Understanding Functions of Somatic and Hereditary Genetic Mutations

June 2019 Vol 10, No 6


Cancer Biomarkers
Kate Partynski, MS, LCGC
Cancer Genetics Program and Cancer Research Program St. Joseph Hospital
Orange of Providence St. Joseph Health System
Lavinia Dobrea, RN, MS, OCN
The Center for Cancer Prevention and Treatment
St Joseph Hospital
Orange, CA

Cancer, at its core, is a genetic disease. In every cell in the body, there are numerous genes that control how cells divide and multiply. When a mutation occurs in one or more of these genes, cells may divide abnormally and uncontrollably, and this uncontrolled growth of abnormal cells defines cancer. Over time, the cancerous cells may 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. Understanding the genetic characteristics of a patient’s cancer is crucial for precision treatment with targeted therapies.

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, we can further improve ways to stop or slow that cancer’s growth.

How Do Genetic Mutations Arise?

Some cancers are caused by inherited mutations in genes that are normally supposed to regulate growth. An inherited or germline mutation is present at birth and occurs in every cell in the body. Such mutations may create a predisposition for cancer, or a higher than average lifetime chance of developing cancer. Hereditary mutations can be passed down through families.

Genetic mutations can also occur in somatic cells and be caused by environmental factors like smoking, exposures to certain chemicals or radiation, the natural aging process, and sometimes just by random chance as a cell divides and copies its DNA. These somatic, or acquired, mutations occur in 1 cell and are specific to the subsequent tumor tissue derived from that cell. Acquired, somatic mutations cannot be passed down to children.

Genetic testing allows for the analysis of both types of mutations: those that are somatic and those that are hereditary. 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.

How Are Somatic Biomarkers Used?

All tumor profiling tests aim to provide precision care for that patient’s cancer, but not all tumor profiling tests are the same because 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 a patient is 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 also why traditional chemotherapy often causes broader side effects, such as hair loss, nausea, and fatigue. Targeted therapy, by contrast, is designed to interact with specific cells having specific mutations that 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 the use of immune checkpoint inhibitors, which can be effective 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. The programmed death ligand 1 (PD-L1) protein is often expressed at an abnormally high level on the surface of cancer cells 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 evade attack from the immune system. An immune checkpoint inhibitor targets PD-L1 and the molecules it interacts with, 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, and certain types of colon cancer.

Importantly, tumor-specific biomarkers may be different at various time points of the cancer’s progression as the cancer evolves. If more advanced disease develops, a new sample of tissue may be required for additional genetic testing so that treatments are congruent with the changing genetic landscape of the tumor.

What Are Hereditary Biomarkers?

Testing for an inherited risk of developing cancer is different from tumor-specific genetic tests. Hereditary cancer tests are typically performed on a blood or saliva sample.

Hereditary mutations account for 5% to 10% of all cancer cases. Although less common than acquired mutations, they can have a significant impact on the patients who carry them. Hereditary biomarkers can provide information about a person’s lifetime risk of developing certain types of cancer, which 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 the current cancer or help reduce the risk of a future cancer.

Well-known examples of hereditary biomarkers are the inherited mutations in the BRCA1 or BRCA2 genes, which are associated with hereditary breast and ovarian cancer syndrome. Women who carry a 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. These women also have a 40% to 64% risk of a second, new breast cancer in their lifetime. Therefore, women who have breast cancer with a 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 a mutation in one of these genes 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 colorectal, endometrial, 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 from the ages of 20 to 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 developing colon cancer.

Identifying a hereditary biomarker can also have important implications for a patient’s family members. By testing for hereditary mutations, at-risk family members are able to assess 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 risk of cancer present 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.

Every cell in the body contains our DNA code, and tumor cells are no different—they originate from normal cells but have acquired 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. A genetic counselor and medical oncologist can review the results from both tests and compare them to ensure the best management options for each patient.

What Does This Mean for Your Patients?

Start with the Basics

As a navigator, you can help your patients understand some genetic aspects of cancer and its treatment. The following are topics and suggestions designed to be shared with your patients:

  • 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 the test result to your next appointment. Further testing may be indicated
  • Precision medicine is treatment specific for your type of cancer based on biomarkers and genetic testing. No 2 people have genetic makeup or cancers that 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 ending with “.org” for scientific and unbiased information. See the list of 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

Additional Advice

Testing/Retesting: If you had genetic testing in the past, make sure your oncology care team has this result and can give its full interpretation. Biotechnology is developing at a very rapid rate, and new tests may be available. Cancer also evolves at a very rapid rate, even after treatment. Your oncologist may suggest a new tissue sample to be tested by biopsy or excision. This gives clinicians an image of the cancer they are dealing with at that specific time, which helps determine the best treatment options.

Know Your Pathology: It’s easy to get overwhelmed by the advice you have received or will receive from friends and family about your diagnosis. Be sure you obtain a copy of your complete 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 at a later time. Add clinical trials to your checklist/talking points for 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.


Rather than taking a one-size-fits-all approach, precision oncology aims to understand the unique biomarkers of each individual patient as well as those of his or her cancer and match them to the most effective treatments. Research is ongoing, and advances in precision oncology will continue to lead to improved options in the treatment of cancer.


  • 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.
  • 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.
  • National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Genetic/Familial High-Risk Assessment: Breast and Ovarian. V.3.2019. 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/professionals/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.
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Last modified: August 10, 2023

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