Non-BRCA Ovarian Cancer

Other Gene Alterations That Are Important in Ovarian Tumors

Non-BRCA ovarian cancer, or ovarian cancer that occurs in women who do not carry a BRCA mutation, can still be hereditary or familial. It's thought that of the roughly 20% of ovarian cancers that are hereditary, only some are related to BRCA gene mutations. Testing (DNA sequencing) to look for other mutations is important as treatments used for people with BRCA mutations may also work for women with these other mutations. These treatments include poly (ADP-ribose) polymerase (PARP) inhibitors.

Being aware of the presence of gene mutations (both BRCA and non-BRCA) that raise ovarian cancer risk can also be helpful for women who do not have the disease, so they have the option of primary or secondary prevention. In fact, some researchers believe that all women should be tested and that it's cost-effective—even for those who don't have a family history of ovarian or breast cancer.

We will look at some of the non-BRCA gene mutations that are associated with ovarian cancer, how common they are, how much they increase risk (when known), and exactly how being a carrier of one of these gene alterations raises the risk.

Defining Terms

When discussing familial ovarian and/or breast cancer it's important to define a few terms. The term "sporadic" ovarian cancer refers to cancers that are not considered to be hereditary.

Hereditary or familial ovarian cancers, in contrast, refer to ovarian cancers that occur in a woman who has a genetic predisposition. This does not always mean that a specific gene mutation can be found. It's likely that there are many gene alterations or combinations of genes that affect risk that remain to be discovered. If a person has a strong family history of ovarian (and/or breast cancer) a cancer may be considered familial even if a specific mutation cannot be identified.

It's also important to note up-front that different gene mutations (or alterations) pose different risks. Some mutations may raise risk significantly, while others only slightly increase risk. This is referred to as "penetrance."

Another confusing term you may come across is "wild type BRCA" or other "wild type" genes. This simply refers to genes that do not carry the particular tumor.

There are different types of genetic testing as well, but it's of particular importance to point out that at-home genetic testing is not sufficient to rule out gene mutations that raise ovarian or breast cancer risk.

Basics

Ovarian cancer occurs in roughly one in 75 women; women have a lifetime risk of developing the disease of 1.6%. When talking about ovarian cancer it's important to note that this includes ovarian cancer, fallopian tube cancer, and primary peritoneal cancer, and in fact, it's thought that most epithelial ovarian cancers originate in the fallopian tubes.

There are different types of ovarian cancer as well, and the particular type of tumor may be important when considering genetic risk:

  • Epithelial ovarian tumors: These account for 85% to 90% of ovarian cancers, and are further broken down into mucinous (most common), endometroid, and serous tumors.
  • Stromal tumors: These tumors can be benign or malignant and occur in the tissues that support the ovaries. Examples include Sertoli-Leydig tumors and granulosa cell tumors.
  • Germ cell tumors: These tumors account for only 3% of ovarian cancers, but are the most common type found in children and young women. Examples include immature teratomas, dysgerminomas, and endodermal sinus tumors.
  • Small cell cancer of the ovary: This rare tumor is responsible for only around 1 in 1000 ovarian cancers.

Most of the mutations discussed below are associated with epithelial ovarian cancer, though some, for example STK11 mutations, may be associated with stromal tumors.

Importance

Ovarian cancer has been termed the "silent killer" as it is frequently in the advanced stages before symptoms become apparent and it is diagnosed. It is currently the fifth most common cause of cancer-related deaths in women

Percent of Ovarian Cancers Considered Hereditary

The exact percentage of ovarian cancers that are considered hereditary varies by study with a range of 5% to 20%, It appears, however, that the higher end of this range (20%, or even more) may be most accurate, and this could increase further in the future as further advances are made. The percent of ovarian cancers considered to be hereditary also varies with geography.

Out of hereditary ovarian cancers, the number due to BRCA mutations alone also varies by study.

