A cancer diagnosis has a huge impact on the patient as well as for their family. In some cases, it can also affect the risk of developing cancer in family members. Regarding breast cancer, it could be generations of women (or men) concerned about their possible predisposition.
Which genes are associated with hereditary breast cancer?
A little over 25 years ago, the BRCA1 (in 1994) and BRCA2 (in 1995) genes were identified as genes predisposing to breast and ovarian cancer. (BRCA stands for « BReastCAncer »). This discovery contributed to cancer research and enabled identifying new opportunities to improve prevention and treatment. BRCA1 and BRCA2 are frequently identified (30-40% of cases) with hereditary breast cancer. Other genes have also been associated with an increased risk of developing breast cancer such as PALB2, CHEK2, CDH1, ATM, to name a few. Research could identify other genes over the next few years.
How common is hereditary breast cancer?
As mentioned in our previous article, most cancers, including breast cancer, are sporadic, which means they have no known cause. Approximately 1 in 8 women (12%) will be diagnosed with breast cancer and about 10% are associated with hereditary predisposition.
Following the discovery of the BRCA genes, it was estimated that approximately 1 in 400 (0.25%) of the general population carried a pathogenic variant in the BRCA1 or BRCA2 genes. Recently, those numbers have been questioned by several studies and it is possible that the number of BRCA carriers could be closer to 1/200 (0.5%) or more. A recent study including over 26,000 “healthy” individuals from the general population tested the participants for BRCA genes. A pathogenic or probably pathogenic variant was identified in 0.66% (or 1/151) of the participants.
Research has also shown that certain populations have an increased risk to hereditary breast cancer. About 1 in 40 people of Ashkenazi Jewish descent carry a BRCA1 or BRCA2 mutation. We also observe a higher frequency of BRCA and PALB2 pathogenic variants in the French Canadian population.
What are the risks of cancer for a carrier?
An individual who carries a pathogenic variant in a c hereditary cancer predisposition gene is at greater risk of developing certain types of cancer compared to the general population. Each gene is associated with an increased risk for different types of cancer, cin women and in men.
Some examples : For a woman BRCA2 carrier, the risk of developing breast cancer during her lifetime is between 38 and 84% and the risk of ovarian cancer is 16 to 27%. A man BRCA2 carrier, has a 7-9% risk of developing breast cancer and a 20% risk of prostate cancer. Men and women with BRCA2 also have an increased risk of developing pancreatic cancer or melanoma. The CHEK2 gene is associated with a 25-40% risk of breast cancer in women and a higher risk of colorectal cancer in both women and men carriers.
Why should I do a genetic test?
A carrier A carrier has access to different screening and risk reduction options than the general population. For example, it is recommended that women begin mammography at age 50. For a woman with BRCA1, it is recommended to begin magnetic resonance imaging of the breasts at the age of 25, plus an annual mammogram beginning at the age of 30. The goal is to detect the cancer at an early stage, if a cancer was to develop. Some women, like Angelina Jolie, choose risk reduction options, such as bilateral prophylactic mastectomy (removal of the breasts before cancer develops).
A person who is not a carrier the pathogenic variant already known in their family does not have an increased risk of cancer despite the family history and can follow the screening recommendations for the general population.
Who should be tested?
A genetic test is usually offered if the person meets the criteria used by the genetic clinic. These criteria may vary from one health centre to another, but they usually include :
- Having a family member with a pathogenic variant identified in a cancer predisposition gene
- Having a personal diagnosis or family history of :
- Breast cancer before the age of 45
- Triple-negative breast cancer before the age of 60
- A person with more than one breast cancer (contralateral or in the same breast) or one breast cancer and another cancer
- Ovarian cancer
- Breast cancer in men
- Pancreatic cancer
- Metastatic prostate cancer or before the age of 55
- Ashkenazi Jewish ancestry and a diagnosis of one of the cancers mentioned
However, several recent studies[v]–[vi]–[vii]–[viii] have shown that 30 to 50% of individuals carrying a pathogenic BRCA variant did not meet testing criteria. There are currently options available in the private sector for proactive genetic testing (preventive) when there is no family history of cancer.
If you have any questions or concerns about the risk of breast cancer associated in relation with your family history, you should discuss with your physician who may refer you to a genetic clinic where a genetic counsellor can assess your risks, determine if you are eligible for genetic testing, and discuss your options.
Nathalie Bolduc, MSc, CGAC, CGC
Certified genetic counselor
[V] Neben CL, Zimmer AD, Stedden W, van den Akker J, O’Connor R, Chan RC, Chen E, Tan Z, Leon A, Ji J, Topper S, Zhou AY. Multi-Gene Panel Testing of 23,179 Individuals for Hereditary Cancer Risk Identifies Pathogenic Variant Carriers Missed by Current Genetic Testing Guidelines. J Mol Diagn. 2019 Jul;21(4):646-657. doi: 10.1016/j.jmoldx.2019.03.001. Epub 2019 Jun 11. PMID: 31201024. https://www.jmdjournal.org/article/S1525-1578(18)30334-9/fulltext
[VI] Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Br J Cancer 83, 1301–1308 (2000). https://doi.org/10.1054/bjoc.2000.1407 https://www.nature.com/articles/6691407
[VII] Grzymski, J.J., Elhanan, G., Morales Rosado, J.A. et al. Population genetic screening efficiently identifies carriers of autosomal dominant diseases. Nat Med 26, 1235–1239 (2020). https://doi.org/10.1038/s41591-020-0982-5
[VIII] Neben CL, Zimmer AD, Stedden W, van den Akker J, O’Connor R, Chan RC, Chen E, Tan Z, Leon A, Ji J, Topper S, Zhou AY. Multi-Gene Panel Testing of 23,179 Individuals for Hereditary Cancer Risk Identifies Pathogenic Variant Carriers Missed by Current Genetic Testing Guidelines. J Mol Diagn. 2019 Jul;21(4):646-657. doi: 10.1016/j.jmoldx.2019.03.001. Epub 2019 Jun 11. PMID: 31201024. https://www.jmdjournal.org/article/S1525-1578(18)30334-9/fulltext