Non-BRCA Gene Mutations That Raise Breast Cancer Risk

What other gene mutations are important in hereditary breast cancer?

In addition to the often talked about BRCA gene mutations, there are a significant number of other inherited gene mutations that increase the risk of developing breast cancer. In fact, it's thought that mutations in over 72 genes contribute to risk, and the number of non-BRCA gene mutations that raise breast cancer risk is expected to grow as our knowledge of the genetics of cancer increases.

In addition to BRCA1 and BRCA2 gene mutations, some of these include mutations in ATM, PALB2, PTEN, CDH1, CHEK2, TP53, STK11, PMS2, and more. Let's look at how important these non-BRCA1/BRCA2 mutations are in familial breast cancer, and some of the characteristics of those more commonly found.

Hereditary Breast Cancer

It's currently thought that 5 percent to 10 percent of breast cancers are genetic or familial (though this number may change as we learn more), but not all of these cancers are due to BRCA mutations.

At most, 29 percent (and likely much fewer) hereditary breast cancers test positive for BRCA1 or BRCA2 gene mutations, and many people are pursuing testing for the other known genetic changes.

Since the science behind hereditary cancer is very anxiety-provoking, not to speak of confusing and incomplete, it's helpful to begin by talking about the biology of gene mutations, and how these changes in DNA play a role in the development of cancer.

Inherited vs. Acquired Gene Mutations

When talking about mutations, it's important to distinguish between inherited and acquired gene mutations.

Acquired or somatic gene mutations have received a lot of attention in recent years, as these mutations cause changes that drive the growth of cancer. Targeted therapies, drugs that target specific pathways related to these changes, have significantly improved the treatment of some cancers such as lung cancer.

Acquired mutations, however, are not present from birth, but rather, are formed any time after birth in the process of a cell becoming a cancer cell. These mutations affect only some cells in the body. They are not inherited from a parent, but rather "acquired" as the DNA in cells is exposed to damage from the environment or as a result of the normal metabolic processes of the body.

Inherited, or germ-line mutations, in contrast, are genetic changes that people are born with, and that are passed down from one or both parents. These mutations affect all the cells of the body. It is these inherited mutations (and other genetic changes) that can increase the chance that a person will develop cancer, and account for what is known as hereditary or familial breast cancer.

Understanding a Family History With Breast Cancer

How Do Hereditary Gene Mutations Raise Cancer Risk?

Many people wonder how exactly an abnormal gene or combinations of genes could lead to breast cancer, and a brief discussion of the biology is helpful in understanding many of the questions, such as why not everyone who has these mutations develops cancer.

Our DNA is a blueprint or code that is used to manufacture proteins. When the map or code is wrong (such as the "lettering" in a particular gene), it gives the wrong directions for synthesizing a protein. The abnormal protein is then unable to perform its usual job. Not all gene mutations raise the risk of cancer, and in fact, most do not. Mutations in genes responsible for the growth and division of cells, or "driver mutations" are what drive the growth of cancers. There are two major types of genes that, when mutated, can lead to uncontrolled growth known as cancer: oncogenes and tumor suppressor genes.

Several of the genes associated with a higher breast cancer risk are tumor suppressor genes. These genes code for proteins that function to repair damage to DNA in cells (damage from toxins in the environment or the normal metabolic processes in cells), serve to eliminate cells that can't be repaired, or regulate growth in other ways. The genes BRCA1 and BRCA2 are tumor suppressor genes.

Many of these genes are autosomal recessive, meaning that each person inherits one copy of the gene from each parent, and both copies must be mutated to increase cancer risk. Simplistically, this means that a combination of genetic and environmental factors (an acquired mutation in the other gene) need to act together to result in cancer developing. Added to this, usually, several mutations must occur for a cell to become a cancer cell.

