Multi-gene panels

Are there other gene mutations other than those in BRCA1 and 2 that increase your risk of developing breast cancer? Monica Araujo expands on the multi-gene panels.

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Breast cancer is the most common cancer affecting females globally. It occurs when cells in the breast become abnormal and multiply uncontrollably to form a tumour. Unlike normal cells, cancer cells make new cells that aren’t needed by the body and don’t die when they should. Cancer cells can also metastasise and grow into other tissues. 

Studies suggest that approximately 1 in 8 females (~12%) will develop breast cancer in their lifetime. Breast cancer accounted for 27.1% of new cancer diagnoses in South African women in 2020. The incidence of breast cancer in SA varies by time, location and ethnic group. Despite the higher incidence of breast cancer in women, breast cancer can also occur in men. The lifetime risk for breast cancer in males is approximately 0.1%. 

A risk factor is linked to your chance of getting a disease. Several risk factors are known to be associated with the development of breast cancer. These include lifestyle-, environmental-, and reproductive factors and your genetics. Besides age, a positive family history is the strongest known factor associated with an increased risk of developing breast cancer. As the number of relatives affected with breast cancer increases, your risk of developing breast cancer also increases. 

What’s your risk?

The majority (85-90%) of breast cancers are considered sporadic and occur for unknown reasons. Still, approximately 10-15% of breast cancers are inherited (genetic). In assessing your risk of having an inherited cancer syndrome, we try to classify them as average-, moderate- or high risk. 

The average risk is slightly higher than the general population risk. Moderate risk is an intermediate risk which is higher than average risk. If you are in this group, you would require increased screening. High risk is commonly associated with a genetic risk, where the risk for cancer development increases and intensive surveillance is needed. 

Some of the following characteristics are usually present in moderate- to high-risk cancer families: at least three first-degree relatives affected with cancers; when the cancers develop at a younger age of onset than the average for particular cancers; a male breast cancer diagnosis; when unusual cancers occur; when you have multiple primary tumours; and when you belong to higher risk ethnic groups (e.g. Ashkenazi Jewish or Afrikaner).

BRCA mutations

Many different cancer syndromes increase your risk of developing certain types of cancer. These cancer syndromes are caused by faults (mutations) in genes. Genes are instructions that tell the body how to perform specific functions. If there is a mutation in one of these genes, the function of that gene may be impaired. 

Several genes are associated with an increased risk of developing breast cancer. Two genes in particular, breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2) which were discovered in the early 1990s, are most frequently (~50% of inherited breast cancers) identified as genetic causes for hereditary breast and ovarian cancers in females and breast and prostate cancer in males.

Mutations in the BRCA1 and BRCA2 genes are known to convey the highest risk for developing breast cancer (up to 72% in females), ovarian cancer (up to 44%), and pancreatic cancer. Mutations in the BRCA2 gene are associated with a 6-8% lifetime risk of male breast cancer and a 60% risk of developing prostate cancer by the age of 80 years. 

Multi-gene panels

In recent years, genetic testing for hereditary breast cancer has moved beyond testing for mutations in the BRCA1 and BRCA2 genes only. With advances in genetic testing capabilities, multi-gene panels are now available for anyone wanting to pursue testing for a hereditary predisposition to breast cancer. 

These panels typically include a variety of genes that are known to be associated with an increased lifetime risk of developing breast cancer. Depending on the provider, these panels can range from approximately nine genes to panels of up to 26 genes or more. 

This type of testing allows for an efficient evaluation of several potential gene targets based on a single clinical presentation. Genetic testing of these genes may help confirm a clinical diagnosis, help predict disease progression and prognosis, allow for early detection of symptoms, inform family planning and genetic counselling, or promote enrolment in clinical trials. 

Common genes on the panel

The genes on these panels are curated based on available evidence to date to provide a comprehensive analysis of genes that are known to be associated with hereditary breast cancer. 

High- and moderate-risk genes are commonly included in these multi-gene panels. These common genes include: 

• Ataxia-telangiectasia mutated (ATM)
• Checkpoint kinase 2 (CHEK2)
• Tumour protein p53 (TP53)
• Phosphatase and tensin homolog (PTEN)
• Cadherin 1 (CDH1) 
• Partner and localiser of BRCA2 (PALB2)
• Serine/threonine kinase 11 (STK11)

As with mutations in the BRCA1 and BRCA2 genes, some of the genes included in these panels may be related to the development of other cancers as well as additional unrelated disorders. The cost of these multi-gene panels varies considerably from one provider to the next. 

Mutations that are known to be associated with an increased risk of developing breast cancer are inherited in an autosomal dominant manner. This means that a carrier of a mutation has one functional gene and one faulty gene. The faulty gene can be passed on to their children. The children of a mutation carrier have a 50% chance of inheriting their parent’s mutation and a 50% chance of not inheriting it. As a result, mutation carriers have a high risk (but not 100% risk) of developing cancer in their lifetime. The type of cancer and associated risk depends on the gene involved.

Whilst testing for several genes at once has its benefits, there is a possibility that one could find a change in a gene for which the significance related to the development of cancer is not yet well-understood; these are called variants of uncertain significance (VUS). Importantly, a VUS, regardless of the gene that it is identified in, is not a clinically-actionable finding. 

Diagnostic vs predictive 

Genetic testing for hereditary breast cancer is offered to symptomatic and asymptomatic individuals identified as being at-risk. Diagnostic genetic testing is offered if you have a personal breast cancer diagnosis and predictive testing is offered if you’re unaffected but have a positive family history of a hereditary cancer syndrome with an already identified mutation in an affected family member. If you’re in this category, you’re at 50% risk of inheriting the familial mutation that is associated with an increased susceptibility to cancer. 

Speak to a genetic counsellor

Genetic counsellors are healthcare professionals with specialised education in genetics and counselling. Genetic counsellors provide risk assessment, education and support to individuals and families affected by, or at risk of, genetic conditions including hereditary cancer syndromes. We interpret and communicate genetic testing results in an understandable manner, provide psychosocial counselling and serve as patient advocates.

Earlier referral to a genetic counsellor can be beneficial because treatment and management options can be better informed if a hereditary cancer syndrome is diagnosed. The outcome of genetic testing may also have important implications for biological relatives. At-risk relatives can then access genetic counselling and testing and, if necessary, put appropriate screening and management practices in place to manage their risk in the future.

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