In this essay we will discuss about the role of heredity in increasing cancer and the main focus of this essay has been on cancer tendencies that run in families.
Contents
1. Essay on Hereditary Risk:
Genes Involved in Restraining Cell Proliferation:
When it is said that certain cancers are hereditary, it does not mean that people inherit cancer from their parents. What can be inherited, however, is an increased susceptibility to developing cancer. Cancers that arise because of such an inherited predisposition are called familial or hereditary cancers, whereas the more common cancers that do not exhibit an obvious inherited pattern are referred to as sporadic or nonhereditary cancers. Inherited mutations in several different categories of genes can predispose a person to developing cancer.
Because carcinogen-induced mutations are largely random, luck also plays a role. If two people have identical exposures to the same carcinogens, one person may develop cancer while the other does not simply because random mutations happened to damage critical genes in the unlucky individual.
But there is more to the story than this. Given the exact same set of circumstances, everyone does not have the exact same chance of developing cancer because heredity makes some people more susceptible than others. Eighty to ninety percent of a population’s overall cancer risk comes from environmental and lifestyle factors, leaving 10% to 20% to be derived from hereditary makeup.
While the impact of heredity is therefore small for populations as a whole that does not mean that heredity is a minor factor for every person. Some individuals inherit gene mutations that enormously increase their cancer risk.
In fact, some inherited mutations increase the risk to almost 100%, making it a virtual certainty that a person will develop cancer within his or her lifetime; other inherited mutations impart smaller, but still significant, increases in cancer risk. The study of such mutations has turned out to illuminate our understanding not just of hereditary cancers, but of nonhereditary forms of cancer as well.
Inherited Mutations and Cancer Risk:
To begin our discussion of inherited mutations and cancer risk, it will be useful to review a few of the basic principles that govern inheritance patterns. Human cells other than sperm and eggs possess two copies of each chromosome and are therefore said to be diploid (from the Greek word diplous, meaning “double”).
A normal diploid cell contains two sets of 23 chromosomes, yielding a total of 46 chromosomes. The two members of each chromosome pair are referred to as homologous chromosomes; one member of each pair is inherited from a person’s father and the other from the mother.
Since each type of chromosome is present in two copies, each gene represented in a pair of homologous chromosomes will be present in two copies. The two versions of each gene—called alleles—may be identical or slightly different. If the two alleles for a given gene are identical, a person is said to be homozygous for that gene; if the two alleles are different, the person is said to be heterozygous.
When a cell is heterozygous for a particular gene, one of the two alleles is often dominant and the other recessive. These terms convey the idea that the dominant allele determines how the trait will appear in a heterozygous individual.
In other words, a person with one dominant and one recessive allele for a given trait will express the dominant allele. Although such heterozygous individuals do not express the recessive trait, they can pass that recessive allele on to their children. To actually express a recessive trait, however, a person must be homozygous for the recessive allele (Figure 1).
Not all individuals who inherit dominant or recessive mutations express the trait that would be expected. The frequency with which a given dominant or homozygous recessive allele yields the expected trait within a population is known as penetrance. For example, we will see shortly that certain gene mutations are inherited as dominant traits that dramatically increase a person’s risk of developing cancer.
In some cases, every person who inherits a mutant copy eventually develops cancer and the penetrance is therefore said to be 100%. More commonly, less than 100% of the individuals who inherit a mutant copy actually develop cancer. In such cases, the mutant form of the gene is said to exhibit incomplete penetrance.
Individuals who inherit the mutation but do not develop cancer themselves can nonetheless pass the mutation on to their children. Incomplete penetrance arises when environmental conditions or other components of a person’s genetic makeup influence whether a particular trait will be expressed.
Retinoblastoma:
Our current understanding of the relationship between inherited mutations in genes that restrain cell proliferation and the development of cancer owes much to the study of retinoblastoma, a rare cancer of young children that arises in the light-absorbing retinal cells located at the back of the eye. Before the mid-nineteenth century, retinoblastoma was almost invariably fatal because tumors were not usually diagnosed until they had invaded through the back of the eyeball and into the brain.
The invention of the ophthalmoscope in 1850 changed the situation dramatically; doctors finally had a tool that permitted them to see inside the eye and detect tumors before they invaded into surrounding tissues, thereby allowing the tumors to be removed in their early stages.
Paradoxically, this impressive medical advance had an unexpected consequence: A new form of retinoblastoma emerged that had not been seen before. Before the ophthalmoscope was invented, few children with retinoblastoma survived to adulthood. Now almost 90% are cured and go on to live normal lives.
When these retinoblastoma survivors grow up and have families of their own, their children may also be at high risk for retinoblastoma. Normally a child has less than a 1-in-20,000 chance of developing retinoblastoma, but in the families of some retinoblastoma survivors, roughly 50% of the children develop the disease (Figure 2).
This particular form of retinoblastoma, which runs in family clusters, is called familial retinoblastoma to distinguish it from the sporadic retinoblastomas seen in children with no family history of the disease. About 40% of retinoblastoma cases are familial and the rest are sporadic. Children with the familial form of the disease often develop multiple tumors in both eyes, whereas sporadic retinoblastoma is almost always a single tumor.
Two-Hit Model to Study the Development of Retinoblastoma:
The pattern of inheritance seen in familial retinoblastoma is consistent with the transmission of a single mutant gene from parent to offspring. But what about the sporadic form of the disease? Is the same gene involved, or do the two forms of eye cancer arise by different mechanisms? In 1971, Alfred Knudson proposed the two-hit model to address this issue. According to his theory, the presence of two mutations is required to create a retinoblastoma.
