15 Cancer and the Cell Cycle

Cancer is a collective name for many different diseases caused by a common mechanism: uncontrolled cell division. Despite the redundancy and overlapping levels of cell-cycle control, errors occur. One of the critical processes monitored by the cell-cycle checkpoint surveillance mechanism is the proper replication of DNA during the S phase. Even when all of the cell-cycle controls are fully functional, a small percentage of replication errors (mutations) will be passed on to the daughter cells. If one of these changes to the DNA nucleotide sequence occurs within a gene, a gene mutation results. All cancers begin when a gene mutation gives rise to a faulty protein that participates in the process of cell reproduction. The change in the cell that results from the malformed protein may be minor. Even minor mistakes, however, may allow subsequent mistakes to occur more readily. Over and over, small, uncorrected errors are passed from parent cell to daughter cells and accumulate as each generation of cells produces more non-functional proteins from uncorrected DNA damage. Eventually, the pace of the cell cycle speeds up as the effectiveness of the control and repair mechanisms decreases. Uncontrolled growth of the mutated cells outpaces the growth of normal cells in the area, and a tumor can result.

In general, cancers result from an accumulation of DNA mutations. These mutations can result in cell populations that do not die when they should and uncontrolled cell proliferation that leads to tumors. Although many tumors are benign (harmless), some produce cells that can mobilize and establish tumors in other organs of the body; this process is referred to as metastasis. Cancers are characterized by their ability to metastasize.

Tumor Suppressor Genes

Like proto-oncogenes, many of the negative cell-cycle regulatory proteins were discovered in cells that had become cancerous. Tumor suppressor genes are genes that code for the negative regulator proteins, the type of regulator that—when activated—can prevent the cell from undergoing uncontrolled division. The collective function of the best-understood tumor suppressor gene proteins, retinoblastoma protein (RB1), p53, and p21, is to put up a roadblock to cell-cycle progress until certain events are completed. A cell that carries a mutated form of a negative regulator might not be able to halt the cell cycle if there is a problem.

Mutated p53 genes have been identified in more than half of all human tumor cells. This discovery is not surprising in light of the multiple roles that the p53 protein plays at the G₁ checkpoint. The p53 protein activates other genes whose products halt the cell cycle (allowing time for DNA repair), activates genes whose products participate in DNA repair, or activates genes that initiate cell death when DNA damage cannot be repaired. A damaged p53 gene can result in the cell behaving as if there are no mutations (Figure 1). This allows cells to divide, propagating the mutation in daughter cells and allowing the accumulation of new mutations. In addition, the damaged version of p53 found in cancer cells cannot trigger cell death.

 

Understanding and Assessing Cancer Risk

So far we have described cancer mutations as errors that arise in body cells during the lifetime of an individual. These are called somatic mutations, and they are not passed to offspring. But a person can also inherit a mutated copy of a cell-cycle gene from a parent. Mutations carried in egg and sperm cells, and therefore present in every cell of the offspring from the moment of fertilization, are called germline mutations. The two kinds of mutation raise cancer risk in different ways, and separating them is the first step in understanding why some people develop cancer and others do not.

Somatic mutations come from two sources. Some are copying errors made during DNA replication, which happens every time a cell divides. Others are caused by mutagens, external agents such as radiation, chemicals, and free radicals that damage DNA. A mutagen is defined by what it does to DNA. A carcinogen is any agent that directly increases the incidence of cancer. Most, but not all carcinogens are mutagens. Carcinogens that do not directly damage DNA include substances that accelerate cell division, thereby leaving less opportunity for cell to repair induced mutations, or errors in replication. Carcinogens that act as mutagens may be biological, physical, or chemical in nature, although the term is most often used in relation to chemical substances.

Tobacco and tobacco smoke together contain more than 9,500 identified compounds, of which 83 have been classified as carcinogens by the International Agency for Research on Cancer. Of the 83 carcinogens found in cigarette smoke, a major one is benzo[a]pyrene (BaP). BaP binds directly to DNA bases and can lead to permanent mutations. One study found that a person who smokes one pack a day for one year accumulates an estimated 150 additional mutations in each lung cell, along with roughly 97 in each cell of the larynx, 23 in the mouth, and 18 in the bladder. Added to its direct impact on DNA, BaP has also been found to indirectly increase the risk of cancers caused by human papillomavirus (HPV) by increasing the production of the virus.

Notice that the paragraph above answers a question about mechanism: how a carcinogen acts to cause cancer at a molecular and cellular level. This is different from stating whether a carcinogen will cause cancer in an individual. That is a question about risk, and risk is measured across populations rather than in cells. Roughly nine out of ten lung cancer deaths in the United States are attributable to smoking or secondhand smoke exposure, yet many people who smoke never develop lung cancer. Both statements are true at once. Mutations accumulate with every exposure, but whether any of them lands in a cell-cycle gene, in a cell that keeps dividing, and escapes repair is a matter of chance. More exposure means more chances. This is also why risk falls when exposure stops: ten to fifteen years after a person quits smoking, their lung cancer risk drops by about half.

This distinction is worth holding onto. A risk factor is something that shifts the probability of a disease in a population. Smoking is a risk factor for developing lung cancer, but as mentioned, not every smoker develops lung cancer, and not every lung cancer case is the result of smoking. Understanding mechanisms allows us to understand risk and to develop treatments.

Germline mutations change risk in a different way. Instead of accumulating over a lifetime of exposure, an inherited mutation is present in every cell from birth.

BRCA1 is a well-known example. Like p53 mentioned above, BRCA1 is a tumor suppressor gene. Its protein product helps repair broken DNA, and a cell that cannot repair damage accumulates further mutations. The set of alleles an individual carries for a gene is that individual’s genotype. The observable traits that result, including whether a disease develops, make up that individual’s phenotype.

A person who inherits one non-functional BRCA1 allele has a different genotype from a person who inherits two functional copies. But that genotype does not, by itself, produce cancer. The remaining functional copy still makes working protein, and the cell cycle stays under control. Cancer becomes possible only when that copy is also lost, through a somatic mutation in some cell at some point during the person’s life. Lifetime breast cancer risk for these individuals is estimated at roughly 55-72%, compared with about 13% in the general population. Significantly higher, but not certain.

So genotype does not always map directly onto phenotype. Rather, one’s genotype can influence one’s phenotype, along with chance, environment, and the interaction with other genes. An inherited BRCA1 mutation and a pack-a-day smoking habit change cancer risk through the same underlying mechanism, the accumulation of mutations in genes that control cell division, but one is written into the genome at fertilization, and the other is acquired one exposure at a time. We will return to how alleles like non-functional BRCA1 are passed from parent to offspring in the chapters on meiosis and inheritance, and to how genes interact with each other and with the environment in the chapter on the genetics of phenotypic variation.

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