The difference between hereditary (germline) and acquired (somatic) gene mutations in cancer can lead to much confusion. This is especially true if you’re hearing about genetic testing for a genetic predisposition to cancer at the same time you hear about genetic testing for mutations that may be treatable in a cancer already present.
Somatic mutations are those that are acquired in the process of a cancer forming, and are not present at birth. They cannot be passed down to children and are present only in the cells affected by cancer. Targeted therapies are now available for many gene mutations found in tumors that can often control the growth of the cancer (at least for a period of time).
Germline mutations, in contrast, are inherited from a mother or father and increase the chance a person will develop cancer. That said, there is overlap between the two that adds further confusion. We will take a look at exactly what a gene mutation is, characteristics of hereditary and acquired mutations, and give examples you may be familiar with.
Gene Mutations and Cancer
Gene mutations are important in the development of cancer as it is the accumulation of mutations (DNA damage) that results in the formation of cancer. Genes are segments of DNA, and these segments, in turn, are the blueprint for the production of proteins.
Not all gene mutations raise the risk of developing cancer, but rather it is mutations in genes responsible for the growth of cells (driver mutations) that can lead to development of the disease. Some mutations are harmful, some do not cause any changes, and some are actually beneficial.
Genes can be damaged in a number of ways. The bases that make up the backbone of DNA (adenine, guanine, cytosine, and thymine) are the code that is interpreted. Each three base sequence is associated with a particular amino acid. Proteins, in turn, are formed by chains of amino acids.
Simplistically, mutations may involve the substitution, deletion, addition, or rearrangement of base pairs. In some cases, parts of two chromosomes may be interchanged (translocation).
Types of Gene Mutations and Cancer
There are two primary types of genes involved in cancer development:
Oncogenes: Protooncogenes are genes that are normally present in the body that code for the growth of cells, with most of these genes being “active” primarily during development. When mutated, protooncogenes are converted to oncogenes, genes that code for proteins that drive the growth of cells later in life when they would ordinarily be dormant. An example of an oncogene is the HER2 gene that is present in greatly increased numbers in roughly 25% of breast cancer tumors as well as some lung cancer tumors.
Tumor suppressor genes: Tumor suppressor genes code for proteins that essentially have an anti-cancer effect. When genes are damaged (see below), these proteins may either repair the damage or lead to death of the damaged cell (so that it can’t continue to grow and become a malignant tumor). Not everyone who is exposed to carcinogens will develop cancer, and the presence of tumor suppressor genes is part of the reason why this is the case. Examples of tumor suppressor genes include BRCA genes and the p53 gene.
It is usually (but not always) a combination of mutations in oncogenes and tumor suppressor genes that leads to the development of cancer.
How Gene Mutations Occur
Genes and chromosomes can be damaged in a number of different ways. They may be damaged directly, such as with radiation, or indirectly. Substances that can cause these mutations are referred to as carcinogens.
While carcinogens may cause mutations that begin the process of cancer formation (induction), other substances that aren’t carcinogenic themselves may lead to progression (promoters). An example is the role of nicotine in cancer. Nicotine alone does not appear to be an inducer of cancer, but may promote the development of cancer following exposure to other carcinogens.
Mutations also occur commonly due to the normal growth and metabolism of the body. Every time a cell divides there is a chance that an error will occur.
There are also non-structural changes that appear to be important in cancer. The field of epigenetics looks at changes in the expression of genes that aren’t related to structural changes (such as DNA methylation, histone modification, and RNA interference). In this case, the “letters” that make up the code that is interpreted is unchanged, but the gene may be essentially turned on or off. An encouraging point that has risen from these studies is that epigenetic changes (in contrast to structural changes) in DNA may sometimes be reversible.
As the science of cancer genomics advances, it’s likely we will learn much more about the particular carcinogens that lead to cancer. Already, the “genetic signature” of a tumor has been found in some cases to suggest a particular risk factor. For example, certain mutations are more common in people who smoke who develop lung cancer, while other mutations are often seen in never smokers who develop the disease.
Somatic (Acquired) Gene Mutations in Cancer
Somatic gene mutations are those that are acquired after birth (or at least after conception as some may occur during the development of the fetus in the uterus). They are present only in the cells that become a malignant tumor and not all the tissues of the body. Somatic mutations that occur early in development may affect more cells (mosaicism).
Somatic mutations are often referred to as driver mutations as they drive the growth of a cancer. In recent years, a number of medications have been developed that target these mutations to control the growth of a cancer. When a somatic mutation is detected for which a targeted therapy has been developed, it is referred to as an actionable mutation. The field of medicine known as precision medicine is a result of medications such as this that are designed for specific gene mutations in cancer cells.
You may hear the term “genomic alterations” when talking about these therapies as not all changes are mutations per se. For example, some genetic changes consist of rearrangements and more.
