Cancer, at its core, is a genetic disease. Therefore, understanding the genetic characteristics of a patient’s cancer is crucial for precision treatment. Cancer is defined as the uncontrolled growth of abnormal cells. The regulators of that uncontrolled cell growth and division are genes. In every cell in the body, there are numerous genes that control how cells divide and multiply. Sometimes a genetic error, or mutation, can occur in 1 or more of these genes. These mutations cause cells to divide abnormally and uncontrollably. Over time, the cancerous cells evolve to develop additional mutations in other genes that make them more and more abnormal. These evolving, abnormal cells can then spread to other parts of the body, leading to a more advanced, metastatic cancer.
There may be hundreds to thousands of mutations in a tumor, but only a few that directly regulate cell growth and drive cancer progression. If we can understand the genetic mutations and pathways that allow a cancer to grow, then we can further improve how to stop or slow that cancer’s growth.
How Do Genetic Mutations Arise?
Genetic mutations can be caused by acquired or environmental factors like smoking, exposures to certain chemicals or radiation, the natural aging process, and sometimes just by random chance as a cell normally divides and copies its DNA. They may also be inherited, rather than acquired.
The majority of cancers are caused by acquired, or somatic, mutations that occur in 1 cell. These mutations are specific to a cell and subsequent tumor tissue and are not passed down to children or other relatives.
Less commonly, cancers may be caused by inherited mutations in genes that are supposed to regulate growth. An inherited mutation is present at birth and creates a predisposition for cancer, or a higher than average lifetime chance. Inherited mutations can be passed down through families.
Genetic testing allows for the analysis of both types of mutations: those that are somatic (or acquired) and those that are hereditary (present at birth). By identifying the exact genetic changes that are driving a cancer, oncologists can better target them and treat the cancer more precisely than by treating based on the site of the cancer alone (eg, colon, ovarian, breast, lung, skin).
How Are Tumor-Specific (Somatic) Biomarkers Used?
All tumor profiling tests aim to provide personalized care for that patient’s cancer, but not all tumor profiling tests are the same. There are many types of tumor-specific biomarkers. Some tests analyze the genetic mutations in a tumor so therapy can be matched to the specific alterations that are present. Others help determine how likely you are to respond to therapy, or what the chances are that a cancer will recur in the future.
Tumor-specific, or somatic, genetic testing helps to identify specific molecular biomarkers in the tumor tissue. This testing involves analyzing the sequence of the DNA of a tumor to determine if there are any mutations that are linked to better treatment response or a particular type of targeted therapy. This is different from traditional chemotherapy, which broadly targets all rapidly dividing cells, both healthy and cancerous. This is why there are broader side effects with traditional chemotherapy, such as hair loss, nausea, and fatigue. Targeted therapy, by contrast, is designed to interact with specific cells that have specific mutations, which make those cells particularly vulnerable to targeted treatment.
For example, a gene in a cancer’s cells may have developed a mutation that allows it to be expressed at an abnormally high level, promoting cancer growth. Targeted therapy may then be used to suppress that gene or block other molecules that it interacts with, stopping cancer growth.
An example of targeted therapy is immune checkpoint inhibitors, which can be used in a variety of cancer types. The T-cells of the immune system play an important role in recognizing and attacking abnormal cells, including cancer cells. On the surface of cancer cells, a protein called PD-L1 is often expressed at an abnormally high level compared with healthy cells. The normal function of PD-L1 is to signal the T-cells of the immune system not to attack normal cells. When overexpressed, however, PD-L1 allows cancer cells to hide from the immune system. A specific type of targeted therapy called an immune checkpoint inhibitor targets PD-L1 and the molecules it interacts with, blocking its function. By blocking its function, the cancer can no longer hide from the immune system, and the T-cells recognize that the abnormal cell should be attacked. Some cancer types in which immune checkpoint inhibition therapy has been effective are non–small cell lung cancer, melanoma, urothelial carcinoma (a kind of bladder cancer), and certain types of colon cancer.
Importantly, tumor-specific biomarkers may be different at various time points of the cancer’s progression. As previously discussed, cancer cells rapidly evolve and may sometimes develop additional mutations that cause a more advanced disease. When this occurs, a new sample of tissue may be required for additional genetic testing, so that treatments are kept up to date with the changing genetic landscape of the tumor.
What Are Hereditary Biomarkers?
Tumor-specific genetic tests are different from testing for inherited risk of developing cancer. Hereditary cancer tests are typically performed on a blood or saliva sample. They examine biomarkers that a person is born with and that do not change over time.
Hereditary mutations account for 5% to 10% of all cancer cases. Although less common, they can have a big impact on the patients who carry them. Hereditary mutations provide information about a person’s lifetime risk of developing certain types of cancer. For people who have hereditary biomarkers for cancer, the risk of developing these cancers over the course of their lifetime may be greatly increased above that of the general population. Depending on the gene and type of hereditary mutation detected, different treatment, surveillance, and surgical options may be available to treat or help reduce the risk of more or future cancer.
One of the more well-known examples of hereditary biomarkers is inherited mutations in the BRCA1 or BRCA2 genes, which are associated with hereditary breast and ovarian cancer syndrome. Women who carry an inherited BRCA1 or BRCA2 mutation have a 43% to 87% risk of developing breast cancer by age 70 years, compared with 12% in the general population. Women also have a 40% to 64% risk of a second, new breast cancer in their lifetime. Therefore, women who have breast cancer and carry an inherited mutation in one of these genes may elect to remove the other healthy breast at the time of their surgery to prevent the risk of a second breast cancer. Women with an inherited mutation in one of these genes may also have an increased risk of developing ovarian cancer. For patients with ovarian cancer, an inherited BRCA1 or BRCA2 mutation provides important information about the molecular mechanism behind the tumor’s growth. If an inherited BRCA1 or BRCA2 mutation is present, it indicates that the tumor has an impaired ability to repair DNA, which leads to unregulated growth. These patients may benefit from targeted therapy that exploits this impaired DNA repair to kill the cancer cells.
