nonfunctional genes.

Genetic linkage maps:

DNA maps that assign relative chromosomal locations to genetic landmarksÑeither genes for known traits or distinctive sequences of DNA - on the basis of how frequently they are inherited together. (See Physical maps.)

Genetics:

the scientific study of heredity: how particular qualities or traits are transmitted from parents to offspring.

Genome:

all the genetic material in the chromosomes of a particular organism.

Genome maps:

charts that indicate the ordered arrangement of the genes or other DNA markers within the chromosomes.

Genotype:

the actual genes carried by an individual (as distinct from phenotypeÑthat is, the physical characteristics into which genes are translated).

Germ cells:

the reproductive cells of the body, either egg or sperm cells.

Germline mutation:

(See Hereditary mutation.)

Hereditary mutation:

a gene change in the body's reproductive cells (egg or sperm) that becomes incorporated in the DNA of every cell in the body; also called germline mutation. (See Acquired mutations.)

Human genome:

the full collection of genes needed to produce a human being.

Human Genome Project:

an international research effort (led in the United States by the National Institutes of Health and the Department of Energy) aimed at identifying and ordering every base in the human genome.

Huntington's disease:

an adult-onset disease characterized by progressive mental and physical deterioration; it is caused by an inherited dominant gene mutation.

Imprinting:

a biochemical phenomenon that determines, for certain genes, which one of the pair of alleles, the mother's or the father's, will be active in that individual.

Inborn errors of metabolism:

inherited diseases resulting from alterations in genes that code for enzymes.

Leukemia:

cancer that begins in developing blood cells in the bone marrow.

Li-Fraumeni syndrome:

a family predisposition to multiple cancers, caused by a mutation in the p53 tumor-suppressor gene.

Linkage analysis:

a gene-hunting technique that traces patterns of heredity in large, high-risk families, in an attempt to locate a disease-causing gene mutation by identifying traits that are co-inherited with it.

Melanoma:

a cancer that begins in skin cells called melanocytes and spreads to internal organs.

Molecule:

a group of atoms arranged to interact in a particular way; one molecule of any substance is the smallest physical unit of that particular substance.

Mutation:

a change in the number, arrangement, or molecular sequence of a gene.

Newborn screening:

examining blood samples from a newborn infant to detect disease-related abnormalities or deficiencies in gene products.

Nucleotide:

A subunit of DNA or RNA, consisting of one chemical base plus a phosphate molecule and a sugar molecule.

Nucleus:

the cell structure that houses the chromosomes.

Oncogenes:

genes that normally play a role in the growth of cells but, when overexpressed or mutated, can foster the growth of cancer.

p53:

(See Tumor-suppressor genes.)

Penetrance:

a term indicating the likelihood that a given gene will actually result in disease.

Phenylketonuria (PKU):

an inborn error of metabolism caused by the lack of an enzyme, resulting in abnormally high levels of the amino acid phenylalanine; untreated, PKU can lead to severe, progressive mental retardation.

Physical maps:

DNA maps showing the location of identifiable landmarks, either genes or distinctive short sequences of DNA. The lowest resolution physical map shows the banding pattern on the 24 different chromosomes; the highest resolution map depicts the complete nucleotide sequence of the chromosomes. (See Contig maps.)

Precancerous polyps:

growths in the colon that often become cancerous.

Predictive gene tests:

tests to identify gene abnormalities that may make a person susceptible to certain diseases or disorders.

Prenatal diagnosis:

examining fetal cells taken from the amniotic fluid, the primitive placenta (chorion), or the umbilical cord for biochemical, chromosomal, or gene alterations.

Probe:

a specific sequence of single-stranded DNA, typically labeled with a radioactive atom, which is designed to bind to, and thereby single out, a particular segment of DNA.

Proofreader genes:

(See DNA repair genes.)

Prophylactic surgery:

surgery to remove tissue that is in danger of becoming cancerous, before cancer has the chance to develop. Surgery to remove the breasts of women at high risk of developing breast cancer is known as prophylactic mastectomy.

