Personalized Cancer Treatment

The Role of Genes in Cancer

Genes play a key role in the development of cancer, and genetic testing can be a valuable tool in the detection and treatment of the disease. Genetic testing for cancer falls into two groups: testing for inherited genetic mutations (abnormalities) and testing to identify and measure the presence of genetic mutations in tumors. Both types of testing give your doctor more information about your tumor and allow him or her to consider personalized options for your care. This section focuses on genetic testing for hereditary mutations; the next section addresses testing for genetic mutations. First, some background information on genes and the two types of genetic mutations – acquired and hereditary – will help you better understand how genes are involved in the development of cancer.

Genes: The basics

Each person has about 25,000 genes, which live in the nucleus (or center) of every cell in the human body. Genes are made up of a small piece of DNA (deoxyribonucleic acid), the most basic building block for all living things. A DNA molecule is made of two strands that wind around each other to form a shape known as a double helix. This double helix is similar to a spiral staircase, and each “step” is formed by a pair of chemicals, also known as bases. A gene is made up of a sequence of these paired bases along the DNA strand (Figure 1).

The specific DNA sequence in a gene provides a code for instructions on how to make a specific protein. Genes send these instructions to a molecule called messenger ribonucleic acid (mRNA). This molecule is similar to DNA, except that it is made of just one strand. It carries the instructions outside of the nucleus to other parts of the cell, where proteins are built. Proteins in the body send signals along pathways that control how cells grow and divide and how long they live. These pathways are called signaling pathways, and as researchers have discovered more about how these pathways work, they have been able to develop more effective cancer treatments. 

Genes are grouped together in specific sequences on chromosomes, and this forms the “blueprint” for the physical and biologic traits unique to every person. The entire set of genetic instructions in a cell is called a genome. In humans, the genome consists of 23 pairs of chromosomes, which together contain more than three billion bases of DNA sequence. The Human Genome Project, a 13-year undertaking to map the entire sequence of human DNA, led to the discovery of more than 1,800 genes associated with various diseases and has enabled researchers to develop approximately 2,000 genetic tests for human disorders. 

Genetic mutations

Genes can become mutated, or abnormal, if the sequence of DNA is changed in some way. A change in the gene’s DNA sequence usually causes the protein it helped to build to either not function normally or not function at all.

As a result, the growth, division or survival of cells may be abnormal. Changes in DNA sequences occur often, mostly during cell division, but DNA can fix these errors. Sometimes, however, the repair method fails, and the genetic mutation is passed on to future copies of the changed cell.

The most common types of mutations in cancer involve four abnormalities:

  • AMPLIFICATION: An increase in the number of copies of a specific fragment (section) of DNA
  • DELETION: The loss of genetic material, ranging from small (a single missing DNA base pair) to large (a piece of a chromosome)
  • INACTIVATION: Loss of the biologic function of the gene
  • TRANSLOCATION: A broken chromosome reattaches to a different chromosome

Genetic mutations may be either acquired or hereditary.

Acquired mutations

Acquired mutations occur when a mistake is made as DNA copies itself during cell division at some time during a person’s lifetime (after birth). Researchers have found more than 120 acquired genetic mutations that drive the development of cancer. Cancers that develop from acquired mutations are known as sporadic cancers, and this type of cancer accounts for 90 to 95 percent of all cancers.

For many sporadic cancers, a genetic mutation may occur because of a factor in the environment, such as exposure to chemicals, tobacco smoke or a virus. Because of this, some people wonder if their cancer resulted from something they did wrong. However, remaining cancer-free over your lifetime is actually an amazing feat. It has been estimated that to live 80 years without cancer requires as many as 10 million billion cells in your body to copy themselves correctly—or requires that any abnormal cells that are produced die off.

Hereditary mutations

Each cell of your body contains 23 pairs of chromosomes. One chromosome in each pair is inherited from your mother and one is from your father. Inherited traits, such as eye and hair color, are passed from parent to child by genes and are present in virtually every cell in the body. Cancer itself cannot be inherited, but a higher risk for cancer can be inherited.

Hereditary mutations are the cause of about 5 to 10 percent of all cancers. Breast and ovarian cancer, colorectal cancer, kidney cancer, thyroid cancer and melanoma have the strongest hereditary links (Table 1, Page 4). An inherited susceptibility (or higher risk) for cancer can be different than a family history of cancer. For example, family history is a risk factor for prostate cancer, but no inherited genetic mutation has been found yet. The increased risk for a hereditary cancer varies according to the hereditary cancer syndrome, and the risk is often increased for other types of cancer as well.

