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Castle Medical BRCA1/2 panel® FAQs
BRCA1/2 genes as one of the important hereditary risk factors for cancer development.
Breast cancer is the most commonly diagnosed cancer among American women. As per the National Cancer Institute statistics,
every 1 in 8 women in the United States will develop breast cancer in their life time (Howlader, 2012). Breast cancer is a complex,
multifactorial disease with a strong interplay between genetic and environmental factors. About 10-12% of all the breast cancer
cases are due to presence of hereditary pathogenic genetic mutations that are passed from one generation to another.
Like breast cancer, ovarian cancer is also a serious health concern for women. Ovarian cancer is the 5th leading cause of cancer
related deaths among women and has been associated with multiple risk factors. Inherited genetic changes are one of the major risk
factors that not only influence person’s own risk but also impact the risk of developing cancer in other family members.
BRCA1 and BRCA2 (BReast CAncer gene 1 and 2) are the most common genes that have been identified to contribute in breast
and ovarian cancer. BRCA1 and BRCA2 are human genes that code for tumor suppressor proteins and aid in DNA repair processes
and therefore maintain the integrity of the cells’ genetic material. BRCA1/2 proteins prevent uncontrolled cell division that leads
to the development of cancer. Pathogenic mutations in BRCA1/2 genes result in the formation of dysfunctional proteins which
increases the risk of developing cancer specially, breast and ovarian cancer (Roy, 2011) (Welcsh, 2001).
Germline mutations in BRCA1/2 genes are inherited from carrier parents to their offspring and only one copy of mutated BRCA1/2
gene is sufficient to increase the risk of developing cancer. This pattern of inheritance is called “Autosomal Dominant Inheritance”.
If one of the parents is a carrier of mutated BRCA1/2 genes, then the offspring have 50% chance of inheriting that mutation. In
addition, if a person is found positive for BRCA1/2 mutation then his/her siblings have 50% chance of getting that mutations.
BRCA1/2 test does not only predict patients own risk but also provides insight about the family risk of developing cancer.
How much cancer risk is associated with BRCA1/2 gene mutations?
As per the National Cancer Institute, a woman’s life time risk of developing breast and ovarian cancer increases significantly if she
inherits a pathogenic mutation in either BRCA1 or BRCA2 gene (Antoniou, 2003) (Chen, 2007) (Howlader, 2012).
The graph below compares the life time breast and ovarian cancer risk between women positive for harmful BRCA1/2 mutations
to women from general population.
Estimated life time risk of developing
breast and ovarian cancer with and
without BRCA1/2 mutations.
70
60
50
40
30
20
10
0
Women in general population
BRCA1 positive women
Percentage Breast cancer risk
BRCA2 positive women
Percentage Ovarian cancer risk
Figure 1. Estimated life time risk of developing breast and ovarian cancer with and without BRCA1/2 mutations (Howlader, 2012).
Castle Medical BRCA1/2 panel® FAQs
In addition to breast and ovarian cancer, mutations in BRCA1/2 genes can also increase the risk for other cancers. Presence of
BRCA1 mutation(s) increases risk of fallopian tube cancer and peritoneal cancer in women (Finch, 2006). In addition, the presence
of pathogenic mutation(s) in BRCA1/2 gene increase the chance of prostate cancer in men (Levy-Lahad, 2007). Other cancer such
as pancreatic cancer (Ferrone, 2009) and melanoma (Cruz, 2011) have been reported to be associated with BRCA1/2 gene
mutations. However, their precise contributions in the pathophysiology of these cancers is not well established.
How prevalent are BRCA1/2 gene mutations in different ethnic population?
Mutations in BRCA1/2 genes are more frequent in certain ethnic populations than others. For example, harmful mutations like
c.5946delT (BRCA2), c.5266dupC (BRCA1) and c.68_69delAG (BRCA1) are more prevalent in people from Ashkenazi Jewish
ancestry than any other population in the United States. Other ethnic and geographic populations like Norwegian, Dutch and
Icelandic people also have relatively higher frequency of carrying specific BRCA1/2 mutations (Janavičius, 2010).
Who should consider BRCA genetic testing?