Protein:

a large, complex molecule composed of amino acids. The sequence of the amino acidsÑand thus the function of the proteinÑis determined by the sequence of the base pairs in the gene that encodes it. Proteins are essential to the structure, function, and regulation of the body. Examples are hormones, enzymes, and antibodies.

Protein product:

the protein molecule assembled under the direction of a gene.

Recessive allele:

a gene that is expressed only when its counterpart allele on the matching chromosome is also recessive (not dominant). Autosomal recessive disorders develop in persons who receive two copies of the mutant gene, one from each parent who is a carrier. (See Dominant allele.)

Recombination:

(See Crossing over.)

Renal cell cancer:

a type of kidney cancer.

Reproductive cells:

egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes.

Restriction enzymes:

enzymes that can cut strands of DNA at specific base sequences.

Retinoblastoma:

an eye cancer caused by the loss of a pair of tumor-suppressor genes; the inherited form typically appears in childhood, since one gene is missing from the time of birth.

RNA:

a chemical similar to DNA. The several classes of RNA molecules play important roles in protein synthesis and other cell activities.

Sarcoma:

a type of cancer that starts in bone or muscle.

Screening:

looking for evidence of a particular disease such as cancer in persons with no symptoms of disease.

Sex chromosomes:

the chromosomes that determine the sex of an organism. Human females have two X chromosomes; males have one X and one Y.

Sickle-cell anemia:

an inherited, potentially lethal disease in which a defect in hemoglobin, the oxygen-carrying pigment in the blood, causes distortion (sickling) and loss of red blood cells, producing damage to organs throughout the body.

Somatic cells:

all body cells except the reproductive cells.

Somatic mutations:

(See Acquired mutations.)

Tay-Sachs disease:

an inherited disease of infancy characterized by profound mental retardation and early death; it is caused by a recessive gene mutation.

Transcription:

the process of copying information from DNA into new strands of messenger RNA (mRNA). The mRNA then carries this information to the cytoplasm, where it serves as the blueprint for the manufacture of a specific protein.

Translation:

the process of turning instructions from mRNA, base by base, into chains of amino acids that then fold into proteins. This process takes place in the cytoplasm, on structures called ribosomes.

Tumor-suppressor genes:

genes that normally restrain cell growth but, when missing or inactivated by mutation, allow cells to grow uncontrolled.

Wilms' tumor:

a kidney cancer (tumor) that occurs in children, usually before age 5.

X chromosome:

a sex chromosome; normal females carry two X chromosomes.

Y chromosome:

a sex chromosome; normal males carry one Y and one X chromosome.

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How do genes work?

Although each cell contains a full complement of DNA, cells use genes selectively. Some genes enable cells to make proteins needed for basic functions; dubbed housekeeping genes, they are active in many types of cells. Other genes, however, are inactive most of the time. Some genes play a role in early development of the embryo and are then shut down forever. Many genes encode proteins that are unique to a particular kind of cell and that give the cell its character - making a brain cell, say, different from a bone cell. A normal cell activates just the genes it needs at the moment and actively suppresses the rest.

Genes, through the proteins they encode, determine all body processes, including how the body responds to challenges from the environment.






















How are genes linked to disease?

Many, if not most, diseases have their roots in our genes. Genes - through the proteins they encode - determine how efficiently we process foods, how effectively we detoxify poisons, and how vigorously we respond to infections. More than 4,000 diseases are thought to stem from mutated genes inherited from one's mother and/or father. Common disorders such as heart disease and most cancers arise from a complex interplay among multiple genes and between genes and factors in the environment.

When a gene contains a mutation, the protein encoded by that gene will be abnormal. Some protein changes are insignificant, others are disabling.

How does a faulty gene trigger disease?

A sound body depends on the continuous interplay of thousands of proteins, acting together in just the right amounts and in just the right places - and each properly functioning protein is the product of an intact gene. Genes can be altered (mutated) in many ways. The most common gene mistake involves a single changed base in the DNA - a misspelling. Other alterations include the loss or gain of a base. Sometimes long segments of DNA are multiplied or disappear. Some mutations are silent; they affect neither the structure of the encoded protein nor its function. Other mutations result in an altered protein. In some instances, the protein is normal enough to function, but not well; this is the case of the flawed hemoglobin, the oxygen-carrying protein in the blood that causes sickle-cell anemia. In other instances, the protein can be totally disabled. The outcome of a particular mutation depends not only on how it alters a protein's function but also on how vital that particular protein is to survival.

