The majority of cancer-causing variants are somatic — they occur at some point after a person is born, and affect cells in the body other than sperm or egg cells. Somatic variants are not heritable and cannot be passed on through families.
A small proportion of the time, cancer develops due to inherited — or germline — variants. These variants are present in sperm or egg cells, and are passed on through families.
Germline variants tend to have large effects on cells, and usually cause people to be at a much higher risk of developing specific types of cancer than the general population. Germline variants often cause a cancer syndrome , meaning that they increase risk of more than one type of cancer, and sometimes non-cancerous conditions as well.
Variants that increase cancer risk are found in two main types of gene — proto-oncogenes and tumour suppressor genes. The usual function of proto-oncogenes is to make proteins that help cells grow and divide. Like all genes, proto-oncogenes can be switched on or off depending on how much of their particular product is required by the cell. Genetic variants can sometimes cause proto-oncogenes to be activated when they are not supposed to be, or even permanently switched on.
When this occurs, the proto-oncogene becomes an oncogene and can cause cancer. For example, the RET gene produces a signalling protein that is essential for the normal development of certain types of cells.
Growth factors — molecules that stimulate cell growth — bind to this signalling protein and trigger the cell to make certain changes, such as dividing or taking on a specific function differentiating.
Variants in the RET gene can cause it to be overactive and express protein constantly, even when the cell might not need it. This can trigger cells to grow and divide in an uncontrolled way, leading to cancer. The role of tumour suppressor genes is to control critical processes in the cell, like repair of damaged DNA, or regulation of when a cell should divide.
In this way, tumour suppressor genes prevent normal cells from becoming cancer cells. TP53 produces a protein, p53, that repairs damage to DNA throughout the body. In contrast with somatic mutations, germ-line mutations are passed on to an organism's progeny. As a result, future generations of organisms will carry the mutation in all of their cells both somatic and germ-line.
What kinds of mutations exist? Base substitution. Base substitutions are the simplest type of gene-level mutation, and they involve the swapping of one nucleotide for another during DNA replication. For example, during replication, a thymine nucleotide might be inserted in place of a guanine nucleotide. With base substitution mutations, only a single nucleotide within a gene sequence is changed, so only one codon is affected Figure 1.
Figure 1: Only a single codon in the gene sequence is changed in base substitution mutation. The nitrogenous bases are paired so that blue and orange nucleotides are complementary and red and green nucleotides are complementary. However, the 5 th nucleotide from the right on both the bottom and top strand form a mismatched pair: an orange nucleotide pairs with a red nucleotide.
This mismatched pair is highlighted in cyan. The sugar molecules of each individual nucleotide in the chain are connected to adjacent sugar molecules, which are represented by gray horizontal cylinders.
The nitrogenous bases hang down from the sugar molecules and look like vertical bars that are twice as long and half as wide as the gray cylinders; the bases are either blue, red, green, or orange. A second chain of 12 nucleotides forms the second DNA strand below the upper template strand; this strand is labeled the replicating strand in the lower right. Here, the nitrogenous bases point upward from the sugar-phosphate chain, nearly meeting the ends of the nitrogenous bases from the upper strand.
Because there are only 12 nucleotides in the lower strand and 16 nucleotides in the upper strand, four nucleotides on the left side of the upper strand are not bound to a complementary nucleotide on the lower strand. A 13 th nucleotide is shown joining the left end of the lower replicating strand. Although a base substitution alters only a single codon in a gene, it can still have a significant impact on protein production.
In fact, depending on the nature of the codon change, base substitutions can lead to three different subcategories of mutations. The first of these subcategories consists of missense mutations , in which the altered codon leads to insertion of an incorrect amino acid into a protein molecule during translation; the second consists of nonsense mutations , in which the altered codon prematurely terminates synthesis of a protein molecule; and the third consists of silent mutations , in which the altered codon codes for the same amino acid as the unaltered codon.
Insertions and deletions. A second chain of 13 nucleotides forms the second DNA strand below the upper template strand; this strand is labeled the replicating strand in the lower right. The sixth nucleotide from right to left has slipped out of place, causing a bulge in the DNA strand. The presence of this bulge causes a misalignment of nucleotide pairs; therefore, an extra nucleotide has been added to complete the remaining DNA strand with correct base pairs.
This extra nucleotide in position 8 from the right has a cyan aura around it. A 14 th nucleotide is shown joining the left end of the lower replicating strand. Figure 3: In a deletion mutation, a wrinkle forms on the DNA template strand, which causes a nucleotide to be omitted from the replicated strand.
A second chain of eight nucleotides forms the second DNA strand below the first strand. The nucleotide that should have paired with nucleotide 7 on the upper strand has been left out of the replicating bottom strand, causing a bulge in the upper strand.
As a result, upper nucleotides 6, 7, and 8 do not align with a complementary nucleotide on the lower strand. The nucleotides in the bottom strand that would have aligned with upper nucleotides 6 and 8 have a cyan aura around them.
