Germline vs Somatic Testing; Genomic vs Genetic Testing — What it Means and Why it Matters

NCCN guidelines for the management of ovarian cancer, as well as fallopian and primary peritoneal cancers, specify that patients diagnosed with those diseases should have germline and somatic testing. But what does this even mean? And how is that different from genetic or genomic testing?

Barbara Norquist, MD
Barbara Norquist, MD

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With so many different names for what sounds like the same procedure, it can seem confusing. But Dr. Barbara Norquist, a gynecologic oncologist and assistant professor of obstetrics and gynecology at the University of Washington, breaks it all down. This article contains information presented by Dr. Norquist at OCRA’s 2022 Ovarian Cancer National Conference.

What is germline testing?

According to Dr. Norquist, germline testing is a type of DNA testing that looks for inherited mutations that are present in every cell of the body and have been present since birth. This is also called genetic testing. Germline genetic testing can be done via cheek swab, spit sample or a blood draw. This type of genetic testing looks for germline mutations, or inherited predispositions to certain types of cancers. The BRCA 1 and 2 mutations are well-known mutations that increase someone’s risk for ovarian and breast cancer. When doctors talk about genetic testing, they are typically referring to the germline tests that look for these inherited mutations, even though genetic testing, technically, can also refer to tumor testing or tumor sequencing. It is important to note that germline or genetic testing cannot detect ovarian cancer. It can only determine if someone has a predisposition for a particular kind of cancer based on genes inherited from a parent.

Is ovarian cancer hereditary?

In some cases, yes. Inherited mutations are quite prevalent in patients with ovarian cancer. In a study that looked at the genetic sequencing of nearly 2,000 ovarian cancer patients, it was found that 18% of them had an inherited mutation that was likely the cause of their cancer. The vast majority of those 18% had the BRCA 1 and/or 2 mutations. This is one of the highest percentages of inherited mutations among any cancer. You can learn more about hereditary breast and ovarian cancer syndrome.

What is BRCA and why is it important to know if you have this mutation?

BRCA 1 and 2 genes are known as tumor suppressor genes, because they control proteins that work with DNA to repair the body. Everyone has BRCA genes; it’s when there’s a mutation on one or both genes that there is cause for concern, because that means the body can’t repair damaged DNA and this can lead to the development of a tumor or cancer. You can learn more about BRCA genes and mutations here. It is important to note, however, that BRCA mutations, while the most common, are not the only mutations that increase the risk for ovarian cancer.

Whether you have been diagnosed with ovarian cancer, or simply have a family history of this or other forms of cancer, it is important to get genetic testing. For those with the disease, a known gene mutation can impact the type of treatment they will receive, and Dr. Norquist shares several studies around PARP inhibitors and BRCA mutations that led to several FDA approvals of certain classes of the drug. For those who are not diagnosed but who are found to have a BRCA mutation, there are screenings one can undergo for breast cancer, such as a mammogram, as well as preventative measures one can take to dramatically reduce the risk of ever getting ovarian cancer.

Who should get germline or genetic testing?

When someone is diagnosed with ovarian cancer and is found to have an inherited mutation like BRCA 1 or 2, it is recommended that their first-degree relatives (siblings, children, and parents) get germline or genetic testing because there is a 50% chance that the relative also has this germline mutation. This mutation is not gender specific, meaning that a father can pass it along to his son or daughter. The good news is that these mutations cannot skip a generation. If your grandparent has a BRCA mutation, but did not pass it along to your parent, then you cannot get the mutation from that line of the family. Likewise, if a sibling has the mutation, but you do not, it cannot be passed to your children by your brother or sister.

Additionally, people who have a family history of breast, ovarian, uterine or colorectal cancer should undergo testing, as those cancers within the family tree can increase an individual’s risk for ovarian cancer. Dr. Norquist said, “Testing is indicated for these family members so they can undergo cancer prevention methods such as screening for breast cancer and removal of the fallopian tubes and/or ovaries.”

Are there other mutations that genetic testing looks for?

While BRCA mutations are the ones that seem to get the most attention, they are not the only inherited mutations that can put someone at higher risk for ovarian cancer. There are known mutations that affect MLH1, MSH2, MSH6, PMS2 and EPCAM genes, and these inherited mutations can cause Lynch Syndrome, which can lead to ovarian and other cancers.

How does someone get tested for inherited mutations?

According to Dr. Norquist, the gold standard would be to meet with a genetic counselor, which one can do in person, via phone or through telehealth (video appointments.) You can search for a genetic counselor through the National Society of Genetic Counselors. The advantages of going through a genetic counselor are that they can explain what the test is looking for, as well as learn more about your family history and thus order the most appropriate tests. They can also help assist other family members to get genetic testing if appropriate; and they can help with insurance coverage. The downside in going this route is that insurance coverage can be inconsistent, and there may be a lack of access to counseling and coverage.