Table 1. Cancers with strong hereditary links

Type of cancer Major gene(s) Risk of developing cancer
(Risk in general population)
Risk for other cancers
Breast and ovarian cancer syndrome BRCA1 and BRCA2
Breast cancer: 50% to 85% (12%)
Ovarian cancer: 15% to 40% (1.4%)
Colorectal Cancer      
  polyposis (FAP)
APC Amost 100% (6%)
Small bowel cancer: 4 to 12%
Pancreatic cancer: 2%
Papillary thyroid cancer: 2%
   colorectal cancer
  (Lynch Syndrome)
80% (6%)
Endometrial cancer: 20 to 60%
Gastric (stomach) cancer: 11 to 19%
Ovarian cancer: 9 to 12%
Urinary tract: 4 to 5%
Kidney (renal) cancer (clear cell) VHL 40% (less than 1%)  
Medullary thyroid cancer (familial)* RET 95% to 100% (less than 1%)  
Melanoma† CDKN2A 70% (2%) Pancreatic cancer: up to 17%

* Associated with multiple endocrine neoplasia (MEN) 2 syndrome.
† Genetic testing not recommended outside of a research study.

Genetic testing and counseling for hereditary cancer syndromes

Genetic testing can be done to determine if a person has an inherited genetic mutation that increases the risk of a particular cancer. Because inherited cancers account for only a small percentage of all cancers, genetic testing is not right for everyone. In addition, genetic testing for some cancers is not recommended because the results are not yet well understood.

The decision about whether to have genetic testing depends on an individual’s personal and/or family history. Several “red flags” are strong signs that you should talk to your health care provider about genetic testing (see box). Genetic testing is easy and convenient; a blood sample is drawn through a needle inserted in your arm, and the sample is analyzed for the suspected genetic mutation.

Genetic testing can be expensive, however, and the costs vary depending on the type and complexity of the test. Be sure to check with your health insurance carrier to understand what costs your plan will cover.

Red flags for the possibility of hereditary cancer

Several factors may be red flags, or signs that hereditary cancer is likely. If you answer yes to any of the questions associated with these red flags, talk to your doctor or other member of your health care team about genetic testing for hereditary cancer.

Red flag Question to ask yourself
Early age at time of cancer diagnosis Was I younger than 50 when cancer was diagnosed?
Multiple cancers in one individual Have I been diagnosed with more than one primary cancer?
Multiple family members with the same type of cancer Do I have more than one family member who has been diagnosed with the same type or related types of cancer? (Examples of related types of cancer are breast and ovarian cancer, colorectal and endometrial cancer, and melanoma and pancreatic cancer.)
Identification of gene mutation in family member Do I have a family member who has been found to have a genetic mutation associated with hereditary cancer?

Genetic Counseling

Genetic counseling should always be done before genetic testing. A genetic counselor evaluates your family history to see how likely it is that you have a hereditary genetic mutation. Based on this information, the counselor will then recommend for or against testing.

Genetic counselors are health care professionals with special experience in counseling and medical genetics. These counselors identify which genes should be tested and will help you better understand your risk for cancer, how genetic testing will affect you and your family, and what options are available to reduce your risk of cancer if a genetic mutation is found. Counseling and testing must be ordered by a doctor or other health care provider. If you are concerned about your risk of an inherited cancer, talk to your doctor about your family history of cancer and the potential benefits of testing. You may also want to talk to family members before being tested to hear their feelings about the test and its results, as it may affect them.

If you decide to have genetic testing done, you will be asked to sign an informed consent form that gives your written permission for the testing. The consent form should cover information about:

  • The purpose of the genetic test and reason for offering the test
  • The type and nature of the genetic condition for which testing is to be done
  • The pros and cons of testing and test accuracy
  • Other testing options available to you
  • Potential treatment options based on test results
  • Potential decisions that may need to be made once test results are back
  • Availability of counseling and support services
  • Your right to refuse testing

Counseling is also important once you receive your test results so that you learn what the results mean and what your options are. Although home-based genetic tests are available, experts recommend genetic testing done through your doctor or health care team. However, if you are considering an at-home testing kit, talk to a genetic counselor first to help you determine if the specific test is right for you as well as its pros, cons and limitations. In addition, you may not be able to understand the results without professional help.

Sharing Genetic Information

The results of genetic testing may also have an impact on other family members, so think about how you may share the results before you complete the testing. Sharing genetic information is important because there is a 50-percent chance that the mutation will be present in a first-degree relative (a sibling, child or parent), and it may be appropriate for some family members to also pursue genetic testing. Testing is not done on children unless the hereditary cancer can occur at a young age, such as familial adenomatous polyposis (FAP), multiple endocrine neoplasia 2 (MEN2) and von Hippel-Lindau syndrome. If a genetic mutation is found, the health care provider will strongly encourage that person to share the results of the genetic testing with family members.

Benefits of Genetic Testing

Genetic testing is not for everyone, and testing has benefits as well as drawbacks (Table 2). Knowing about an inherited genetic mutation can help you and your doctor personalize your cancer management. This may include earlier or more regular screenings to detect cancer at an earlier stage, when treatment is most effective, or other preventive measures, such as lifestyle modifications or preventive surgery. Even a negative test result is useful: Knowing that there is no genetic mutation can relieve stress and lessen the need for frequent follow-up visits and screenings.