In the sporadic form of the disease, where no mutations are inherited, the two mutations must arise spontaneously within the same cell. Because typical mutation rates in human cells are about one in a million per gene per cell division, the chance that the two required mutations will occur in the same cell is extremely remote.
In familial retinoblastoma, one mutation is already inherited from a parent and is therefore present in all body cells, including those of the retina. An individual retinal cell therefore needs to sustain only one additional mutation to create the two mutant genes required to produce a cancer.
Since there are more than ten million cells in the retina and since the mutation rate is about one in a million per gene per cell division, it is likely that one or more retinal cells will spontaneously incur the second mutation required for cancer to arise. That would explain why retinoblastoma rates are so high in families with the hereditary form of the disease and why children in such families often develop multiple tumors.
However, the preceding model leaves an important question unanswered: Do the two mutations involve different genes, or are we dealing with two defective alleles of the same gene, one residing on each member of a chromosome pair? Microscopic examination of the chromosomes of retinoblastoma cells provided an early clue.
Cells from individuals with familial retinoblastoma were sometimes found to exhibit a deleted segment in a particular region of chromosome 13. Moreover, the deletion was observed not just in tumor cells but in all cells of the body, suggesting that the inherited defect leading to retinoblastoma involved a gene located in the deleted region of chromosome 13.
A similar deletion is occasionally observed in sporadic retinoblastomas as well (although in this case only in tumor cells and not elsewhere in the body). Taken together, such observations suggest that chromosome 13 contains a gene whose loss is associated with both the hereditary and nonhereditary forms of retinoblastoma.
By itself, inheriting a single deletion in this region of chromosome 13 does not cause cancer. For cancer to develop, a mutation involving the same region of the second copy of chromosome 13 must arise during the many rounds of cell division that occur as the retina is formed. This second mutation was eventually localized to a small region of chromosome 13 containing a gene that was given the name RB (for “retinoblastoma”).
So Knudson’s two-hit theory for retinoblastoma could finally be restated in more precise terms (Figure 3). The “two hits” required for the development of retinoblastoma involves the two copies of the RB gene that we each inherit, one from our father and one from our mother.
Each “hit” is a mutation (or deletion) that disrupts the function of one copy of the RB gene. According to this model, the RB mutation is recessive because both alleles must be mutant (or deleted) for cancer to arise. However, the cancer risk syndromes in which children inherit a greatly elevated risk of developing cancer is a dominant trait because only a single RB mutation needs to be inherited to create a very high cancer risk.
If a child inherits such a defective RB gene, mutation of the good copy of the RB gene in a single retinal cell is all that is needed for cancer to develop. Since there are millions of cells in the retina and since normal mutation rates are about one in a million per gene per cell division, the chance that such an inactivating mutation will occur in at least one retinal cell is quite high.
Roughly 90% of the children who inherit a mutant RB gene from one parent eventually acquire this second mutation and develop cancer. In other words, the penetrance of retinoblastoma in children who inherit a single defective RB gene is 90%.
In families with no history of retinoblastoma, children are born with two good copies of the RB gene. As a result, retinoblastoma only arises in the very unlikely event that both copies of the RB gene happen to undergo mutation in the same cell, leading to the same genetic outcome as in familial retinoblastoma.
Retinoblastoma is one of a very few cancers in which inactivation of both copies of a single gene appears to be so crucial in leading directly to cancer. It is more common for cancers to arise as a multistep process involving sequential mutations in several different genes.
RB Gene as a Suppressor of Cell Proliferation:
What kind of gene is RB that makes it so central to the development of cancer? The only groups of cancer- causing genes we have discussed so far are oncogenes, which are a class of genes whose presence can trigger the development of cancer. In contrast, RB is a gene whose absence (or inactivation) rather than presence is associated with the development of cancer. Such a gene must operate on totally different principles than do oncogenes, which code for proteins that promote cell proliferation and survival.
It turns out that the normal function of the RB gene is not to promote cell proliferation and survival but rather to restrain them. Getting rid of a gene that restrains cell proliferation and survival is analogous to releasing the brake pedal on a car; in other words, it allows cells to proliferate in an uncontrolled fashion.
The way in which the RB gene performs its normal restraining function is by coding for the Rb protein, a molecule that plays a key role in controlling cell proliferation by regulating passage through the restriction point of the cell cycle. The role of the Rb protein in controlling progression through the cell cycle helps explain why retinoblastoma is only observed in young children.
By the time a child reaches 5 or 6 years of age, the retina is fully formed and most of the retinal cells exit from the cell cycle and permanently stop dividing. Once that happens, these cells are no longer susceptible to uncontrolled proliferation because the cell cycle has been permanently stopped.
Genes like RB—whose loss opens the door to excessive cell proliferation and cancer—are referred to as tumor suppressor genes. This name is slightly misleading, however, because the normal function of tumor suppressor genes is to restrain cell proliferation in general, not just the formation of tumors.
But if the RB gene is involved in the general restraint of cell proliferation, shouldn’t its loss lead to cancers in tissues other than the retina? In fact, retinoblastoma is not the only cancer to appear in children who inherit RB mutations. Such individuals often develop a second type of cancer as well, usually osteosarcoma but sometimes leukemia, melanoma, lung cancer, or bladder cancer. The tumor cells in these cancers exhibit mutations in the second copy of the RB gene, just as occurs with retinoblastoma.