How do gene mistakes occur?

Gene mutations can be either inherited from a parent or acquired. A hereditary mutation is a mistake that is present in the DNA of virtually all body cells. Hereditary mutations are also called germline mutations because the gene change exists in the reproductive cells (germ cells) and can be passed from generation to generation, from parent to newborn. Moreover, the mutation is copied every time body cells divide.
Acquired mutations, also known as somatic mutations, are changes in DNA that develop throughout a person's life. In contrast to hereditary mutations, somatic mutations arise in the DNA of individual cells; the genetic errors are passed only to direct descendants of those cells. Mutations are often the result of errors that crop up during cell division, when the cell is making a copy of itself and dividing into two. Acquired mutations can also be the byproducts of environmental stresses such as radiation or toxins.
Mutations occur all the time in every cell in the body. Each cell, however, has the remarkable ability to recognize mistakes and fix them before it passes them along to its descendants. But a cell's DNA repair mechanisms can fail, or be overwhelmed, or become less efficient with age. Over time, mistakes can accumulate.

Hereditary mutations are carried in the DNA of the reproductive cells. When reproductive cells containing mutations combine to produce offspring, the mutation will be present in all of the offspring's body cells.

Acquired mutations develop in DNA during a person's lifetime. If the mutation arises in a body cell, copies of the mutation will exist only in descendants of that particular cell.

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In dominant genetic disorders, if one affected parent has a disease-causing allele that dominates its normal counterpart, each child in the family has a 50-percent chance of inheriting the disease allele and the disorder.














How does heredity influence disease?

Genes come in pairs, with one copy inherited from each parent. Many genes come in a number of variant forms, known as alleles. A dominant allele prevails over a normal allele. A recessive gene becomes apparent if its counterpart allele on the other chromosome becomes inactivated or lost.
For example, in cystic fibrosis (a disease that seriously impairs breathing and digestion), the gene that causes abnormal mucus production and disease is a recessive allele. A person who inherits one copy of the recessive allele does not develop disease because the normal allele predominates. However, such a person is a carrier who has a 50-50 chance of passing the altered recessive allele to each of his or her descendants. When both parents are carriers, the chance is one in four that a child will inherit two of the recessive alleles, one from each parent, and develop disease. (This chance remains one in four for each pregnancy.) Although most recessive mutations are rare, a few, including those for cystic fibrosis and sickle-cell anemia, are fairly common in specific ethnic groups.
However, most diseases and traits don't follow simple patterns of inheritance; a variety of factors influence a gene's performance. To begin with, not all mutated alleles invariably lead to disease. Even with a dominant allele such as the BRCA1 breast cancer susceptibility gene, for instance, the risk of disease by age 65 is 80 percent, not 100 percent. This quality - an indication of the probability that a given gene mutation will produce disease - is referred to as penetrance.
Not only can different mutations in the same gene produce a wide range of effects in different individuals, as is the case with cystic fibrosis, but also mutations in several different genes can lead to the identical outcome, as is the case with some forms of Alzheimer's disease. Some traits require simultaneous mutations in two or more genes. And a phenomenon known as imprinting can determine which of a pair of genes, the mother's allele or the father's, will be active or silenced.

In diseases associated with altered recessive genes, both parents - though disease-free themselves- carry one normal allele and one altered allele. Each child has one chance in four of inheriting two altered alleles and developing the disorder; one chance in four of inheriting two normal alleles, and two chances in four of inheriting one normal and one altered allele, and being a carrier like both parents.













What are the uses of genetic testing?