Oncologists can also order testing and then patients can see a counselor. This can be faster, Dr. Norquist said, but cautions that “without pre-test counseling, a patient might get the wrong test if their oncologist is not totally up on it.”

If I had genetic testing previously, do I need to be retested?

To answer this question, Dr. Norquist refers to a timeline:

1990 – The BRCA 1 gene was discovered.

1995 – A patent was filed for the BRCA 1 sequencing, and shortly after that, the BRCA 2 mutation. It wasn’t until 1996 that someone would have been able to get a commercial genetic test.

1996-2013 – Only one company owned the patent for gene sequencing.

2006 – Rearrangement testing was developed, which could pick up more BRCA mutations, but it wasn’t until 2013 that this type of testing was used routinely.

2009 – Next generation sequencing, or gene panel testing, was developed that enabled geneticists to look at more than one gene at a time. However, this was not available clinically.

2013 – A unanimous Supreme Court decision ruled that sequencing a gene was not something that could be patented. This led to an explosion of companies offering gene panel testing.

“If you had testing prior to 2013 that was negative,” said Dr. Norquist, “it’s worth it to get another test to see if any other predisposition genes could be identified.” As always, OCRA recommends speaking with your medical team to discuss any questions or concerns.

What is somatic testing?

Somatic testing is another form of genetic testing, but unlike germline, which looks for inherited mutations, somatic genetic testing is looking for acquired mutations in a confined set of cells or tissue. Somatic testing is also known as tumor testing or tumor sequencing. Where germline mutations are in every cell in the body and have been there since birth, somatic genetic testing will examine a piece of tissue or tumor taken through a biopsy or surgery and look for mutations that have occurred spontaneously. These mutations are typically isolated to the tumor or area where cancer exists in the body, whereas germline mutations will be present in the tumor as well as in every cell in the body.

Somatic testing is used to find predictors that may impact treatment. Certain genes found in cancerous tumors, such as HRD (homologous recombination deficiency) can be used to predict a patient’s response to a type of therapy like PARP inhibitors. Microsatellite instability (MSI) is another mutation that might appear when undergoing tumor testing. MSI is more commonly useful with endometrial cancer, but if it is found in ovarian cancer patients, it can help predict responses to immunotherapy.

One thing to note — it is possible for a BRCA mutation to show up in the tumor, but not in the healthy cells. In other words, it could be an acquired mutation and not an inherited one. This is why it is important to have both germline and somatic testing when one is diagnosed with ovarian cancer.

NCCN (National Comprehensive Cancer Network) guidelines recommend germline testing and somatic testing for those diagnosed with ovarian or other gynecologic cancers. Identifying an inherited genetic mutation can help family members take preventative action if inherited mutations are found. Furthermore, knowing whether there are any genetic mutations, either inherited or in the tumor, will help guide the best treatment options. Visit National Society of Genetic Counselors for help finding a genetic counselor.

Should I have repeat tumor testing at time of recurrence?

Dr. Norquist is clear on this answer. “Right now, in 2022, this is most likely to just be additional cost and not terribly helpful for treating your cancer,” she said, explaining that major drivers of drug response (BRCA, HRD, MSI) don’t tend to change on a repeat biopsy.

“Exceptions to this include research studies that are trying to predict responses to therapy and following patients, as well as clinical trial eligibility based on testing,” she noted. “Those would be the only reasons to get testing on a biopsy of cancer recurrence.”

What is genomic testing?

Genomic testing is another word that is sometimes used, “as a catchall to describe multiple genetic tests,” said Dr. Norquist, explaining that genomic testing looks at the entire genome — a person’s complete set of DNA – rather than individual genes. According to the NIH National Human Genome Research Institute, “Genomics is a more recent term that describes the study of all of a person’s genes (the genome), including interactions of those genes with each other and with the person’s environment.” Genomics is involved in the study of specific diseases like cancer because these diseases are usually due to genetics (inherited genes) as well as environmental factors, rather than an individual’s genes alone.

In conclusion

The standard of care for ovarian cancer treatment is to have full germline and somatic testing. Germline testing can help family members of the patient avoid cancer if inherited mutations are found. And somatic testing will help guide the patient and medical team to the best treatment options.

Dr. Norquist advises everyone to save copies of any genetic testing reports they receive. “Most medical records aren’t designed to keep this in a place that’s easy to find. This can be critically important to keep track of.”

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