What It Means to Have a Genetic Predisposition to Cancer

Gene Penetrance

Not all gene mutations or genetic changes increase the risk of breast cancer to the same degree, and this is an important concept for anyone considering genetic testing, especially as many people have heard of the very high risk conferred by BRCA mutations. Gene penetrance is defined as the proportion of people with a mutation who will experience the condition (in this case, develop breast cancer).

For some mutations, the risk of breast cancer is very high. For others, the risk may be increased by only a factor of 1.5. This is important to understand when talking about possible preventive options.

Epigenetics

Another important concept that is important in understanding genetics and cancer, though too complex to explore in detail here, is that of epigenetics. We have learned that changes in DNA that don't involve changes in the base pairs (nucleotides) or the "letters" that code for a protein, may be just as important in the development of cancer. In other words, instead of structural changes in the backbone of DNA, there can be molecular changes that change how the message is read or expressed.

Non-BRCA Gene Mutations

BRCA gene mutations are the most well known genetic abnormality associated with breast cancer, but it's been clear that there are women who are predisposed to breast cancer based on their family history, who test negative.

A 2017 study found that BRCA mutations accounted for only 9 percent to 29 percent of hereditary breast cancers. Even when testing was done for another 20 to 40 known mutations, however, only 4 percent to 11 percent of women tested positive. In other words, 64 percent to 86 percent of women suspected to have hereditary breast cancer tested negative for both BRCA mutations and 20 to 40 others.

Non-BRCA1/BRCA2 Familial Breast Cancer

Our knowledge about gene mutations that raise breast cancer risk is still incomplete, but we now know that there are at least 72 gene mutations linked to hereditary breast cancer. These mutations (and others yet undiscovered) are thought to be responsible for the 70 percent to 90 percent of hereditary breast cancers that test negative for BRCA gene mutations. The acronym BRCAX has been coined to describe these other mutations, standing for non-BRCA1 BRCA2- related familial breast cancer.

72 Genetic Mutations Linked to Hereditary Breast Cancer

The genetic abnormalities below differ in their frequency, the amount of risk associated, the type of breast cancer they are linked with, and other cancers associated with the mutations.

Most of these breast cancers are similar in characteristics (such as cancer type, estrogen-receptor status, and HER2 status) to non-hereditary or sporadic breast cancers, but there are exceptions. For example, some mutations are more strongly associated with triple negative breast cancer, including mutations in BARD1BRCA1BRCA2PALB2, and RAD51D.

Variability Within Mutations

Not all people who have the following gene mutations are the same. In general, there can be hundreds of ways in which these genes are mutated. In some cases, the gene will produce proteins that suppress tumor growth, but the proteins will not function as well as the normal protein. With other mutations, the protein may not be produced at all.

BRCA (A Brief Review for Comparison)

BRCA 1 gene mutations and BRCA2 gene mutations are both associated with an increased risk of developing breast cancer, as well as some other cancers, though the two differ somewhat in that risk.

On average, 72 percent of women who have BRCA1 mutations and 69 percent who have mutated BRCA2 genes will develop breast cancer by the age of 80.

In addition, the breast cancers associated with these mutations can differ. Breast cancers in women who have BRCA1 mutations are more likely to be triple negative. Around 75 percent are estrogen receptor negative, and they are also less likely to be HER2 positive. They are also more likely to have a higher tumor grade. Breast cancers in women with BRCA2 mutations, in contrast, are similar to cancers in women who are not BRCA gene mutation carriers.

ATM Gene (ATM Serine/Threonine Kinase)

The ATM gene codes for proteins that help control the rate of growth of cells. They also assist in the repair of damaged cells (cells that have sustained DNA damage from toxins) by activating enzymes that repair this damage.

Those who have two copies of the mutated gene have an uncommon autosomal recessive syndrome known as ataxia-telangiectasia. With ataxia-telangiectasia, the defective proteins not only increase the risk of cancer, but result in some cells in the brain dying off too soon, resulting in a progressive neurodegenerative disorder.