Genetic tests can be used to look for possible predisposition to disease as well as to confirm a suspected mutation in an individual or family.
The most widespread type of genetic testing is newborn screening. Each year in the United States, four million newborn infants have blood samples tested for abnormal or missing gene products. Some tests look for abnormal arrangements of the chemical bases in the gene itself, while other tests detect inborn errors of metabolism (for example, phenylketonuria) by verifying the absence of a protein that the cell needs to function normally.
Carrier testing can be used to help couples to learn if they carry - and thus risk passing to their children - a recessive allele for inherited disorders such as cystic fibrosis, sickle-cell anemia, or Tay-Sachs disease (a lethal disorder of lipid metabolism). Genetic tests - biochemical, chromosomal, and DNA-based - also are widely available for the prenatal diagnosis of conditions such as Down syndrome.
In clinical research programs, doctors make use of genetic tests to identify telltale DNA changes in cancer or precancer cells. Such tests can be helpful in several areas: early detection (familial adenomatous polyposis genes prompt close surveillance for colon cancer); diagnosis (different types of leukemia can be distinguished); prognosis (the product of a mutated p53 tumor-suppressor gene flags cancers that are likely to grow aggressively); and treatment (antibodies block a gene product that promotes the growth of breast cancer).
Much of the current excitement in gene testing, however, centers on predictive gene testing: tests that identify people who are at risk of getting a disease, before any symptoms appear. Tests are already available in research programs for some two dozen such diseases, and as more disease genes are discovered, more gene tests can be expected.

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Different types of genetic tests are used to hunt for abnormalities in whole chromosomes, in short stretches of DNA within or near genes, and in the protein products of genes.




















How are disease genes identified?

Tracking down every chemical base in each of the estimated 50,000 to 100,000 genes as well as the spaces between them - mapping the human genome - is the task of an international 15-year collaboration known as the Human Genome Project. (The United States effort is shared by the National Center for Human Genome Research at the National Institutes of Health and the Office of Health and Environmental Research of the Department of Energy.) Scientists expect that having a detailed map of the entire set of human genes will revolutionize medical practice and biomedical research.
The Human Genome Project is focusing on the creation of genome maps, both genetic linkage maps and physical maps. Genome maps depict the order in which genes, genetic markers, and other landmarks are found along the chromosomes.

In narrowing the search for a specific gene, researchers often identify gene markers - characteristic segments of DNA or genes for known traits - thet lie close to the target gene and are inherited along with it.

Genetic linkage maps assign chromosomal locations to genetic landmarks - either genes or distinct short sequences of DNA - on the basis of how frequently markers are inherited together. Linkage maps exploit a phenomenon called recombination or crossing over. As developing sperm and egg cells divide, pairs of maternal and paternal chromosomes sometimes break and exchange pieces with one another. Genes and markers that are physically close to one another on the chromosome are said to be tightly linked; they are much less likely to be separated by recombination than are gene markers that are located far apart. In 1994, international collaborators published a comprehensive linkage map charting more than 5,000 markers and more than 400 genes.
After scientists use genetic linkage maps to assign a gene to a relatively small area on a chromosome, they next examine the region up close to learn the gene's precise location. To do this, scientists turn to physical maps.
To construct a physical map, a chromosome (or in some cases, the whole genome) is first broken into smaller pieces of DNA. Scientists then copy or clone the pieces in the laboratory, obtaining millions of identical copies of specific DNA segments. They next line up the clones to reflect the order that existed on the original chromosome. Information about the location and known genetic content of these unique and ordered DNA fragments (called contigs) is stored in a computer, while clones of the ordered pieces themselves are stored in laboratory freezers. When genetic linkage maps indicate that a gene lies in a particular region, scientists can go to the freezer and retrieve clones of interest; they then use the clones as the raw material for DNA sequencing - actually identifying the order of each and every chemical base in the gene.
Benefiting from the increasingly detailed maps and sophisticated DNA sequencing techniques and tools, scientists are mapping and isolating new disease genes at the rate of several per month. By the year 2005, scientists hope to pinpoint the location of each of the 50,000 to 100,000 genes and to identify the exact sequence of their chemical bases.

Maps of DNA can have several levels of detail; from the banding patterns of the chromosomes, to clones of overlapping segments of DNA, and ultimately to the base-by-base sequence of DNA.



















What types of diseases can be predicted with gene tests?