A few examples of genomic changes in cancer include:
- EGFR mutations, ALK rearrangements, ROS1 rearrangements, MET, and RET in lung cancer
- BRAF mutations in melanoma (also found in some lung cancers)
Germline (Hereditary) Gene Mutations in Cancer
Germline mutations are those that are inherited from a mother or father and are present at the time of conception. The term “germline” is due to the mutations being present in eggs and sperm which are called “germ cells.” These mutations are in all cells of the body and remain throughout life.
Sometimes a mutation occurs at the time of conception (sporadic mutations) such that it is not inherited from a mother or father but can be passed down to offspring.
Germline mutations may be “dominant” or “recessive”. In autosomal dominant diseases, one parent has a normal copy of the gene and a mutated copy; there is a 50-50 chance a child will inherit the mutation and be at risk for the disease. In autosomal recessive diseases, two copies of the mutated gene are required to cause the disease. Each parent has one normal gene and one mutated gene; only one in four children will inherit the mutated gene from both parents and therefore be at risk of the disease.
Germline mutations also vary in their “penetrance.” Gene penetrance refers to the proportion of people who carry a particular variant of a gene who will express the “trait.” Not everyone who carries a BRCA mutation or one of the other gene mutations that raise breast cancer risk develops breast cancer due to “incomplete penetrance.”
In addition to differences in penetrance with a specific gene mutation, there is also a difference in penetrance across gene mutations that raise the risk of cancer. With some mutations, the risk of cancer may be 80%, whereas with others, the risk may be increased only slightly.
High and low penetrance is easier to understand if you think about the function of a gene. A gene usually codes for a specific protein. The protein that results from an abnormal “recipe” may be only slightly less effective at doing its job, or may be completely unable to do its job.
A specific type of gene mutation such as BRCA2 mutations may raise the risk of a number of different cancers. (There are actually many ways in which the BRCA2 gene can be mutated.)
When cancers develop due to germline mutations they are considered hereditary cancers, and germline mutations are thought to be responsible for 5% to 20% of cancers.
The term “familial cancer” may be used when a person has a known genetic mutation that increases risk, or when a mutation or other change is suspected based on clustering of cancers in the family, but current testing is unable to identify a mutation. The science surrounding the genetics of cancer is expanding rapidly, but in many ways still in its infancy. It’s likely that our understanding of hereditary/familial cancer will increase significantly in the near future.
Genome-wide association studies (GWAS) may also be revealing. In some cases, it may be a combination of genes, including genes that are present in a significant proportion of the population, that confers an increased risk. GWAS look at the entire genome of people with a trait (such as cancer) and compare that to people without the trait (such as cancer) to look for differences in DNA (single nucleotide polymorphisms). Already, these studies have found that a condition previously thought to be largely environmental (age onset macular degeneration) actually has a very strong genetic component.
Overlap and Confusion
There can be overlap between hereditary and acquired mutations, and this can lead to considerable confusion.
Specific Mutations May Be Somatic or Germline
Some gene mutations can be either hereditary or acquired. For example, most p53 gene mutations are somatic, or develop during adulthood. Much less commonly, p53 mutations can be inherited, and give rise to a syndrome known as Li-Fraumeni syndrome.
Not All Targetable Mutations are Somatic (Acquired)
EGFR mutations with lung cancer are usually somatic mutations acquired in the process of the cancer developing. Some people treated with EGFR inhibitors develop a resistance mutation known as T790M. This “secondary” mutation allows the cancer cells to bypass the blocked pathway and grow again.
When T790M mutations are found in people who have not been treated with EGFR inhibitors, however, they could represent germline mutations, and people who have germline T790M mutations and have never smoked are more likely to develop lung cancer than those without the mutation who have smoked.
Effect of Germline Mutations on Treatment
Even when somatic mutations are present in a tumor, the presence of germline mutations can affect treatment. For example, some treatments (PARP inhibitors) may have relatively little use among people with metastatic cancer in general, but may be effective in those who have BRCA mutations.
Interaction of Hereditary and Somatic Gene Mutations
Adding further confusion, it’s thought that hereditary and somatic gene mutations may interact in the development of cancer (carcinogenesis) as well as progression.
Genetic Testing vs. Genomic Testing With Breast Cancer
Genetic testing in the setting of breast cancer has been particularly confusing, and is now sometimes referred to as either genetic testing (when looking for hereditary mutations) or genomic testing (when looking for acquired mutations, such as determining if particular mutations are present in a breast tumor that increase the risk of recurrence, and would therefore suggest that chemotherapy should be given).
A Word From Get Meds Info
Learning about the differences between hereditary and acquired gene mutations is confusing but very important. If you have a loved one who has been told they have a gene mutation in a tumor, you may be frightened that you could also be at risk. It’s helpful to know that the majority of these mutations are not hereditary and therefore do not raise your risk. On the other hand, having an awareness of germline mutations allows people the opportunity to have genetic testing when appropriate. In some cases, actions can then be taken to reduce the risk. People who have a germline mutation and hope to reduce their risk of developing cancer are now referred to as previvors (surviving a PRE disposition to cancer).