In other cases, more frequent or earlier screening may be pursued. Men and women who carry an inherited mutation in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes have Lynch syndrome, a condition characterized by a high lifetime risk of colon, uterine, and other cancers. Due to the high risk of colon cancer (up to 87%, compared with 5%-6% in the general population), which often occurs before age 50 years, individuals with Lynch syndrome typically begin colonoscopy screening between the ages of 20 and 25 years, compared with age 45 years in the general population. They also undergo colonoscopy screening every 1 to 2 years compared with every 10 years. In this way, precancerous colon polyps can be detected early and removed, greatly reducing the risk of them developing into a colon cancer.
Identifying a hereditary biomarker can also have important implications for a patient’s family members. As opposed to somatic mutations, which are present only in the tumor tissue, hereditary mutations are usually inherited from a parent and can be passed on to children. Testing for hereditary mutations in at-risk family members enables them to individualize their risk and receive the most appropriate screening and interventions. Individuals in the family who carry these hereditary biomarkers can receive increased screening, surveillance, and risk reduction options. Individuals who do not carry the familial mutation are able to receive average-risk screening like the general population because they did not inherit the “cause” of cancer in their family.
Overlap Between Hereditary and Tumor Biomarkers
Although testing for hereditary and somatic biomarkers have different purposes, sometimes information about inherited genes may be incidentally picked up through tumor genetic testing.
The reason for this is that tumor cells originate from normal, healthy cells. Every cell in the body contains our DNA code, and tumor cells are no different—they have just acquired additional genetic changes compared with their original healthy counterparts. The technology used to sequence DNA (sometimes called next-generation sequencing, or NGS) cannot always differentiate between the genetic changes that were present in the cell before it became a cancer and the genetic changes that developed in the cancer cell over time.
It may sometimes be beneficial to obtain paired testing, in which both hereditary biomarkers and tumor-specific biomarkers are analyzed in complementary tests. The results of the hereditary testing can be cross-referenced with the results from the tumor-specific testing to provide additional understanding about the inherited versus acquired origin of a mutation, the mechanism of disease, the patient’s risk for other cancers, and effective treatment options. Your genetic counselor and medical oncologist can review the results from both tests and compare them to ensure the best management options for you.
What Does This Mean for Me?
Start with the Basics
- Biomarkers: are determined by specialty tissue or blood testing (not routine blood work). Work with your oncology care team to determine the best tests for you. If you use a commercially-based test that does not require a physician order, bring that result to your next appointment. Further testing may be indicated
- Precision medicine: is treatment specific for your type of cancer based on biomarker and genetic testing. No 2 people’s cancers or genetic makeup are the same
- Gather your results: keep a binder/dossier with all your medical records, including biomarker/genetic testing results
- Use credible sources for information: ask your oncology care team for literature and use websites with “.org” for scientific and unbiased information. See suggested patient resources below
- Keep an ongoing and open dialogue with your oncology care team. Always ask questions even if they seem silly or redundant.
Testing/Retesting: If you had genetic or molecular testing in the past, make sure your oncology care team has this result and can give its full interpretation. Biotechnology develops at a very rapid rate, and new tests may be available for you that were not done at the time you had your testing. Cancer also evolves at a very rapid rate, even after treatment. Your oncologist may suggest a new tissue sample to be tested by way of a biopsy or excision. This gives clinicians a snapshot of the type of cancer they are seeing at this specific time to determine best treatment options.
Know Your Pathology: It’s easy to get overwhelmed by the advice you have or will receive from friends and family about your diagnosis. Be sure you obtain a copy of your full pathology report and review this with your oncologist so you have a full understanding of the type of cancer you have. Your inherited genetic makeup is unique to you, and your tumor’s genetic makeup is also unique to your tumor.
Clinical Trials: Routinely ask your physician if there is a clinical trial for you. Cancer clinical trials are available for many types of cancers at various times during cancer screening, treatment, and beyond. Even if there isn’t a trial for you at this time, there may be one appropriate for you the next time. Add clinical trials to your checklist/talking points at your scheduled oncology appointment. Some trials are tissue or blood donation trials designed to advance the study of genetics to help people in the future.
Stay Informed and Hopeful: Write down every question you have even if you don’t fully understand what to ask about your genetics. This is a complex field of science that is continuously advancing. Your oncology care team and certified genetic counselors can answer many general and specific questions you may have about precision medicine and your unique cancer.
Genetics Home Reference
National Society of Genetic Counselors
All of Us Research Program
National Cancer Institute
- Remarks by the President in State of the Union Address. January 20, 2015. https://obamawhitehouse.archives.gov/the-press-office/2015/01/20/remarks-president-state-union-address-January-20-2015. Accessed March 2019.
- National Institutes of Health. About the All of Us Research Program. https://allofus.nih.gov/about/about-all-us-research-program. Accessed March 2019.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Genetic/Familial High-Risk Assessment: Breast and Ovarian. V.3.2019. www.nccn.org/store/login/login.aspx?ReturnURL= https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed March 2019.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Genetic/Familial High Risk Assessment: Colorectal. V.1.2018. www.nccn.org/profes sionals/physician_gls/f_guidelines.asp. Accessed March 2019.
- Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews (Internet). Seattle, WA: University of Washington; September 4, 1998.
- Kohlmann W, Gruber SB. Lynch Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews (Internet). Seattle, WA: University of Washington; February 5, 2004.
- Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29-39.