Predictive gene tests look for disorders that "run in families" as the result of a faulty gene that is inherited. When a mutated gene is inherited because it was carried in the reproductive cells (egg or sperm), the mutation will be present in cells throughout the body. This means that the mutation can be detected in white blood cells in a blood sample, for instance.
Predictive gene tests are presently available for diseases such as Tay-Sachs disease and cystic fibrosis, and tests are being developed for many more conditions, including a predisposition to ALS, or amyotrophic lateral sclerosis, the fatal nerve degeneration known as Lou Gehrig's disease; Huntington's disease, a devastating disorder of middle age that causes dementia and ends in death; some forms of Alzheimer's disease; and catastrophically high cholesterol.
Genes have also been found for several types of cancer that can run in families.
Several of these are rare conditions that affect only a few people: a childhood eye cancer known as retinoblastoma; Wilms' tumor, a kidney cancer that usually appears before age 5; and the Li-Fraumeni syndrome, in which children and young adults of the family develop an assortment of cancers, including sarcomas in the bones and soft tissues of the arms and legs, brain tumors, acute leukemia, and breast cancer. In 1993, scientists identified the gene that causes familial adenomatous polyposis, an inherited predisposition to form precancerous polyps. This condition is believed to be responsible for about 1 percent of colon cancers.
More recently, scientists have identified gene mutations that are linked to inherited tendencies toward common cancers, including colon cancer and breast cancer. Families who carry these altered genes may also have an increased risk of other cancers. Women with an altered copy of the BRCA1 breast cancer susceptibility gene, in particular, are susceptible to ovarian cancer as well. People who inherit cancer genes are more likely to develop cancer at a young age, because the predisposing gene damage is present throughout their lives, ready to set cancer's uncontrolled growth in motion should the normal allele be lost or inactivated.
Such inherited, or familial, forms of cancer represent perhaps about 5 to 10 percent of all cancers. The great majority of people who get breast cancer or colon cancer have not inherited such highly active altered genes. This is true even for many families that have several members with cancer; certain cancers are so common that some clusters are bound to happen purely by chance. Cases that are diagnosed at older ages, in particular, are more likely to be caused by acquired mutations.
Nevertheless, because breast and colon cancer are so widespread, even a small fraction of the total equals a very large number. It is estimated that as many as 1 in 300 women may carry inherited mutations of breast cancer susceptibility genes, and approximately the same proportion of Americans carry mutations that make them susceptible to colon cancer.

Inherited forms of cancer represent perhaps 5 or 10 percent of all cancers. The great majority of people who get brest cancer (or colon cancer) acquire mutations during their lifetimes.

What is the relationship between genes and cancer?

Cancer is a disease of genes gone awry. Genes that control the orderly replication of cells become damaged, allowing the cell to reproduce without restraint and eventually to spread into neighboring tissues and set up growths throughout the body.
All cancer is genetic, in that it is triggered by altered genes. However, just a small portion of cancer is inherited: a mutation carried in reproductive cells, passed on from one generation to the next, and present in cells throughout the body. Most cancers come from random mutations that develop in body cells during one's lifetime - either as a mistake when cells are going through cell division or in response to injuries from environmental agents such as radiation or chemicals.
Cancer usually arises in a single cell. The cell's progress from normal to malignant to metastatic appears to follow a series of distinct steps, each one controlled by a different gene or set of genes. Several types of genes have been implicated. Oncogenes normally encourage cell growth; when mutated or overexpressed, they can flood cells with signals to keep on dividing. Tumor-suppressor genes normally restrain cell growth; when missing or inactivated by a mutation, they allow cells to grow and divide uncontrollably. (The inherited genes that predispose for breast and ovarian cancer, Li-Fraumeni syndrome, retinoblastoma, Wilms' tumor, and familial adenomatous polyposis are malfunctioning tumor-suppressor genes.) DNA repair genes appear to trigger cancer - and perhaps other inherited disorders - not by spurring cell growth but by failing to correct mistakes that occur as DNA copies itself, letting mutations accumulate at thousands of sites. (Genes that have been linked to hereditary colon cancer are such "proofreader" genes.)

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Cancer usually arises in a single cell. The cell's progress from normal to malignant to metastatic appears to follow a series of distinct steps, each controlled by a different gene or set of genes. Persons with hereditary cancer already have the first mutation.