RB mutations have also been detected in several kinds of cancer that do not involve a hereditary predisposition. For example, small cell lung carcinomas—a type of cancer that arises mainly in cigarette smokers with no family predisposition to cancer—frequently exhibit RB mutations that are created by the carcinogens present in tobacco smoke rather than being inherited.
Non-inherited RB mutations have likewise been implicated in the development of some bladder and breast cancers. The RB gene therefore plays a broader role in the development of cancer than its name would seem to imply. The gene is called “RB” because it was initially discovered in families at high risk for retinoblastoma, but its role in the control of cell proliferation and cancer is much broader.
Familial Adenomatosis Polyposis:
The RB gene is an example of a gene that imparts a high risk for a rare childhood cancer when inherited in a mutant (or deleted) form. Another group of genes create hereditary predispositions for some of the common adult cancers. For example, about 5% of all colon cancer cases are directly linked to inherited mutations in a small group of genes that increase colon cancer risk.
Although 5% is not a very high proportion, it represents a large number of people because colon cancer is among the most frequently encountered cancers in adults. About 150,000 new cases of colon cancer are diagnosed in the United States each year, so 5% of 150,000 equals’ 7500 new colon cancers caused by high-risk hereditary factors.
In the case of retinoblastoma, a much higher proportion of the cases are hereditary (about 40%), but retinoblastoma itself is very rare. Roughly 200 new cases of retinoblastoma are detected each year, so a 40% rate corresponds to 80 new cases of hereditary retinoblastoma compared with 7500 new cases of hereditary colon cancer.
Mutations in several different genes have been implicated in hereditary colon cancers. One is the gene responsible for familial adenomatous polyposis, an inherited condition in which numerous polyps develop in the colon. The term polyp refers to a tiny mass of tissue that arises from the inner lining of a hollow organ and protrudes into the lumen. Most colon polyps are tiny adenomas—that is, benign tumors composed of glandular cells.
The presence of polyps that are adenomas explains why the disease is called familial adenomatous polyposis. In people who inherit this condition, the inner surface of the colon becomes carpeted with hundreds or even thousands of benign polyps (Figure 4), and at least one of the polyps is likely to turn malignant by the time the person is 40 years old.
Unless the entire colon is removed, virtually everyone with familial adenomatous polyposis will eventually develop colon cancer. Such individuals are also at increased risk for cancers of the bile duct, small intestine, and stomach. In Japan, where stomach cancer is more common than in the United States, the risk of stomach cancer may even be greater than that for colon cancer.
The inherited mutation responsible for familial adenomatous polyposis resides in a gene called APC (for Adenomatous Polyposis Coli). As in the case of the RB gene, the two-hit model applies to the behavior of the APC gene. Individuals with familial adenomatous polyposis inherit a single defective or missing copy of APC from one parent, and an inactivating mutation then occurs in the second copy of the gene in a colon epithelial cell.
The resulting loss of APC function leads to uncontrolled cell proliferation that can set the stage for cancer development. The APC gene, like the RB gene, is therefore an example of a tumor suppressor gene—that is, a gene whose loss or inactivation is associated with the development of cancer.
The APC gene normally exerts its restraining effects on cell proliferation by producing a protein, also called APC, that inhibits the Wnt signaling pathway. (“Wnt” is an abbreviation for “wingless-type,” which refers to the fate of fruit flies with mutations in this pathway.) The Wnt pathway plays a prominent role in regulating cell proliferation and differentiation, especially during embryonic development.
When APC mutations arise that cause a loss of functional APC protein, the resulting uncontrolled activity of the Wnt pathway leads to enhanced cell proliferation. Epithelial cells lining the colon are especially sensitive to such effects. In people who inherit an APC mutation, excessive proliferation of the colon epithelium leads to the formation of numerous polyps and, sooner or later, colon cancer.
This connection between APC mutations and colon cancer is not restricted to hereditary colon cancers; mutations in APC also occur in about two-thirds of the more common forms of colon cancer that arise in people with no family history of the disease.
The Li-Fraumeni Syndrome:
The two hereditary syndromes described thus far each involve an inherited risk for one main type of cancer, either retinoblastoma for individuals inheriting a mutant RB gene or colon cancer for those inheriting a mutant APC gene. In the hereditary condition to be described next, called the Li-Fraumeni syndrome, susceptibility to cancer in general rather than to a specific type of cancer is transmitted from parent to offspring.
The family pedigree shown in Figure 5 illustrates such a case. The woman marked by the arrow is typical of someone who might seek genetic counseling because of a fear that “cancer runs in the family.”
Her father had colon cancer when he was 40, a sarcoma at age 45, and lung cancer when he was 53; her sister had brain cancer as a teenager; her brother developed an osteosarcoma at age 3 and rhabdomyosarcoma (skeletal muscle cancer) at age 14; a cousin had leukemia as a teenager; an aunt died of breast cancer; an uncle had stomach cancer; and her grandfather died of melanoma.
What clearly distinguishes this scenario from other hereditary syndromes is the variety of cancers involved. Individuals inheriting a mutant RB or APC gene have roughly a 90% chance of developing a single type of cancer, either retinoblastoma in the case of RB or colon cancer in the case of APC.
The mutation responsible for Li-Fraumeni syndrome also confers about a 90% risk of developing cancer, but no single cancer predominates. Cancers commonly associated with Li-Fraumeni syndrome include osteosarcomas, breast cancers, leukemias, adrenal carcinomas, brain tumors, soft tissue sarcomas, melanomas, and cancers of the stomach, colon, and lung.