Because there are only eight nucleotides in the lower strand and 13 nucleotides in the upper strand, several nucleotides on the left side of the upper strand are not bound to a complementary nucleotide on the lower strand. One additional free-floating nucleotide is about to be added to the growing bottom strand.
Frameshift mutations. Figure 4: If the number of bases removed or inserted from a segment of DNA is not a multiple of three a , a different sequence with a different set of reading frames is transcribed to mRNA b. The nitrogenous bases hang down from the sugar molecules and look like vertical bars that are twice as long and half as wide as the gray cylinders; the bases are blue, red, green, or orange.
A second chain of 12 nucleotides forms the lower DNA strand, labeled the replicating strand in the lower right. The first, fifth, tenth, and fifteenth nucleotides from left to right are absent in the replicating strand. The effect of the missing nucleotides is illustrated in panel B. The intended sequence of the replicating strand is shown color-coded below the template strand sequence. Researchers have used fatty nanoparticles to carry Crispr-Cas9 molecules to the liver, and tiny zaps of electricity to open pores in embryos through which gene editing molecules can enter.
Does it have to be done in the body? When the virus enters the body, it infects and kills immune cells. But to infect the cells in the first place, HIV must first latch on to specific proteins on the surface of the immune cells. Without the proteins, the HIV virus can no longer gain entry to the cells. Having edited the cells to make them cancer-killers, scientists grow masses of them in the lab and infuse them back into the patient. The beauty of modifying cells outside the body is that they can be checked before they are put back to ensure the editing process has not gone awry.
What can go wrong? Modern gene editing is quite precise but it is not perfect. The procedure can be a bit hit and miss, reaching some cells but not others. Even when Crispr gets where it is needed, the edits can differ from cell to cell, for example mending two copies of a mutated gene in one cell, but only one copy in another.
For some genetic diseases this may not matter, but it may if a single mutated gene causes the disorder. Another common problem happens when edits are made at the wrong place in the genome. Will it lead to designer babies? The overwhelming effort in medicine is aimed at mending faulty genes in children and adults. But a handful of studies have shown it should be possible to fix dangerous mutations in embryos too.
In , scientists convened by the US National Academy of Sciences and the National Academy of Medicine cautiously endorsed gene editing in human embryos to prevent the most serious diseases, but only once shown to be safe. Any edits made in embryos will affect all of the cells in the person and will be passed on to their children, so it is crucial to avoid harmful mistakes and side effects.
Engineering human embryos also raises the uneasy prospect of designer babies, where embryos are altered for social rather than medical reasons; to make a person taller or more intelligent, for example. Traits like these can involve thousands of genes, most of them unknown.
So for the time being, designer babies are a distant prospect. However, the mutation would not be passed on to your future offspring, if you had a baby later. Sunlight is one thing that can cause mutations. How does sunlight affect our DNA? Sunlight creates structures called thymine dimers , which means that two thymine T bases T on the same DNA strand become connected in an abnormal way, instead of correctly attaching to the complementary base adenine A on the opposite strand.
Thymine dimers create kinks in the DNA shape see Figure 3 [ 2 ]. These kinks make DNA difficult to copy, which can cause a mutation. In order to avoid thymine dimers from developing in our cells, it is very important to use sunscreen to help block ultraviolet A and B UVA and UVB rays.
Sunscreen should be reapplied every 2 h or after swimming, sweating, bathing, or using a towel [ 4 ]. Some individuals who have especially sensitive or light skin should consider higher levels of UV protection and are encouraged to consult a doctor called a dermatologist, who is an expert on keeping skin healthy.
X-ray radiation is the kind used in X-rays medical images taken of teeth, bones, and other hard body parts. X-ray radiation has a very high energy level that can create molecules called free radicals. Free radicals are very unstable, and to become more stable, they can steal electrons from DNA, which can lead to mutations [ 5 ]. We can reduce exposure to X-ray radiation by using other forms of medical images when possible and wearing protective equipment to protect the body when x-rays are taken.
If you have ever gone to the dentist and had an X-ray of your teeth, you probably remember having a heavy lead apron draped over your body. The lead apron protects the parts of the body that the dentist is not taking pictures of.
Getting X-rays only when necessary is a good practice to prevent any excessive negative effects on your DNA see Table 1 [ 5 ]. This is why X-rays are not taken if a doctor is fairly sure a patient has sprained, not broken, an ankle.
How does smoking lead to cancer? Cigarettes and tobacco products contain chemicals referred to as carcinogens , which are mutagens that are also known to cause cancer. All cancer cells have DNA mutations, and it is the carcinogens that cause the mutations.
Carcinogens cause mutations by damaging the way the cell repairs DNA or makes proteins. If the cancer cell is not able to repair this DNA damage, then it will keep dividing to make new cells and will pass the mutation on to all the new cells that are made.
Because cancer cells grow and divide faster than normal cells, masses of these abnormal cells, called tumors, can form. The best way to avoid these carcinogens is not to smoke or use tobacco products see Table 1.
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