What does a predictive gene test tell you?

An accurate gene test will tell you if you do or do not have a disease-related gene mutation. If you do, a variety of factors can influence the gene's penetrance and the chances that you will actually develop disease. Nearly everyone with the familial adenomatous polyposis genes will - unless he or she takes effective preventive measures - someday develop colon cancer. On the other hand, women who carry the BRCA1 breast cancer susceptibility gene have an 80-percent chance of developing breast cancer by the age of 65; their risk is high but not absolute.
Of course, even family members who escape the inherited susceptibility gene are not exempt from risk. Like anyone else, they could develop mutations in that same gene during their lifetimes. Or, they could have inherited a different, unknown susceptibility gene.

Scientists looking for a disease gene often begin by studying DNA samples from members of 'disease families' that have numerous relatives, over several generations, who have developed an illness.

How do scientists develop predictive gene tests?

Scientists looking for a disease gene typically have begun by studying DNA samples from members of "disease families," in which numerous relatives, over several generations, have developed the same illness such as colon cancer. Researchers look for genetic markers - easily identifiable segments of DNA - that are consistently inherited by persons with the disease but are not found in relatives who are disease-free. Then, they painstakingly narrow down the target DNA area, pull out candidate genes, and look for specific mutations.
Before a specific gene is located, linked genetic markers can be used to test members of the family under study. However, to test wider populations, it is necessary to find the gene itself. Because the DNA highway is so vast, this can be enormously difficult. In the case of Huntington's disease, it took 10 years to advance from linkage markers to the gene.
Once a disease gene has been cloned (copied to get enough to study in detail) and identified, scientists can construct DNA probes - lengths of single-stranded DNA that match parts of the known gene. (This is possible because, in double-stranded DNA, adenine in one strand always pairs with thymine in the other, and guanine pairs with cytosine.) The single-stranded probe then seeks and binds to complementary bases in the gene. When the probe has been tagged with a radioactive atom, the area of DNA it binds to - the gene - lights up. The fact that some diseases exhibit multiple mutations within the same gene adds to the complexity of gene testing.
Functional gene tests, which detect protein rather than DNA, can demonstrate not only that a mutated gene is present but also that it is actively making an abnormal protein or no protein at all.

To find a target gene mutation in a sample of DNA, scientists use a DNA probe - a length of single-stranded DNA that matches part of the gene and is linked to a radioactive atom. The single-stranded probe seeks and binds to the gene. Radioactive signals from the probe are then made visible on x-ray film, showing where the probe and gene matched.
























What is the current status of predictive gene testing for cancer?

Tests for a few rare cancers are already in clinical use. Predictive gene tests for more common types of cancer are still primarily a research tool, difficult to execute and available only through research programs to small numbers of people who have a strong family history of disease. But the field of gene testing is evolving rapidly, with new genes being discovered almost daily and innovations in testing arriving almost as quickly. For example:

Predictive tests already are being used routinely in selected families with retinoblastoma and Wilms' tumor.

A gene test is available for persons in the rare cancer-prone Li-Fraumeni families. However, it is available only to participants in a research study, and experts caution that it must be offered with great care, weighing benefits against risks.

A test is in place for the gene that triggers familial adenomatous polyposis, a tendency to form hundreds of colon polyps, some of which, if not removed, will go on to become cancerous. (But the condition can also be diagnosed without the gene test.)

A set of genes that predispose a person to a much more common type of colon cancer (hereditary nonpolyposis colon cancer, or HNPCC) has been identified in high-risk families. These genetic alterations are thought to be carried by as many as 1 million Americans, and to cause about 90 percent of all inherited colon cancers, or about 15 percent of the 160,000 colon cancers diagnosed in the United States each year. The genes have also been linked to cancers of the uterus, stomach, ovary, small intestine, gall bladder, kidney, and ureter. Very high-risk families (three or more affected members, at least one before age 50, over two or more generations) are being tested at a few research centers. A blood test is expected in a year or two.

