Hereditary breast cancer

Editorial

How common is breast cancer?


More than one in ten Swedish women will be diagnosed with breast cancer during their liftetime, which makes breast cancer the most common type of cancer in Swedish women1. The majority of women are diagnosed between 60 and 69 years of age. Breast cancer is uncommon in men and about 40 men were diagnosed with breast cancer in Sweden in 2017.

What causes breast cancer?

About 80 to 85% of all breast cancer2 is caused by DNA damage, which can occur during DNA replication or be due to environmental factors. DNA damage occurs all the time and most of the time it is repaired. But with age comes an accumulation of DNA damage, and in turn a higher likelihood that a normal cell transforms into a cancer cell. Age is therefore the leading risk factor for cancer.

The remaining 15 to 20% of all breast cancer is explained by hereditary factors2. The impact of hereditary factors on the risk of developing breast cancer can range from small to very large. What they have in common is that individuals with a hereditary risk of cancer are born with one high-risk genetic variant or several low-risk DNA variants that are present in all cells. These variants often affect proteins involved in DNA repair or in other ways protect cells from becoming cancer cells. Therefore, the ability to protect cells from becoming cancer cells may be impaired which results in DNA damage. Normal cells in individuals with a hereditary risk of cancer thus have a higher probability of becoming cancer cells.

In families where several women have been diagnosed with breast cancer, or where one woman has been diagnosed at a young age, hereditary cancer can be suspected. Other factors indicating heredity are cases of ovarian, prostate (before 65 years of age), pancreatic or male breast cancer in the same family1.

Underlying genetic factors

In about half of the families with a heredity risk for breast cancer it is possible to identify underlying genetic factors2. Some of these factors are also associated with an increased risk of ovarian, prostate, pancreatic and male breast cancer.

Pathogenic genetic variants associated with a moderate to high risk of breast cancer

About 20% of the familial risk is explained by pathogenic variants (mutations) in the genes BRCA1, BRCA2, TP53, STK11, CDH1 and PTEN2. These are so-called high-risk genes, meaning that carriers of a pathogenic variant have a high risk of developing breast cancer. Some of these genes are associated with increased risk of other types of cancer, such as diffuse gastric cancer in the case of CDH1.

An additional 5% of the hereditary risk is explained by pathogenic variants in genes associated with a moderate risk of developing breast cancer. Among these genes are PALB2, CHEK2, ATM and NF13.

The clinical genetic testing performed today includes genes* associated with a moderate to high risk of breast cancer. For women, a pathogenic variant in any of these genes indicates participation in an established screening program consisting of yearly breast exams with the aim of early discovery of a possible breast cancer. For carriers of pathogenic variants in genes associated with a high risk of breast as well as ovarian cancer (mainly BRCA1 and BRCA2) the risk can be reduced by prophylactic surgery.

Genetic regions associated with a minimally increased risk of breast cancer

In addition to the pathogenic variants contributing to a high or moderate risk of breast cancer there are almost 200 genetic regions that are associated with a minimally increased risk of breast cancer2. On their own, variants in these regions are associated with a minimally increased risk of breast cancer but together they account for approximately 18% of the hereditary risk.

Hereditary breast cancer with an unknown genetic cause

As previously mentioned it is possible to identify underlying genetic factors in about half of the families with heredity risk for breast cancer2. Given that the genetic regions associated with a minimally increased risk of breast cancer are not included in clinical genetic testing, a genetic cause can be identified in about 25% of families that meet the criteria for hereditary breast cancer by todays method’s (described under ”Pathogenic genetic variants associated with a moderate to high risk of breast cancer”). As a result, there are families that are determined to have an increased risk for breast cancer based on their family history, but without an identifiable genetic cause.

Healthy females with an increased risk of breast cancer based on family history of are recommended yearly breast exams. In the case of very high hereditary risk, prophylactic surgery is offered. Breast exams are recommended to start five years of age before the family’s earliest breast cancer diagnosis or by age 40, whichever comes first1. The GeneMate® test includes a genetic test and an assessment of your family’s cancer history, either of which can indicate an increased risk of breast cancer. Therefore, it is important that you fill in your family history when ordering the test. We will help you to get in contact with the appropriate care giver if cancer screening is motivated.

* GeneMate® tests for pathogenic variants in the following genes: BRCA1, BRCA2, PALB2, TP53, PTEN, CDH1, STK11, NF1, CHEK2 and ATM. The complete panel is available at genemate.se.

 

ORDER

 

Anna Hellquist, Genetic Counselor at iCellate Medical AB, PhD Cell and Microbiology

 

References

  1. Nationellt vårdprogram bröstcancer - RCC Kunskapsbanken. https://kunskapsbanken.cancercentrum.se/diagnoser/brostcancer/vardprogram/arftlig-brostcancer/. Published August 25, 2020. Accessed September 9, 2020.
  2. Wendt C, Margolin S. Identifying breast cancer susceptibility genes - a review of the genetic background in familial breast cancer. Acta Oncol. 2019;58(2):135-146. doi:10.1080/0284186X.2018.1529428
  3. Angeli D, Salvi S, Tedaldi G. Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?. Int J Mol Sci. 2020;21(3):1128. Published 2020 Feb 8. doi:10.3390/ijms21031128