These cancers arise in adults as well as children, but the age of onset is usually earlier than would be typical for the particular type of cancer involved. A single individual may develop several different kinds of cancer in succession, which rarely happens with nonhereditary cancers.
As you might expect from the diversity of the cancers involved, Li-Fraumeni syndrome arises from defects in a gene that is critical for the control of cell proliferation and survival in many tissues. The gene in question is the p53 gene (also called TP53 in humans). The p53 gene produces the p53 protein, in several different contexts.
The p53 protein plays a very important role in the pathway that causes cells with damaged DNA to self-destruct by apoptosis; also sunlight-induced mutations in the p53 gene trigger the development of skin cancer; and a viral on co-protein produced by the human papillomavirus binds to and promotes destruction of the p53 protein, thereby contributing to the development of cervical cancer. The diversity of these examples suggests that the p53 protein is broadly important in protecting against the development of cancer.
It is therefore not surprising that individuals with Li-Fraumeni syndrome, who inherit a mutation in one copy of the p53 gene, are at great risk of developing cancer. The chances are about one in a million per dividing cell that a mutation in the second copy of the p53 gene will arise.
Since billions of cells divide throughout the body during a person’s lifetime, the probability is extremely high that a mutation disrupting the second, good copy of the p53 gene will appear in at least one cell somewhere in the body. Since cancers develop when p53 function is lost, the p53 gene is another example (like RB and APC) of a tumor suppressor gene.
Li-Fraumeni syndrome is an extremely rare condition; only a few hundred families have been diagnosed with the condition worldwide. That does not mean, however, that p53 mutations are rare in human cancers. To the contrary, p53 mutations are detected in almost half of all nonhereditary cancers, making it the most commonly mutated gene in human cancer.
In some cases, a linkage between p53 mutations and specific environmental carcinogens has been clearly established, for example, the role of sunlight-induced p53 mutations in non-melanoma skin cancers.
In addition, about half of all lung cancers have been found to exhibit p53 mutations in DNA bases that are attacked by the polycyclic hydrocarbons present in tobacco smoke. Carcinogen-induced mutations in p53 are also common in many other types of cancer, including cancers of the colon, pancreas, ovary, bladder, liver, stomach, and breast.
Hereditary Cancer Syndromes:
The three inherited cancer syndromes described thus far:
i. Familial retinoblastoma,
ii. Familial adenomatous polyposis, and
iii. Li-Fraumeni syndrome—share several features in common.
(1) Each is caused by a mutation in a single tumor suppressor gene (RB, APC, or p53) inherited from one parent.
(2) The elevated risk of developing cancer is a dominant trait because only a single mutation needs to be inherited to impart a very high risk of developing cancer, usually in the range of 90% to 100%.
(3) For cancer to actually arise, the second copy of the gene must also become inactivated (the “second hit” of the two-hit model). The likelihood of that happening in at least one dividing cell is very high.
(4) If a person with one of these hereditary syndromes has children, each child will have a 50:50 chance of inheriting the gene defect and its associated cancer risk (see Figure 3, left).
(5) Children who are among the 50% that do not receive the genetic defect will not be at increased risk for cancer and will not pass the risk on to their children.
(6) The gene mutations responsible for these hereditary cancer syndromes involve the inactivation or loss of a tumor suppressor gene whose normal role is to restrain cell proliferation.
(7) Carcinogen-induced mutations in the same tumor suppressor genes can cause nonhereditary cancers.
In addition to RB, APC, and p53, several other tumor suppressor genes behave according to the same principles (Table 1, top). However, even though these genes all share the property of restraining cell proliferation and survival, they differ significantly in the molecular mechanisms involved.
2. Essay on Hereditary Risk: Genes affecting DNA Repair and Genetic Stability:
The hereditary cancer syndromes discussed thus far are caused by loss-of-function mutations in tumor suppressor genes whose normal role is to restrain cell proliferation and survival. A second group of tumor suppressor genes act through a fundamentally different set of mechanisms involving DNA repair and chromosome stability.
Whereas the first group of tumor suppressors produce proteins involved in the control of cell proliferation, and whose loss therefore leads directly to tumor formation, the loss of genes involved in repairing DNA or maintaining chromosome stability acts indirectly by permitting an increased mutation rate for all genes. This increased mutation rate increases the likelihood that random mutations will disrupt genes that do impact cell proliferation directly.
The terms gatekeepers and caretakers are used to distinguish between the two classes of tumor suppressors. Genes like RB, APC, and p53, whose normal role is to restrain cell proliferation, are considered to be “gatekeepers” because their loss opens the gates to tumor formation directly. Genes involved in DNA maintenance and repair, on the other hand, are viewed as “caretakers” that preserve the integrity of a cell’s genome (its total genetic information).
The loss of a caretaker gene does not directly affect cell proliferation. Instead, it leads to disruptions in DNA maintenance and repair that cause an increased mutation rate for all genes (including gatekeepers), and it is only through subsequent mutation of these additional genes that cancer arises. We will now examine some of the hereditary cancer syndromes that are caused by mutations in caretaker genes.
Xeroderma Pigmentosum is an Inherited Sensitivity to Sunlight-Induced Skin Cancer:
The first reports of a connection between DNA repair and cancer susceptibility came from the study of a rare hereditary disease known as xeroderma pigmentosum. Individuals with this condition are so sensitive to ultraviolet radiation that sunlight can be fatal. Exposure to even a few minutes of daylight is enough to cause severe burning and various skin cancers, including basal cell carcinoma, squamous cell carcinoma, and melanoma.