The BRCA1 gene mutation predisposes a person to hereditary breast cancer and ovarian cancer. A mutant BRCA1 gene on chromosome 17 is probably responsible for about 5 percent of the 182,000 cases of breast cancer predicted for a single year, and as many as a quarter of the cases occurring in women ages 45 and younger. A mutant BRCA1 gene is found in nearly half of the families with a high incidence of breast cancer and in at least 80 percent of the families with a history of both early onset breast and ovarian cancer. With the isolation of the gene, a blood test is expected, but before it becomes available, research studies must address important questions about optimum management of BRCA1 mutation carriers. (On chromosome 13, scientists have also found evidence of a second breast cancer gene called BRCA2.)

Genes have been reported for melanoma, leukemia, thyroid and renal cell cancer, and scientists are closing in on genes for several other cancers.

What are the benefits of gene testing?

Persons in high-risk families live with troubling uncertainties about their own future as well as that of their children. A negative test - especially one that is strongly predictive - can create a tremendous sense of relief.
A negative test, especially one that is strongly predictive, also may eliminate the need for frequent checkups and tests such as annual colonoscopy (a procedure that allows a physician to view the upper reaches of the large intestine), which are routine for high-risk families concerned about cancer.
A positive test can also produce benefits. It can relieve uncertainty, and it can allow a person to make informed decisions about his or her future.
Under the best of circumstances, a positive test creates an excellent opportunity for counseling and interventions to reduce risk. The prime example is colon cancer. When tumors are caught early, chances for survival are greatest, and screening potentially could prevent thousands of cancer deaths a year. A positive gene test sounds the alert to keep up regular screening practices (annual colonoscopies to check for precancerous polyps or the earliest signs of cancer) and to maintain healthful lifestyle measures such as a high-fiber, low-fat diet and regular exercise. Another option is surgery to remove the colon before cancer has a chance to develop.

What additional benefits may be expected from gene testing?

Tracking down the gene that causes an inherited cancer has implications for all cancers, inherited or not. A healthy allele of the same gene, if it undergoes mutations triggered by the environment during a person's lifetime, may lead to noninherited cancers. Thus, by identifying a cancer gene, scientists are able to explore mechanisms relevant to all people with cancer.
Genes and gene markers may also provide tools for improving cancer diagnosis and treatment. By spotting a mutated gene (or its protein product) in cells shed into stool, urine, or saliva, or in tissue biopsies, doctors may be able to detect cancers years earlier than with conventional diagnostic techniques. (It has even been suggested that some day probes for a mutated gene could be injected, then traced on an x-ray.)
Evaluating cancer-preventing drugs, too, should prove more efficient once the drugs can be tested in populations that are highly likely to develop the cancer. Or, if a gene is found to produce some antitumor protein, it might be possible to synthesize that protein and use it as a drug. Ultimately, it may become possible to thwart disease with gene therapy - inactivating the flawed gene or replacing it.

What are the limitations of gene testing?

First, current gene tests cannot provide a satisfactory answer for everyone who seems to be at risk for inherited breast or colon cancer. In some families, multiple cases may reflect shared environmental exposures rather than inherited susceptibility. Even when an inherited gene is to blame, it is not necessarily the test gene; the BRCA1 gene mutation, for example, is found in only about half of the families with hereditary breast cancer.
Second, despite major advances in DNA technology, identifying mutations remains a great challenge. Many of the genes of greatest interest to researchers are enormous, containing many thousands of bases. Mutations can occur anywhere, and searching through long stretches of DNA is difficult.
In addition, a single gene can have numerous mutations, not all of them equally influential. The cystic fibrosis gene, for instance, can display any one of more than 300 different mutations, which cause varying degrees of disease; some seem to cause no symptoms at all. Thus, a positive test does not guarantee that disease is imminent, while a negative test - since it evaluates only the more common mutations - cannot completely rule it out.
Furthermore, predictive tests deal in probabilities, not certainties. One person with a given gene, even one that is dominant like the hereditary breast cancer gene, may develop disease, while another person remains healthy, and no one yet knows why. A gene may respond to the commands of other genes or be switched on by an environmental factor such as sunlight.
Perhaps the most important limitation of gene testing is that test information often is not matched by state-of-the-art diagnostics and therapies. Many diseases and many types of cancer still lack optimal screening procedures; it is often not possible to detect an early cancer even in an individual with a known predisposition.
In inherited breast cancer, frequent screening with mammography offers the best chance of early detection, but falls short of prevention. Moreover, mammography is least effective in the glandular breasts of young women, the very ones at greatest risk from an inherited susceptibility. For the moment, the best assurance of prevention may lie in drastic and costly surgery to remove the breasts - but even a total mastectomy can leave some breast cells behind. As for the ovarian cancer that threatens high-risk families, available screening measures often cannot discover disease in time. Here, too, women in high-risk families often opt for prophylactic surgery to remove the ovaries. To date, however, neither type of prophylactic surgery has been proven to prevent completely the occurrence of cancer.
Scientists are actively studying interventions aimed at the prevention of cancer. For example, ongoing clinical trials are evaluating the use of tamoxifen, an anticancer drug, as a breast cancer preventive. However, such approaches are still in the realm of research.