Genetic testing can also help people who have already been diagnosed with cancer. Finding an inherited mutation may lead to a decision to have more extensive surgery to help prevent the risk of a second cancer. In addition, studies have shown that some hereditary cancers have distinct features that may make some treatments more effective than others.

Table 2. Benefits and Limitations of Genetic Testing

Benefits Limitations
Indicate an inherited disposition to a certain disease before symptoms begin. Only 5 to 10 percent of cancers are hereditary.
Measure the risk of developing a disease and indicate whether it can be prevented or treated. Some genetic mutations may not be detected, and many cancers cannot be tied to a certain gene.
Diagnose a disease in a person with symptoms and help assess the prognosis (outlook). A positive test doesn’t always mean that the cancer will develop, nor does a negative test guarantee that a cancer will not develop.
Provide a sense of relief if your results are negative and there is a high risk of cancer in the family. Tests results may be uncertain.
Help a person make life decisions, such as career choice, family planning and insurance coverage. Confirmation of a high risk of cancer can have a serious psychological impact.
Result in more aggressive treatment, if an inherited mutation is found, which may help prevent development of the disease. The accuracy of genetic tests varies with the condition being tested.

Privacy and Confidentiality

Because genetic testing provides a great deal of personal health information, you may be concerned about the privacy of the results. The Genetic Information Nondiscrimination Act (GINA) became a law in May 2009 for insurers and in November 2009 for employers with more than 15 employees. GINA prohibits discrimination by employers and health insurers on the basis of a person’s own genetic tests, genetic tests of family members, or one or more family members known to have a genetic disease or disorder.

Testing for genetic alterations in nonhereditary cancers

Testing can also be done to see if genetic alterations are present in nonhereditary cancers. These alterations act as genetic biomarkers and can be beneficial in guiding treatment decisions. A genetic biomarker is sometimes referred to as a pharmacogenetic marker because it affects the response or resistance to a drug.

One of the most well-known examples of a genetic biomarker – the HER2 gene – is found in the treatment of breast cancer. The development of drugs designed to attack tumors with a higher level of this gene changed the treatment of that disease. In fact, genetic biomarkers have been found for several types of cancer, including breast, colorectal and non-small cell lung cancers; melanoma; some types of leukemia and lymphomas; and gastrointestinal stromal tumors (Table 3).

Table 3. Some genetic alterations used as biomarkers to guide treatment

Gene Genetic mutation Type of cancer Use
ABL, BCR Translocation Chronic myeloid leukemia
▪ Aids in diagnosis and guides treatment decisions
▪ Testing done routinely, as it is associated with
  response to specific targeted therapy
▪ Found in almost all patients
BRAF Mutation Melanoma
▪ May help to determine response to targeted therapy
▪ Testing should be done for people with malignant
EGFR Mutation, amplification Non-small cell lung cancer
▪ Helps guide treatment decisions, as it determines
  response to some targeted therapy
▪ Routine testing has started in many cancer centers
▪ Found in up to 35% of adenocarcinoma patients
EML4-ALK Translocation Non-small cell lung cancer
▪ Found in about 3 to 5% of patients
▪ Helps guide treatment decisions, as it determines
  response to some targeted therapy
HER2 Amplification Breast cancer
▪ Guides treatment decisions, as appropriate treatment
  depends on results
▪ Routine testing highly recommended
▪ Found in about 20% of patients
KIT Mutation Gastrointestinal stromal tumor (GIST)
▪ Aids in diagnosis and guides treatment decisions
▪ Testing recommended
▪ Found in about 95% of patients
KRAS Mutation Colorectal cancer

Non-small cell lung cancer
▪ Helps guide treatment decisions, as it is associated
  with lack of response to some targeted therapies
▪ Testing recommended
▪ Found in about 40% of patients

▪ Helps guide treatment decisions, as it is associated
  with lack of response to some targeted therapies
▪ Testing recommended
▪ Found in about 25% of patients
MMR Mutation Colorectal cancer
▪ Helps guide treatment decisions, as it is associated
  with good prognosis
▪ Testing recommended for some patients
▪ Found in about 15 to 20% of sporadic colon cancer

Words to know

Chromosomes Strands of DNA with specific sequences of genes; each cell has 23 pairs of chromosomes
DNA (deoxyribonucleic acid) Molecule in a cell that holds genetic information; basic building block of all living things
Genes Segments of DNA that carry instructions for making proteins
Genome Complete genetic material of an individual
Genomics Study of the entire genome of a person (or other living thing)
Hereditary Passed from parents to children through genes
Mutation Alteration in the DNA of a gene that affects its function
Proteins Chemicals that control activities in the cell and functions of the body; proteins make up body structures such as tissues and organs
RNA (ribonucleic acid) A molecule similar to DNA but consists of just one strand; messenger RNA (mRNA) carries instructions from DNA to other parts of a cell to help build proteins
Somatic Acquired after birth (rather than inherited)

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