Because it is only safe for them to go outside at night, children with xeroderma pigmentosum are sometimes referred to as “children of the moon.” There is even a special camp in upstate New York, called Camp Sundown that allows affected children to participate in normal recreational activities but on a different time clock: Outdoor activities begin after sundown and take place during the night, allowing the children to be back indoors and safely behind drawn curtains by sunrise.
Scientists from NASA have taken an interest in the problem, working on the design of a special space suit that provides enough sunlight protection to allow children with xeroderma pigmentosum to play outdoors occasionally (Figure 6).
Xeroderma pigmentosum does not exhibit the same inheritance pattern, which involved a single mutation inherited from a person’s mother or father. Xeroderma pigmentosum requires two mutant copies of the same gene to be inherited, one from each parent.
Because it is unlikely that both parents will carry a mutant version of the same gene, xeroderma pigmentosum is a very rare condition. However, if each parent does happen to carry a mutation in the same responsible gene (along with a second, normal copy), their children will have a 50% chance of inheriting the mutant version from their father and a 50% chance of inheriting a mutant version from their mother. The overall probability that any given child will inherit both mutations and have xeroderma pigmentosum is therefore 50% X 50% = 25%.
Since two mutant copies of the same gene must be inherited to cause the disease, xeroderma pigmentosum exhibits a recessive pattern of inheritance. Family pedigrees for xeroderma pigmentosum therefore look different from the pedigrees for familial retinoblastoma and Li-Fraumeni syndrome.
In familial retinoblastoma and Li-Fraumeni syndrome, which exhibit a dominant pattern of inheritance, parents who transmit the high-risk trait to their children are at high risk for cancer themselves because the trait is dominant, and 50% of their children will acquire the high-risk condition (see Figures 2 and 5).
With cancer syndromes that exhibit a recessive pattern of inheritance, such as xeroderma pigmentosum, the parents do not have a high cancer risk because they each carry only a single recessive gene; the high-risk condition will, however, appear in 25% of their offspring (Figure 7).
Despite their differing patterns of inheritance, the underlying behavior of the tumor suppressor genes involved in recessive and dominant cancer syndromes is not as different as these distinctions seem to imply. With recessive cancer syndromes, a high risk for cancer arises when two defective copies of a gene are inherited and normal gene function is therefore lost (Figure 8a).
With dominant cancer syndromes (Figure 8b), inheriting one defective copy imparts a high risk of developing cancer, but cancer only arises after the second copy is mutated or lost (the “second hit” of the two-hit model). The final result is therefore similar in both cases; that is, both copies of a tumor suppressor gene lose their function.
Xeroderma Pigmentosum is Caused by Inherited Defects in Excision Repair:
The susceptibility to skin cancer that is the hallmark of xeroderma pigmentosum has been traced to inherited defects in DNA repair. In Ultraviolet radiation absorbed by skin cells leads to DNA mutations—especially pyrimidine dimers—that can cause cancer if the mutations are not repaired.
One mechanism for repairing pyrimidine dimers is excision repair, a pathway that recognizes major distortions in the DNA double helix and uses a series of enzymes to excise the damaged region and fill the resulting gap with the correct sequence of nucleotides.
It was first reported in the late 1960s that cells from individuals with xeroderma pigmentosum are unable to perform excision repair. DNA mutations therefore accumulate and cancer eventually arises. Subsequent studies have revealed that mutations in seven different genes can cause xeroderma pigmentosum through their effects on excision repair.
Each of these seven genes, designated XPA through XPG, codes for an enzyme involved in a different step of the excision repair pathway. Inheriting two defective copies of any one of these seven genes halts excision repair and creates the cancer predisposition syndrome that is the hallmark of xeroderma pigmentosum.
An eighth gene, designated XPV, produces a variant form of xeroderma pigmentosum in which the excision repair pathway is unaffected but individuals nonetheless inherit an increased sensitivity to sunlight-induced cancers. This particular mutation affects the enzyme DNA polymerase ƞ (eta), a special form of DNA polymerase that catalyzes translesion synthesis—that is, the synthesis of new error-free stretches of DNA across regions in which the template strand is damaged.
DNA polymerase n is capable of accurately replicating DNA in regions where pyrimidine dimers are present, correctly inserting the proper bases. Therefore, inherited defects in DNA polymerase n, like inherited defects in excision repair, interfere with the ability of cells to correct pyrimidine dimers created by ultraviolet radiation.
Because individuals with xeroderma pigmentosum cannot repair pyrimidine dimers, they exhibit skin cancer rates that are 2000-fold higher than normal. Moreover, their average age for developing skin cancer is 8 years old, compared with age 60 for the general population. The defects in DNA repair associated with xeroderma pigmentosum also cause a 20-fold increase in cancers of the brain, lung, stomach, breast, uterus, and testes, as well as leukemias.
Hereditary Nonpolyposis Colon Cancer Is Caused by Inherited Defects in Mismatch Repair:
A second hereditary syndrome, called hereditary non polyposis colon cancer (HNPCC), also increases a person’s risk of developing colon cancer, in this case because of an inherited defect in DNA repair.
Cancer again tends to arise from colon polyps, although people with HNPCC typically have only a few polyps rather than the hundreds or thousands of polyps observed with familial adenomatous polyposis. (Polyposis literally means “numerous polyps”, so the presence of only a few polyps in HNPCC explains why the term non polyposis is included as part of its name)
The inherited mutations responsible for HNPCC disrupt the mismatch repair pathway, which is normally responsible for correcting errors involving bases that are incorrectly paired between the two strands of the DNA double helix. Mismatch repair requires the participation of many different proteins, and defects in genes coding for at least eight of these proteins have been implicated in HNPCC.