People who have only one mutated copy of the gene (roughly 1 percent of the population) have a 20 percent to 60 percent lifetime risk of developing breast cancer.

People who have this mutation are thought to be predisposed to breast cancer at an early age, as well as to developing bilateral breast cancer.

Breast cancer screening with breast MRIs is recommended starting at age 40, and women may wish to consider preventive mastectomies. People with one mutated ATM gene appear to also be predisposed to thyroid and pancreatic cancers and are more sensitive to radiation.

PALB2

Mutations in the PALB2 gene are also an important cause of hereditary breast cancer. The gene PALB2 codes for a protein that works in conjunction with the BRCA2 protein to repair damaged DNA in cells. Overall, the lifetime risk of breast cancer with a PALB2 mutation is as high as 58 percent though this can vary by age. The risk is 8 times to 9 times average for women less than age 40, but around 5 times average for women over the age of 60.

Among those who carry one copy of the gene, 14 percent will develop breast cancer by age 50 and 35 percent by age 70 (less than with BRCA mutations).

People who have a PALB2 mutation and develop breast cancer may have a higher risk of dying from the disease.

People who inherit 2 copies of the mutated PALB2 gene have a type of Fanconi anemia characterized by very low counts of red blood cells, white blood cells, and platelets.

CHEK2

The CHEK2 gene codes for a protein that is activated when damage occurs to DNA. It also activates other genes involved in cell repair.

The lifetime risks for carriers of CHEK2 truncating mutations are 20 percent for a woman with no affected relative, 28 percent for a woman with one second-degree relative affected, 34 percent for a woman with one first-degree relative affected, and 44 percent for a woman with both a first- and second-degree relative affected.

For both men and women, the gene also increases the risk of colon cancer and non-Hodgkin's lymphoma.

CDH1

Mutations in CDH1 cause a condition known as hereditary gastric cancer syndrome.

People who inherit this gene have a lifetime risk of up to 80 percent for developing stomach cancer, and up to 52 percent for developing lobular breast cancer.

The gene codes for a protein (epithelial cadherin) that helps cells stick to each other (one of the differences between cancer cells and normal cells is that cancer cells lack these adhesion chemicals that make them stick). Cancers in people who inherit this mutation are more likely to metastasize.

PTEN

Mutations in the PTEN gene are one of the more common tumor suppressor gene mutations. The gene codes for proteins that regulate cells' growth, and also helps cells stick together.

Mutations in the gene appear to increase the risk of cancer cells breaking off from a tumor and metastasizing. PTEN is associated with a syndrome called PTEN hamartoma tumor syndrome as well as Cowden syndrome.

Women who carry a PTEN mutation have a lifetime risk of developing breast cancer up to 85 percent, and also have an increased risk of benign breast changes such as fibrocystic disease, adenosis, and intraductal papillomatosis.

The mutations are also linked with an increased risk of uterine cancer (and benign uterine fibroids), thyroid cancer, colon cancer, melanoma, and prostate cancer.

Non-cancer related symptoms include large head size (macrocephaly) and the tendency to form benign tumors known as hamartomas.

STK11

Mutations in STK11 are associated with a genetic condition known as Peutz-Jegher syndrome. STK11 is a tumor suppressor gene involved in cell growth.

In addition to an increased risk of breast cancer (with a lifetime risk of up to 50 percent), the syndrome carries an increased risk of many cancers, some of which include colon cancer, pancreatic cancer, stomach cancer, ovarian cancer, lung cancer, uterine cancer, and more.

Non-cancer related conditions associated with the mutation include non-cancerous polyps in the digestive tract and urinary system, freckling on the face and the inside of the mouth, and more. Breast cancer screening is often recommended for women beginning in their 20s, and often with MRI with or without mammograms.

TP53

The TP53 gene codes for proteins that halt the growth of abnormal cells.

