BRCA1: Increased Susceptibility to Breast and Ovarian Cancers
What is BRCA1?
BRCA1, formally known as "breast cancer 1, early onset," plays a key role in cancer susceptibility, particularly breast and ovarian cancers (1). Despite its negative association with cancer, BRCA1 and its cousin BRCA2 are not oncogenes--BRCA1 is a tumor suppressor gene that actually guards against cell damage and unregulated growth. It is a mutation in BRCA1 that increases one's susceptibility to early-onset cancers. And though the gene is most frequently linked to breast cancer, a BRCA1 mutation may also contribute to ovarian cancer and/or cancer of the fallopian tubes (in women), prostate cancer (in men), peritoneal cancer, and pancreatic cancer (2). And to a lesser extent, breast cancer can also affect men.
Location on the Chromosome
Fig. 1
From Genetics Home Reference:
"The BRCA1 gene is located on the long (q) arm of chromosome 17 at position 21. More precisely, the BRCA1 gene is located from base pair 43,044,294 to base pair 43,125,482 on chromosome 17."
BRCA1 has over 81,000 base pairs.
"The BRCA1 gene is located on the long (q) arm of chromosome 17 at position 21. More precisely, the BRCA1 gene is located from base pair 43,044,294 to base pair 43,125,482 on chromosome 17."
BRCA1 has over 81,000 base pairs.
The BRCA1 Protein
Fig. 2
Function in the Cell:
BRCA1 interacts with other proteins in the cell’s nucleus to repair damage to DNA caused by environmental factors like radiation or chemical exposure. It also regulates the process of crossing-over before mitosis so that no mistakes are made in the replication process (1).
BRCA1 interacts with other proteins in the cell’s nucleus to repair damage to DNA caused by environmental factors like radiation or chemical exposure. It also regulates the process of crossing-over before mitosis so that no mistakes are made in the replication process (1).
The Genetics of BRCA1
The BRCA1 gene is part of a family of genes called the RNF gene family. This group of genes are known to produce RING-type zinc finger proteins, proteins that have many cellular functions. These proteins are stable, break down targeted proteins in the cell, and manage cell growth (1). BRCA1 reportedly interacts with other genes, receptors, kinases, and proteins, including BRCA2 (6).
Many other mammals, such as mice, share a homologous version of the BRCA1 gene, thought to be descended from an ancestral version of the gene (SOURCE NEEDED).
Many other mammals, such as mice, share a homologous version of the BRCA1 gene, thought to be descended from an ancestral version of the gene (SOURCE NEEDED).
Why BRCA1 Matters
Mutations of the BRCA1 gene hold a prominent role in contributing to likelihood of developing breast cancer and ovarian cancer. About 3 out of 5 women with a harmful variation of the gene will develop breast cancer before the age of 70, while 2 out of 5 women with a harmful variation will develop ovarian cancer by the same age. Women with harmful mutations are also at a higher risk of developing Fallopian tube cancer and peritoneal cancer (cancer of the peritoneum, a membrane lining the abdomen). In addition, men with mutations are at a higher risk of breast and prostate cancer. Both men and women with a harmful mutation are at a higher risk of pancreatic cancer (2).
Genetic Testing for BRCA1
All information in this section is courtesy of Susan G. Komen.
The majority of breast cancers are not directly related to BRCA1 and/or BRCA2 (7). However, since the cancers resulting from a mutation in these genes can be particularly virulent and occur earlier in life, genetic testing is recommended for women with specific family medical histories. The BRCA1 genetic test is widely marketed, but Susan G. Komen, a leading breast cancer-awareness nonprofit, recommends testing only if a person has:
The test for a BRCA1 mutation is a blood test, but it can be expensive and carry emotional costs as well. Most tests are carried out on patients already diagnosed with breast or ovarian cancer, as the results of the test can guide the patient's treatment and warn family members who may also be carriers of the mutation. Susan G. Komen lists the three outcomes of a BRCA1 gene test:
Testing should always be carried out by specially-trained medical professionals—home kits are available but their use is strongly discouraged. If currently non-cancerous patient finds out they
have a BRCA1 mutation linked to cancer, this does not mean they will most definitely get cancer!
There are plenty of people who carry the gene and never develop cancer. However, more frequent
cancer screenings and the maintenance of a healthy lifestyle will be highly recommended for these patients.
- A personal history of breast cancer at age 50 or younger
- A personal history of triple negative breast cancer (breast cancer that is estrogen receptor-negative , progesterone receptor-negative, and HER2/neu receptor-negative
- A personal or family history of male breast cancer
- A personal or family history of bilateral breast cancer (cancer in both breasts)
- A personal history of ovarian cancer
- A parent, sibling, child, grandparent, grandchild, uncle, aunt, nephew, niece or first cousin diagnosed with breast cancer at age 45 or younger
- A mother, sister, daughter, grandmother, granddaughter, aunt, niece or first cousin diagnosed with ovarian cancer
- A family history of both breast and ovarian cancers on the same side of the family (either mother's or father's side of the family)
- Ashkenazi Jewish heritage and a family history of breast or ovarian cancer
The test for a BRCA1 mutation is a blood test, but it can be expensive and carry emotional costs as well. Most tests are carried out on patients already diagnosed with breast or ovarian cancer, as the results of the test can guide the patient's treatment and warn family members who may also be carriers of the mutation. Susan G. Komen lists the three outcomes of a BRCA1 gene test:
- No mutation (negative or normal)
- A mutation linked to cancer (positive or carrier)
- A mutation not currently known to increase breast cancer risk (called a variant of uncertain significance)
Testing should always be carried out by specially-trained medical professionals—home kits are available but their use is strongly discouraged. If currently non-cancerous patient finds out they
have a BRCA1 mutation linked to cancer, this does not mean they will most definitely get cancer!