The disease exhibits a dominant pattern of inheritance, which means that inheriting a single mutant copy of any of the eight genes is sufficient to create an increased susceptibility to developing colon cancer.
However, cancer only arises if the second, functional copy of the affected gene becomes mutated in a proliferating epithelial cell lining the colon. If that happens, the affected cell becomes deficient in mismatch repair and its proliferation produces cells that accumulate mutations at higher-than-normal rates, which can in turn lead to cancer.
About 75% of the individuals who inherit one of the eight mutant genes responsible for HNPCC eventually develop colon cancer. Smaller increases in risk are also observed for cancers of the uterus, ovary, stomach, and kidney.
Mutations in the BRCA1 and BRCA2 Genes are Linked to Inherited Risk for Breast and Ovarian Cancer:
Among women in the Western world, breast cancer is the second most frequent type of cancer (next to skin cancer) and the second most common cause of cancer deaths (next to lung cancer). Current statistics suggest that about 1 in every 8 women in the United States will develop breast cancer within her lifetime.
Breast cancer risk is roughly doubled in women who have had a close blood relative with the disease (mother, sister, or daughter), and two close relatives increases the risk about fivefold. Risk is also increased by a history of breast cancer in more distant family members (e.g., aunt or grandmother), which may be on either the mother’s or father’s side of the family.
However, having a close relative with breast cancer does not always mean that the disease runs in the family. Breast cancer is a common disease, and many women will have a relative with breast cancer solely by chance.
About 10% of all breast cancer cases can be traced to a high-risk hereditary predisposition, usually created by an inherited mutation in either the BRCA1 or BRCA2 gene (BRCA is an abbreviation for Breast Cancer). Inherited defects in these genes are responsible for familial breast cancer, which is characterized by the onset of breast cancer at an early age and, in some cases, cancer in both breasts or breast and ovarian cancer in the same individual.
Depending on the exact nature of the particular BRCA1 or BRCA2 mutation that is inherited, risk typically falls in the range of 40% to 80% for breast cancer and 15% to 65% for ovarian cancer.
Interestingly, women born after 1940 who carry mutations in the BRCA1 or BRCA2 genes have a higher risk of developing breast (but not ovarian) cancer on an age-adjusted basis than do women with the same mutations who were born before 1940 (Figure 9). Such findings indicate that non-genetic factors significantly affect the risk of developing breast cancer, even in individuals who inherit a high-risk predisposition.
When the BRCA1 and BRCA2 genes were first discovered, they were thought to play a role in the control of cell proliferation. Later studies revealed, however, that the proteins produced by these genes are involved in repairing DNA damage, especially double-strand breaks. It has therefore been concluded that BRCA1 and BRCA2 mutations do not directly open the gates to excessive cell proliferation but instead hamper the process of DNA repair, thereby increasing the rate of subsequent mutations that can lead to cancer.
This conclusion is consistent with the finding that mutations involving the classic “gatekeeper” tumor suppressors, such as RB, APC, and p53, are observed in both hereditary and nonhereditary cancers because they act directly on cell proliferation and directly open the gates to uncontrolled proliferation and cancer.
Mutations involving BRCA1 and BRCA2, on the other hand, are rarely seen in nonhereditary cancers, presumably because they are “caretaker” genes that do not directly control cell proliferation and so are only indirectly related to cancer development.
Inherited Defects in DNA Repair Underlie Ataxia Telangiectasia, Bloom Syndrome, and Fanconi Anemia:
Inherited defects in DNA repair are responsible for several additional high-risk cancer syndromes in addition to the ones described thus far. Although they all arise from inherited defects in DNA repair, these syndromes exhibit a remarkable diversity of symptoms. One striking example is an inherited condition known as ataxia telangiectasia (ataxia = “lack of coordination,” telangiectasia = “dilation of capillaries”).
The first abnormality seen in children with ataxia telangiectasia, usually arising between 1 and 3 years of age, is an inability to walk steadily caused by degeneration of the cerebellum, which is the part of the brain that governs muscle coordination and balance.
Other symptoms include abnormal eye movements, slurred speech, retarded growth, recurrent infections arising from a deficient immune system, and red marks on the skin and inner surface of the eyelids caused by abnormal dilation of small blood vessels. The preceding symptoms are accompanied by a roughly 40% risk of developing cancer, mostly lymphomas and leukemias, but also cancers of the skin, breast, stomach, pancreas, ovary, and brain.
The gene responsible for ataxia telangiectasia, called the ATM gene (for Ataxia Telangiectasia Mutated), exhibits a recessive pattern of inheritance in which two mutant ATM genes must be inherited, one from each parent, to create the syndrome. Neither parent is likely to exhibit any disease symptoms because they each carry a single mutant ATM gene whose effects are recessive and thus are not expressed.
The ATM gene codes for a protein involved in the DNA damage response, an intricate network of cellular pathways invoked as a protective response to assaults on DNA integrity. The ATM protein plays a central role both in detecting the occurrence of DNA damage— especially double-strand breaks—and in activating a cascade of appropriate responses.