What are the risks of gene testing?

The physical risks of the gene test itself - usually no more than giving a blood sample - are minimal. Any potential risks have more to do with the way the results of the test might change a person's life.
Psychological impact. First, there are the emotions aroused by learning that one is - or is not - likely to develop a serious disease. Many people in disease families have already seen close relatives fall victim to the disorder. The news that they do indeed carry the disease gene can elicit depression, even despair.
Few studies to date have looked directly at the outcome of gene testing for cancer. One study found that, after 3 to 6 weeks, the women identified as gene carriers experienced persistent worries, depression, confusion, and sleep disturbance. Even half of the noncarriers reported that they continued to worry about their risk status.

A gene test confirming the risk of a serious disease can trigger profound psychological consequences.

Family relations. Unlike other medical tests, gene tests reveal information not only about ourselves but about our relatives, and the decision to have a gene test, as well as the test results, can reverberate throughout the family. If a baby tests positive for sickle-cell trait, for example, it follows that one of his or her parents is a carrier. It is also possible for gene tests to inadvertently disclose family secrets involving paternity or adoption. Emotions elicited by test results can produce a shift in family dynamics. Someone identified as carrying the gene may feel anger, while one who has escaped may be overwhelmed by guilt for avoiding a disease that afflicts a close relative.
Family issues are especially prominent in research programs where genetic linkage tests depend on testing many members of the same family. Some family members may not want to participate in the study or know their genetic risks. People considering gene tests may want to find out how their relatives would feel about knowing whether or not they have a disease gene or allowing the information to be given to others.
Someone who elects to have a gene test needs to consider whether or not to share the test results with other members of the family. Do they want to know? Who should be told - spouse, children, parents, fiancŽ? Should someone in a high-risk family be tested before she or he marries? What will a positive test mean to one's relationships? If one chooses not to learn the results of the family's gene testing, can such a request be respected? How?

The question and issues raised by gene testing can challenge family and other personal relationships.

Medical choices. Someone who tests positive for a cancer susceptibility gene may opt for preventive or therapeutic measures that have serious long-term implications and are potentially dangerous or of unproven value. In the first family to be tested for a BRCA1 mutation, for instance, some women chose surgery to remove their breasts - and ovaries, too, after childbearing was completed. Other families told the genetic counselor that they were not interested in even discussing surgery.

Finding ways to ensure the confidentiality of gene test results is a major concern.

Privacy. Our genes hold an encyclopedia of information about us and, indirectly, about our relatives. Who should be privy to that information? Will a predisposition for cancer, for instance, remain secret - or could the information slip out? The concern is that test results might someday be used against a person. Some people have been denied health insurance, some have lost jobs or promotions, and some have been turned down for adoptions because of their gene status. Small research studies have conscientiously established safeguards to keep DNA results under wraps. Assurances of confidentiality may be more difficult to come by when larger numbers of people have access to the results. Clinical test results are normally included in a person's medical records. Even if gene testing information could be kept out of the medical record, a person's need for more frequent medical checkups, for example, could provide a tip-off to susceptibility. Might a genetic flaw constitute a "preexisting condition" that would be excluded from insurance coverage?