These mutations are extremely common in cancer, with acquired mutations in the p53 gene being found in around 50 percent of cancers.

Hereditary mutations are less common and associated with conditions known as Li-Fraumeni syndrome, or Li-Fraumeni-like syndrome (that has a lower cancer risk). The majority of people who inherit the mutation develop cancer by the age of 60, and in addition to breast cancer, are prone to develop bone cancer, adrenal cancer, pancreatic cancer, colon cancer, liver cancer, brain tumors, leukemia, and more. It's not uncommon for people with the mutation to develop more than one primary cancer.

Inherited mutations in the p53 gene are thought to account for around 1 percent of cases of hereditary breast cancer. Breast cancers associated with the mutation are often HER2 positive and have a high tumor grade.

Lynch Syndrome

Lynch syndrome or hereditary non-polyposis colorectal cancer is associated with mutations in several different genes including PMS2, MLH1, MSH2, MSH6, and EPCAM.

PMS2, in particular, has been associated with double the risk of breast cancer. The gene functions as a tumor suppressor gene, coding for a protein that repairs damaged DNA.

In addition to breast cancer, these mutations carry a high risk for cancers of the colon, ovary, uterus, stomach, liver, gallbladder, small intestine, kidney, and brain.

Other Mutations

There are several other gene mutations associated with an increased risk of developing breast cancer, and it's expected that more will be discovered in the near future. Some of these include:

  • BRIP1
  • BARD1
  • MRE11A
  • NBN
  • RAD50
  • RAD51C
  • SEC23B
  • BLM
  • MUTYH

Breast Cancer and Genetic Testing

At the current time, testing is available for BRCA gene mutations, as well as mutations ATM, CDH1, CHEK2, MRE11A, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, SEC23B, and TP53, with this area expected to expand dramatically in the near future.

Having these tests available, however, raises many questions. For example, who might have hereditary breast cancer and who should be tested? What should you do if you test positive for one of these genes?

Ideally, any testing should be done only with the guidance and help of a genetic counselor. There are two reasons for this.

One is that it can be devastating to learn that you carry a mutation that may increase your risk, and the guidance of someone who is aware of recommended management and screening is invaluable.

As noted earlier, some mutations confer a high risk and others a much lower risk. Some mutations might be of more concern earlier in life (say, in your 20s), whereas others might not require early screening. A genetic counselor can help you learn about what is currently recommended with regard to screening for your particular mutation while taking into account any other risk factors you might have.

The other reason genetic counseling is so important is that you may have a significant risk of developing breast cancer even if your tests are negative. There is much yet to learn, and a genetic counselor can help you look at your family history to see if you may carry a high risk despite negative testing, and plan screening accordingly.

Genetic Testing for Breast Cancer

Support for Hereditary Breast Cancer

Just as people who have been diagnosed with breast cancer need support, those who carry genes that increase risk need support. Fortunately, there are organizations that focus specifically on supporting people in this situation.

One organization, FORCE, which is an acronym for Facing Our Risk of Cancer Empowered, offers a helpline, message board, and information for those who are facing hereditary cancer.

Other organizations and support communities are available to help people cope with the decisions related to a diagnosis of hereditary breast cancer.

The term "previvor" was coined by FORCE to describe people who are surviving a predisposition to breast cancer. If this is the situation you are facing, you are not alone, and using the hashtag #previvor, you can find many others on Twitter and other social media outlets.

A Word From Verywell

It can be overwhelming to learn about the many different gene mutations that raise breast cancer risk beyond BRCA mutations, but these "other" mutations are of significant importance knowing that BRCA mutations account for a relative minority of familial breast cancers. At the same time, the science looking at hereditary breast cancer is still in its infancy and there is much to learn. If you are concerned you may have a mutation or have learned that you do, it's helpful to learn as much as you can. Hereditary cancer organizations such as FORCE can not only provide you with further information but can help you connect with others who are facing a journey with similar questions and concerns.

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