Deficiencies in the DNA damage response also occur in several other hereditary syndromes, each of which exhibits a distinctive pattern of symptoms and cancer risks. For example, individuals with Bloom syndrome are characterized by short stature, sun-induced facial rashes, immunodeficiency, decreased fertility, and an elevated risk of developing cancer before age 20, most commonly lymphomas, leukemias, and cancers of the mouth, stomach, larynx, lung, esophagus, colon, skin, breast, and cervix.
The BLM gene, whose mutation causes Bloom syndrome, exhibits a recessive pattern of inheritance and codes for a DNA helicase, which is a protein that unwinds the DNA double helix during the repair of double-strand breaks and other types of DNA damage.
In Fanconi anemia, the main symptom is the inability of the bone marrow to produce a sufficient number of blood cells, accompanied by skeletal malformations, organ deformities, reduced fertility, and marked predisposition to developing leukemias and squamous cell carcinomas. Fanconi anemia exhibits a recessive pattern of inheritance and is caused by inactivating mutations in any of at least 11 different genes.
The proteins produced by these genes interact with one another and with various components of DNA damage response pathways, including the proteins produced by the ATM and BRCA1 genes. One of the 11 genes that can cause Fanconi anemia is BRCA2, the same gene that causes familial breast cancer.
BRCA2 exhibits a dominant pattern of inheritance for familial breast cancer and a recessive pattern of inheritance for Fanconi anemia. In other words, the familial breast cancer syndrome arises from the inheritance of a single mutant allele of BRCA2, and Fanconi anemia arises from the inheritance of two mutant alleles.
3. Essay on Other Genes and Issues that Cause Heredity Risk:
The high-risk cancer syndromes discussed thus far all stem from mutations in tumor suppressor genes, either gatekeeper genes involved in controlling cell proliferation and survival or caretaker genes involved in DNA maintenance and repair. Tumor suppressors, however, are not the only genes that affect hereditary cancer risk.
Multiple Endocrine Neoplasia Type II:
The hereditary cancer syndromes we have been considering so far all involve loss-of-function mutations—that is, on mutations that inactivate or delete genes, or cause them to produce nonfunctional products. By definition, the affected genes are tumor suppressor genes because a tumor suppressor gene is defined as a gene whose loss of function leads to cancer.
Gain-of-function mutations, which cause a gene to produce a protein exhibiting new or excessive activity, can also influence hereditary cancer risk. Perhaps the best characterized syndrome that works in this way is multiple endocrine neoplasia type II, an inherited condition associated with the development of both benign and malignant tumors of endocrine glands.
The disease usually starts in childhood and is characterized by developmental abnormalities stemming from the overproduction of specific hormones. About 70% of affected individuals develop cancer by age 70, usually thyroid cancer.
Multiple endocrine neoplasia type II is caused by inheriting a single mutant RET gene, which codes for the Ret receptor protein. The Ret receptor is located on the surface of endocrine cells, where it binds external growth factors and transmits a signal that stimulates cell proliferation.
Normally the Ret receptor is only active when stimulated by an appropriate growth factor, but the mutant RET gene produces an abnormal Ret receptor that is constitutively active; in other words, the receptor transmits a signal that stimulates cell proliferation whether a growth factor is present or not.
The new function created in this “gain-of-function” mutation is therefore the production of a protein whose abnormal structure allows it, unlike the normal version of the protein, to stimulate cell proliferation independent of the presence of growth factor.
The mutant form of the RET gene is thus an oncogene because its presence can lead to cancer, and the normal RET gene is a proto-oncogene because it is closely related to, and can be converted into, an oncogene.
Figure 10 summarizes the fundamental difference in the behavior of mutations involving proto-oncogenes and tumor suppressor genes. In essence, tumor suppressor genes are genes in which loss-of-function mutations lead to cancer, and proto-oncogenes are genes in which gain- of-function mutations lead to cancer.
To lose the function of a tumor suppressor gene, both copies must usually undergo an inactivating mutation (or deletion). In contrast, mutation of one copy of a proto-oncogene can be sufficient to create an oncogene whose presence contributes to the development of cancer.
Inherited Variations in Immune Function and Metabolic Enzymes:
We have seen that cancer risk increases when immune function is disrupted either through HIV infection or in organ transplant recipients who use immunosuppressive drugs.
It is therefore not surprising that inherited deficiencies in immune function can increase cancer risk as well. In some cases, disruptions in immune function are an indirect effect of inherited mutations whose primary effect is not on the immune system itself. Examples include ataxia telangiectasia and Bloom syndrome, which arise from inherited defects in DNA repair that trigger increased mutation rates but also impair the ability of lymphocytes to perform their normal immune functions.
The resulting loss in immune activity may contribute to the elevated cancer rates seen in such syndromes, along with the primary role played by defective DNA repair in increasing mutation rates in the cells that are actually destined to become cancerous.
Primary immunodeficiency diseases, caused by inherited mutations that directly incapacitate the immune system, are likewise associated with modest increases in cancer risk, although an increased susceptibility to infections is usually the main symptom.
The most frequently encountered cancers are lymphomas, often triggered by EBV infections that proceed unrestrained in the absence of an effective immune response. Immunodeficiencies caused by malaria or HIV are similarly associated with an increased incidence of EBV-induced lymphomas.
Inherited deficiencies in immune function have an indirect effect on cancer risk rather than directly targeting the cells destined to form tumors. Another type of indirect effect stems from hereditary differences in the liver enzymes that metabolize foreign chemicals. Some carcinogens must be metabolically activated by cytochrome P450 enzymes in the liver before they can trigger mutations and cancer.