There are plenty of people who carry the gene and never develop cancer. However, more frequent
cancer screenings and the maintenance of a healthy lifestyle will be highly recommended for these patients.
The Potential for Breast Cancer Treatments
In 2009, a study under the Gynecologic Medical Oncology Program tested a targeted gene therapy for a group of individuals with mutations of the BRCA1 and BRCA2 genes. A group of patients took a set of pills called PARP inhibitors, a type of polymerase targeted against breast and ovarian cancers. One particular patient, Fermina Hanson, experienced a receding tumor over a period of 8 months (4).
QUESTIONS TO RESEARCH
● How was the gene discovered and located on the chromosome?
● What processing has to happen in the expression of the gene? Is it known how many exons and introns it has? Are there multiple ways in which the gene can be spliced?
● What do we know about about when/where the gene is expressed? (What cell type, body tissue, at what age, etc.)
● Is it known what other genes are involved in regulating the expression of this gene? Are other gene interactions known?
● What gene product (protein or RNA molecule – assume protein for the other questions, but related questions can be posed about RNA genes) does the gene encode for? What does this protein do? How does it function?
○ How does the protein act within the cell? How does this affect the body?
● Does the gene affect other genes? Do we know if the gene product interacts with other gene products – protein/protein interactions?
● Are there epigenetic effects associated with this gene?
● How was the gene discovered and located on the chromosome?
● What processing has to happen in the expression of the gene? Is it known how many exons and introns it has? Are there multiple ways in which the gene can be spliced?
● What do we know about about when/where the gene is expressed? (What cell type, body tissue, at what age, etc.)
● Is it known what other genes are involved in regulating the expression of this gene? Are other gene interactions known?
● What gene product (protein or RNA molecule – assume protein for the other questions, but related questions can be posed about RNA genes) does the gene encode for? What does this protein do? How does it function?
- ○ What shape does the protein take? How does this affect its purpose in the cell?
○ How does the protein act within the cell? How does this affect the body?
● Does the gene affect other genes? Do we know if the gene product interacts with other gene products – protein/protein interactions?
● Are there epigenetic effects associated with this gene?
Works Cited
- "BRCA1." Genetics Home Reference. National Library of Medicine, 5 May 2014. Web. 7 May 2014. <http://ghr.nlm.nih.gov/gene/BRCA1>.
- "BRCA1 and BRCA2: Cancer Risk and Genetic Testing." National Cancer Institute. National Institutes of Health, 22 Jan. 2014. Web. 7 May 2014. <http://www.cancer.gov/cancertopics/factsheet/Risk/BRCA>.
- "Breast Cancer 1, Early Onset." Gene Cards. Weizmann Institute of Science, n.d. Web. 7 May 2014. <http://www.genecards.org/cgi-bin/carddisp.pl?gene=BRCA1>.
- McCaffrey, Pat. "2009 Turning Point: Targeted Therapy Takes Aim at Breast and Ovarian Cancers." Dana-Farber Cancer Institute. Dana-Farber Cancer Institute, n.d. Web. 7 May 2014. <http://www.dana-farber.org/Newsroom/Publications/Targeted-therapy-takes-aim-at-breast-and-ovarian-cancers.aspx>.
- McKusick, Victor A. "113705 Breast Cancer 1 Gene; BRCA1." Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University, 14 Jan. 2014. Web. 7 May 2014. <http://www.omim.org/entry/113705>.
- "P38398 (BRCA1_HUMAN) Reviewed, UniProtKB/Swiss-Prot." UniProt. UniProt Consortium, 16 Apr. 2014. Web. 7 May 2014. <http://www.uniprot.org/uniprot/P38398>.
- "Testing for BRCA1 & BRCA2 Mutations." Susan G. Komen. Susan G. Komen, 16 Jan. 2014. Web. 7 May 2014. <http://ww5.komen.org/BreastCancer/GeneMutationsampGeneticTesting.html>.
Image Credits
- Figure 1: "PDB rendering based on 1jm7." Wikipedia. Wikimedia Commons, n.d. Web. 7 May 2014. <http://en.wikipedia.org/wiki/BRCA1>.
- Figure 2: "Location of the BRCA1 gene on chromosome 17." Wikipedia. Wikimedia Commons, n.d. Web. 7 May 2014. <http://en.wikipedia.org/wiki/BRCA1>.
- Susan G. Komen logo. Susan G. Komen. Susan G. Komen, n.d. Web. 7 May 2014. <http://ww5.komen.org/Default.aspx>.