Studying Genetic Predisposition to Ovarian Cancer

As noted, there are many unknowns as to the exact frequency of gene mutations in ovarian cancer, and there are many reasons for this. The ability to look at the whole genome (whole-exome sequencing) is only recent. In addition, not everyone is tested for mutations.

How Ovarian Cancer Develops

Ovarian cancer begins when a series of gene mutations gives rise to a cell (a cancer cell) that grows in an out-of-control fashion. This usually includes mutations in both oncogenes, genes that code for proteins that control the growth of the cell, and tumor suppressor genes, genes that code for proteins that repair damaged DNA or get rid of abnormal cells that can't be repaired (so the cell doesn't continue to survive and become a cancer cell).

Somatic vs. Germline Mutations

Distinguishing between somatic (acquired) and germline (inherited) mutations is very important, especially with the advent of targeted therapies for ovarian cancer.

Germline (Hereditary) Mutations

Germline mutations are hereditary and can be passed from a parent to his or her offspring. They are present in every cell in the body. These gene mutations can be either autosomal dominant (such as BRCA) or autosomal recessive. With autosomal dominant genes, only one gene needs to be mutated to increase the risk of cancer.

Gene mutations themselves do not cause cancer, but rather increase the risk or confer a genetic predisposition. This is easier to understand by noting that many of these mutations occur in tumor suppressor genes. When the proteins produced by these genes do not function properly, that is, do not repair or eliminate damaged cells, the cells may develop into cancer cells. In this case, the chance of developing cancer is higher.

Hereditary cancer genes don't directly cause cancer. What is inherited is the predisposition to develop cancer.

Not all genetic risk is likely related to specific gene mutations or alterations. A combination of genes or interactions between different common genes may also lead to greater risk. Studies known as genome-wide association studies have identified loci associated with ovarian cancer.

Somatic (Acquired) Mutations

Most mutations involved in ovarian cancer (at least according to current thought) occur after birth (somatic mutations), or at least after conception. These mutations are the ones that you often hear about when someone has testing done on their tumor to determine if a targeted therapy may be effective for their cancer.

This is simplistic, and germline mutations may affect treatment, a focus of this article.

Hereditary Ovarian Cancer

Not everyone who has hereditary ovarian cancer has a known mutation or even a family history of the disease. Ovarian cancer may easily be hereditary if nobody in the family has had ovarian or breast cancer, and mutations are frequently found when not expected. That said, some women are more likely to have hereditary ovarian cancer than others.

Chance That an Ovarian Cancer Is Hereditary

An ovarian cancer is more likely to be hereditary when:

  • Epithelial ovarian cancer is diagnosed in a younger woman
  • A woman has a family history of ovarian, breast, or colon cancer

Hereditary Breast and Ovarian Cancer

Ovarian cancer and breast cancer are often linked together under the heading "hereditary breast and ovarian cancer." While many hereditary mutations raise the risk of both, they can do so to different degrees. And some mutations linked to ovarian cancer are not associated with breast cancer, and vice versa.

Some mutations linked to ovarian cancer that do not appear to raise breast cancer risk include those in RAD51C, RAD51D, BRIP1, MSH2, and PMS2.

BARD1 mutations are associated with breast cancer, but did not appear to be associated with ovarian cancer, at least in one study.

Defining Penetrance

Not all gene mutations or alterations associated with ovarian cancer confer the same risk. The risk related to the mutation, or penetrance, is easier to understand by talking about BRCA mutations. BRCA mutations are considered to have high penetrance, meaning that the presence of the mutation is associated with a significant increase in risk. Having a BRCA1 mutation is associated with a lifetime risk of developing ovarian cancer of 40% to 60%, while that associated with BRCA2 mutations is 20% to 35%. Some mutations only raise the risk to a small degree, say, a lifetime risk of 4%.