Because of this requirement, inherited differences in liver enzymes may influence a person’s susceptibility to developing cancer. For example, cigarette smokers who inherit certain forms of cytochrome P450 have been found to exhibit higher lung cancer rates than those exhibited by other smokers.
Cancer Susceptibility:
High-risk mutations—that is, mutations responsible for the conspicuous clustering of cancer within families—account for no more than 5% of cancer cases overall. However, the role of heredity in determining cancer risk is not limited to high-risk mutations; it also includes the smaller contributions of many other genes. The individual effects of these small-risk genes are not strong enough to create obvious patterns of cancer inheritance, but as a group, their effects on cancer susceptibility can be significant.
Small-risk genes are difficult to identify because they do not create obvious family patterns of cancer inheritance. Identifying such genes is also complicated by the fact that cancer arises through an interaction between heredity and environment. With high-risk inherited mutations, the impact on cancer rates is so great that it overshadows environmental factors.
The effects of small- risk genes, on the other hand, are easily obscured by environmental or lifestyle conditions. For example, suppose a variant form of a gene were to exist that doubles a person’s risk of developing lung cancer.
In practice, it would be difficult to detect the existence of such an increase because differences in smoking behavior (or radon or asbestos exposure) have a much larger influence on lung cancer rates and would therefore tend to obscure the effects of the smaller-risk genetic factor.
Differences that have been observed in the cancer rates of various racial and ethnic groups illustrate how hard it can be to determine the exact role played by heredity. Consider, for example, the black and white populations of the United States, which exhibit several distinctive differences in cancer patterns.
One pattern that is easy to explain involves melanoma, a form of skin cancer whose incidence is about 15 times higher among whites than blacks. The explanation for this difference is quite straightforward. People with darkly pigmented skin produce large amounts of melanin, a pigment that absorbs ultraviolet radiation and thereby lowers sunlight-induced mutation rates in the skin.
Other racial differences in cancer rates are not as easily explained. For example, blacks living in the United States have higher cancer rates than whites for most common cancers, including colon, lung, and prostate cancers, although not breast cancer (Figure 11, left). In theory, such differences might be caused by subtle variations in small-risk cancer genes, but nonhereditary mechanisms are equally plausible.
One possibility that has received serious consideration is socioeconomic status. Figure 11 (right) illustrates the findings of a study that compared cancer rates by race for individuals of varying educational levels, which is an indicator of a person’s overall socioeconomic environment.
The data show that when cancer rates are compared among individuals with equivalent levels of education, blacks have similar (or even lower) cancer rates than whites. So rather than being related to genetic differences between racial groups, many of the disparities in cancer incidence observed among blacks and whites may be linked to socioeconomic variables. The risk factors associated with lower socioeconomic status that are most likely to affect cancer rates include exposure to tobacco and alcohol, poor nutrition, lack of physical activity, and obesity.
Genetic Testing for Cancer Predisposition:
The main focus of this essay has been on cancer tendencies that run in families. Of course, if several people in the same family develop cancer, it does not necessarily mean that heredity is responsible. Cancer is a common disease, and the presence of several cases of cancer in a single family may be a coincidence.
Shared lifestyle or environmental factors may also be responsible for the clustering of cancer cases within a family. Nonetheless, when people suspect that a genetic predisposition may be involved because cancer rates in their family are unusually high.
The answers to several questions can provide clues as to whether the condition is likely to be hereditary:
(1) Have several family members developed the same type of cancer without an obvious environmental or lifestyle explanation, such as smoking cigarettes?
(2) Are family members developing cancer during childhood or earlier in adulthood than is typical?
(3) Have individual family members developed multiple primary cancers of the same type or different types of cancer in succession?
If the preceding patterns exist, a variety of laboratory tests can be performed to analyze a person’s DNA for inherited mutations. Such genetic testing is currently available for almost all the cancer-susceptibility genes listed in Table 1, and additional tests are being developed at a rapid pace.
Before deciding to pursue genetic testing, it is important to understand the potential risks as well as benefits of testing (Table 2). To begin with, the failure to find a cancer-risk mutation only tells you about the gene for which the test is designed, and hence a different mutation could be present that is not detected by the procedures being used. Or, the test might detect a type of mutation that has not been seen before and is thus of uncertain significance. It is therefore important to be prepared for the possibility of ambiguous results.
If genetic testing does indicate the presence of a high- risk mutation, this discovery might produce significant fear and anxiety, and may also raise the possibility of discrimination by insurance companies or employers.
A strain on family relationships is possible because other family members might not welcome the news that a high- risk cancer gene runs in the family. Moreover, the ability to detect high-risk mutations is not always accompanied by effective medical strategies for treatment and prevention. Some people therefore risk being told that they have a high probability of developing cancer and that little can be done about it.
On the positive side, a benefit of genetic testing is that it ends uncertainty about a person’s status, especially if the individual is already worried because cancer seems to run in the family. A test that indicates that high-risk mutations are not present will be especially good news.
And for people who discover that they do carry a high-risk mutation, frequent and rigorous medical screening for early diagnosis and, where relevant, preventive therapies or behavioral changes may improve their chances of survival.
The results of a genetic test may also help clarify the risks for other family members and can reveal whether the possibility exists of passing on a high-risk cancer gene to one’s children.
In the end, deciding whether or not to pursue genetic testing is a personal choice that requires careful homework and a good understanding of your own psychological nature. If two people are confronted with the same exact set of circumstances, the use of genetic testing to peek into the crystal ball and predict the future may be an appropriate choice for one person and not for the other.