Difference between BRCA1 and BRCA2

What is BRCA1 and BRCA2?

BRCA1 and BRCA2 are tumor suppressor genes, which means that they keep cells from growing too rapidly. Breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) are found in a wide variety of organisms and help stabilize the genome. If you have been tested positive for either BRCA1 or BRCA2 you’re at high risk for breast and ovarian cancer, including other cancers like prostate and colorectal cancer. Another gene PALB2 is also responsible for increasing the risk of breast cancer. Breast cancer risk for normal women is around 12% and chances are they might develop breast cancer in some stages of their lives. However for men the chances are about 0.13%. While if you have BRCA1 or BRCA2 mutation your risk of developing breast cancer is in between 45% to 70% compared to women who do nor harbour any mutation, i.e. around 6 times at higher risk.

Association of BRCA1 and BRCA2 with risk of various cancers: 

BRCA genes mutation carriers have an increased risk for other cancers like colon, prostate, pancreatic, melanoma, and gastric cancers. BRCA1 gene mutation is mostly responsible for development of breast cancer with increased risk of ovarian cancer in women, and prostate cancer in men. While BRCA2 mutation leads to increased ovarian cancer in women and breast cancer in men. BRCA1 mutation leads to development triple-negative breast cancer (TNBC) where there is no overexpression of estrogen receptor (ER), progesterone receptor, or human epidermal growth factor receptor-2 (HER-2). Since there are no overexpression present, targeted therapy cannot be given and the given treatment would only target cells which carry BRCA1 mutation and not the healthy cells.

Pattern of Inhertiance of BRCA1 and BRCA2: 

And if you have been diagnosed with either of the BRCA mutation using genetic testing such as Myriad BRCAnalysis there is 50% chances of passing the mutation on to your children. If BRCA is inherited from both parents can cause rare conditions like Fanconi anemia which is associated with acute myeloid leukemia and childhood tumors. And if a person has inherited BRCA1 and BRCA2 mutation which means that each of their siblings have 50% chances of being inherited with that mutation as well. BRCA1 mutation carries have the increased risk of breast cancer and mortality than BRCA2 mutation. Women with BRCA1 mutation had poor prognosis with respect to women carrying BRCA2 mutation.

Clinical management of BRCA1 and BRCA2 positive Breast cancer: 

If you have been diagnosed with breast cancer carrying BRCA mutation, the choice of treatment depends on which of the BRCA mutation you have been tested positive for (BRCA1/BRCA2). Types of treatment included can be ranging from surgery, chemotherapy, hormonal therapy, targeted therapy and so on. The most known targeted therapy for BRCA mutation include PARP inhibitors which have been approved by FDA for treating metastatic breast cancer. PARP inhibitors are targeted therapy for people with hereditary BRCA1 or BRCA2 mutations diagnosed with cancers like breast, ovarian and prostate cancers. BRCA1 can be used as a predictive marker with respected to different type of chemotherapy agents.

With compared to BRCA2 mutation, BRCA1 has been studied on the basis of clinical evidence to have benefited DNA damage-based chemotherapy. Taxanes and platinum agents are been used for chemotherapeutic treatment in breast cancer. Docetaxel and paclitaxel are the most widely used as taxanes for breast cancer treatment which has been approved since 1990. BRCA1 mutation carries were less sensitive to taxane chemotherapy than non-BRCA1 mutation carriers hormone-negative patients. However platinum based therapy had better response with respect to BRCA1 associated breast cancer and than taxanes therapy. Studies have been reported where the combination of chemosynthetic drugs which might have better benefit, like anthracycline-taxane showed complete response, addition of platinum agents with standard therapy lead to better response by including cisplatin or carboplatin in triple negative breast cancer. Several clinical trials are now focusing these combination therapies including in combination with PARP inhibitors, taxanes and platinum based therapy. Though BRCA1 mutation can help from prevention to management and treatment options, the main motto is to find particular drug either in alone or in combination therapies including clinical trails which matches and benefits the individual patients and the cancer type.

References:

Godet, Inês, and Daniele M. Gilkes. “BRCA1 and BRCA2 mutations and treatment strategies for breast cancer.”Integrative cancer science and therapeutics 4.1 (2017).

Haque, Reina, et al. “Survival Outcomes in BRCA1 or BRCA2 Mutation Carriers and the Influence of Triple-Negative Breast Cancer Subtype.” The Permanente Journal 22 (2018).

https://www.cancer.gov/types/breast/risk-fact-sheet

https://ovarian.org.uk/ovarian-cancer/brca/i-have-a-genetic-mutation/starting-family/

https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet

https://www.breastcancer.org/research-news/20101024

https://www.breastcancer.org/research-news/20070907

https://www.breastcancer.org/symptoms/testing/genetic/pos_results

https://www.nationalbreastcancer.org/what-to-do-if-youve-tested-positive

https://www.mayoclinic.org/tests-procedures/brca-gene-test/about/pac-20384815

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Nielsen, Finn Cilius, Thomas van Overeem Hansen, and Claus Storgaard Sørensen. “Hereditary breast and ovarian cancer: new genes in confined pathways.” Nature Reviews Cancer 16.9 (2016): 599.

Mehrgou, Amir, and Mansoureh Akouchekian. “The importance of BRCA1 and BRCA2 genes mutations in breast cancer development.” Medical journal of the Islamic Republic of Iran 30 (2016): 369.

Pfeffer, Claire M., Benjamin N. Ho, and Amareshwar TK Singh. “The evolution, functions and applications of the breast cancer genes BRCA1 and BRCA2.” Cancer Genomics-Proteomics14.5 (2017): 293-298.

Tung, Nadine M., and Judy E. Garber. “BRCA 1/2 testing: therapeutic implications for breast cancer management.”British journal of cancer 119.2 (2018): 141.

van den Broek, Alexandra J., et al. “Worse breast cancer prognosis of BRCA1/BRCA2 mutation carriers: what’s the evidence? A systematic review with meta-analysis.” PloS one10.3 (2015): e0120189.

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By ~ Kartik Sharma

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