Penetrance with particular mutation is important when it comes to preventive treatments. A preventive salpingo-oophorectomy (removal of the ovaries and fallopian tubes) may be a good option when there is a high risk of cancer developing (such as with BRCA1 mutations). In contrast, if a mutation only doubles the risk of ovarian cancer (twice that of the average incidence of 1.6%), the risks related to surgery (and lack of estrogen in young adults) may easily outweigh the potential benefit.

Non-BRCA Mutations Associated With Ovarian Cancer

Non-BRCA mutations are very important in ovarian cancer, as a woman who carries one of these mutations may have a greater risk of developing the disease than someone who has a strong family history of ovarian cancer. In women who already have ovarian cancer, knowing that one of these mutations is present may affect treatment choices.

Incidence of Non-BRCA Gene Mutations in Ovarian Cancer

The science is still young, but researchers have found that mutations in 11 genes are associated with a significantly increased risk of ovarian cancer. These include:

  • ATM OR 1.69
  • BRCA1
  • BRCA2
  • BRIP1
  • MLH1
  • MSH6
  • NBN
  • RAD51C
  • RAD51D
  • STK11: risk 40 times OR 41.9
  • (There was a slightly increased risk associated with PALB2 mutations, but this needs further study)

The risk of developing ovarian cancer if you have one of these mutations (penetrance) is highest with STK11 mutations (risk 41.9 times average), and lowest with ATM mutations (although ATM mutations are relatively common).

Lynch Syndrome

Some of these are Lynch syndrome susceptibility genes, including mutations in MLH1, MSH2 (most common with ovarian cancer), and MSH6. Overall, Lynch syndrome is thought to account for 10% to 15% of hereditary ovarian cancers.

MSH6

Mutations in MSH6 are considered "moderate risk" mutations, and are associated more strongly with ovarian cancer than breast cancer. The risk with ovarian cancer was 4.16 times normal, and the mutation was associated with the diagnosis of epithelial ovarian cancer at a young age. (It was also associated with early-onset invasive lobular breast cancer).

ATM

ATM gene mutations are relatively common, being found in roughly 1 in 200 people, and appear to increase the risk of ovarian cancer roughly 2.85 times. ATM mutations are also associated with an increased risk of breast cancer. The frequency of these mutations is one example that has prompted some researchers to recommend screening all women, as many people who carry the mutation (and are at risk of ovarian cancer) do not have a family history of the disease.

RAD51C and RAD51D

RAD51C and RAD51D mutations are uncommon, and the exact increase in risk could not be determined in the JAMA study.

BRIP1

BRIP1 is a tumor suppressor gene, and mutations in BRIP1 are thought to be present in roughly 1 in 2000 women. It is associated with early-onset breast cancer but findings with ovarian cancer are mixed. In the penetrance study, the risk of ovarian cancer was 2.6 times average.

TP53

Li-Fraumeni syndrome is a rare syndrome related to a germline mutation in TP53. It is associated with early age ovarian cancer with an 18.5 fold increased risk, as well as many other cancers.

STK11

As noted, STK11 mutations were associated with the highest risk. In addition to epithelial ovarian cancers, these mutations may also increase the risk of stromal tumors.

Treatment Implications of BRCA and Non-BRCA Gene Mutations

For those who have ovarian cancer, determining whether either a BRCA or non-BRCA gene mutation is present can affect ovarian cancer treatment, as tumors harboring these mutations may behave differently.

For example, PARP inhibitors (of which three are now approved for ovarian cancer in women with BRCA mutations) appear to be particularly effective when a BRCA mutation (and likely several of the others) is present. In addition, women who have BRCA gene mutations tend to respond better to platinum based chemotherapy and may have fewer side effects.

Why Ovarian Cancers Harboring Hereditary Mutations Respond Differently to Treatment

Most of the non-BRCA mutations associated with ovarian cancer are found in tumor suppressor genes. Similar to proteins coded for by BRCA genes, the proteins produced by these genes often result in cells that are unable to properly repair their DNA. This can certainly affect the risk of developing ovarian cancer, but also treatment.

PARP Inhibitors

Proteins known as poly (ADP-ribose) polymerases (PARP) are used by cells in the process of repairing DNA. In tumors that have mutations in tumor suppressor genes (DNA repair genes) such as BRCA, inhibition of PARP results in the preferential death of cancer cells by eliminating two methods of repair.

(BRCA mutations result in cells being unable to repair double-stranded breaks in DNA and PARP inhibitors leave cells unable to repair single-stranded breaks.)

PARP inhibitors currently approved for ovarian cancers in women with BRCA mutations include:

  • Lynparza (laparib)
  • Zejula (niraparib)
  • Rubraca (rucaparib)

Genetic Testing and Counseling

Genetic testing, as well as genetic counseling for those who do not have an apparent mutation, is important in both treatment and prevention of ovarian cancer.

Reasons to Test Women With Ovarian Cancer

Every woman who has been diagnosed with ovarian cancer should have multigene testing—testing to look both for BRCA and non-BRCA mutations. This includes both women with and without a family history, as testing only those with a family history will miss half of the women who carry these mutations. Next-generation sequencing has dropped considerably in price, and contrary to beliefs that knowing of a mutation could lower quality of life, this does not appear to be the case.

Reasons to include:

  • To guide treatment: Knowing of mutations not only indicates who may respond to PARP inhibitors, but predicts sensitivity to some chemotherapy medications.
  • To benefit family members: If you have a hereditary mutation, it will allow you to inform other family members so that they can consider options for primary or secondary (screening) prevention.
  • To assess your risk of other cancers: Some mutations raise the risk of not only ovarian cancer, but others. For example, BRCA2 gene mutations are associated not only with ovarian cancer, but breast cancer, pancreatic cancer, prostate cancer, and others. It's not uncommon for people to develop a second primary cancer (a second, unrelated cancer), and in some cases, people are more likely to die from a second primary than their original diagnosis.

In the past, only women with a family history of ovarian cancer were referred for testing, but it appears that this would miss over 40% of women with BRCA mutations alone.

The National Comprehensive Cancer Network (NCCN) states that every woman (regardless of family history) who has been diagnosed with epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer should receive genetic counseling and consider BRCA testing. Based on recent findings, it's likely that this should include testing for other ovarian cancer associated mutations as well.

Screening Everyone Is Cost Effective and Saves Lives

Not only should everyone who has been diagnosed with ovarian cancer be screened, but it's recently been found to be cost-effective to screen all women, including those who have no family history of cancer. Screening everyone (population testing) over the age of 30 for mutations in BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, and PALB2 alone would not only reduce costs in a strained health care system, according to this study, but would prevent thousands of ovarian and breast cancers in the U.S.

Primary and Secondary Prevention in Ovarian Cancer Survivors

For those who have ovarian cancer, finding the presence of a mutation (BRCA or non-BRCA) may affect screening for other cancers such as breast cancer. There are guidelines in place that you can discuss with your doctor.

A Word From Verywell

Genetic testing for non-BRCA gene mutations in addition to BRCA mutations should be considered for everyone with ovarian cancer. The results may not only affect your current treatment options, but may provide guidance in measures to reduce your risk of any other cancers associated with the mutation. In addition, testing can provide your family members with important information that may ultimately reduce their risk of developing cancer themselves (or at least find the cancer in the earlier stages).

There is much to be learned, and the science surrounding non-BRCA mutations is still in its infancy. If you learn you have one of these mutations, it's important to find a physician who is knowledgable and has experience with patients with your particular mutation. Seeking out others who have your mutation in online cancer communities can not only provide your support (there's nothing like talking to someone who has "been there"), but is often an excellent way to stay abreast of the latest research. Since standards aren't in place as with BRCA mutations, you may want to consider clinical trials. Most importantly, be your own advocate in your cancer care and ask enough questions that you're satisfied you're on the right course.

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Article Sources

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