Genetic tests are available to detect the pathogenic mutations in BRCA1/2 genes that can predict patient’s risk of developing breast
cancer and ovarian cancer. Since these mutations are not common in general population it is recommended that individuals should
be screened before undergoing genetic testing. The following factors should be considered when evaluating an individual’s
eligibility for the BRCA1/2 testing:
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If the person has been diagnosed with breast cancer before age 50
If the person has been diagnosed for ovarian/fallopian tube/primary peritoneal cancer at any age
If the person has been diagnosed with male breast cancer at any age
If the person has bilateral breast cancer or two separate tumors in both the breasts
If the person is diagnosed with triple-negative (ER/PR/HER2-neu negative) breast cancer
If the person has a close relative with both breast and ovarian cancer
If two or more close relatives on the same side of the family have had breast cancer
If the person has a close blood relative with cancer in both breasts
If member(s) of the family has been tested positive for BRCA1/2 hereditary pathogenic mutation(s)
If the person has Ashkenazi Jewish ethnicity
If a close family relative on the same side of the family has multiple cancers that suggest the presence of an inherited
cancer syndrome
How does Castle Medical BRCA1/2 panel® work?
Our molecular diagnostic team has developed and validated a test panel for BRCA1 and BRCA2 genes which can detect all possible
pathogenic, non-pathogenic variants in these genes and predicts patients’ risk of developing breast/ovarian cancer. We have listed
the specimen type and other necessary items required to run this test:
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Specimen type: Minimum of 5 ml whole blood collected in lavender top (EDTA containing) TWO separate tubes.
Samples should be stored/transported at room temperature. This sample is stable at room temperature for about 5-7 days.
Castle Medical’s molecular diagnostic requisition form: Requisition form filled with all the necessary information that
includes patients’ demographics, name of the test requested, patient’s and physician’s signature.
Precertification authorization number from patient’s insurance company.
A consent form (can be downloaded from the Castle’s website) signed by the patient and his/her healthcare provider.
All the above mentioned items are required for us to proceed with the testing. Once all the necessary items are received, specimens
are processed to extract DNAs and after proper quality assessment the entire coding regions of BRCA1 and BRCA2 genes are
sequenced by Next generation sequencing method. Appropriate positive and negative controls are included in each reaction in order
to ensure precision and data quality.
Castle Medical BRCA1/2 panel® FAQs
What is the turnaround time for the BRCA1/2 test?
Average turnaround time for BRCA1/2 test is about 25 days from the day sample and all the other requested items are received.
Results will be sent to the designated healthcare provider by fax as well as by HIPPA secure online portal. Incomplete information
or failure to provide correct information might lead to delay in the results or rejection of the test.
What are the other criteria which might lead to delay or rejection of the test?
Wrong specimen type: Samples like serum, plasma can not be used for this purpose. Wrong specimen will lead to rejection of the
test.
Incorrectly stored/shipped sample: Clotted blood, frozen blood, leaking tube will result in the rejection of the test.
Incomplete/wrong requisition form: Wrong requisition form, incomplete information on the requisition form will result in delay in
the results.
Failure to provide Precertification authorization number might cause delay or rejection of the test results.
Incomplete/failure to provide patient consent form might lead to delay or rejection of the test results.
What are the implications for the test results?
BRCA genetic test report can give several possible results. According to American College of Medical Genetics and Genomics
(ACMG) guidelines mutations are classified as “Pathogenic”, “Likely Pathogenic”, “Benign”, “Likely Benign” and “Uncertain
significance”. The term “Likely benign” and “Likely pathogenic” defines the variants that can be called as benign and pathogenic
respectively with more than 90% certainty (Richards, 2015). To assess the cancer risk associated with each variant, we review
published evidence in the literature and other mutation databases. In addition to this, some computer models like SIFT, PolyPhen2 are also utilized to predict the clinical significance of the variants.
In the results we only report pathogenic, likely benign, likely pathogenic and mutations of unknown significance. Our reports will
not reflect the presence of any benign mutations but we can provide this information if requested. It is very important for the
healthcare providers to interpret the BRCA test report correctly and take proper clinical actions according to the patient results.
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Positive results: Positive BRCA test results implies that the patient carries a harmful mutation(s) in either or both BRCA1
and BRCA2 genes, which increases patient’s risk of developing breast and ovarian cancer as compared to general
population. However, positive test results don’t necessarily mean that the patient will develop cancer. Not all the carriers
of harmful BRCA1/2 mutations are known to develop breast/ovarian cancer. In addition to patient’s own risk, a positive
test results can also predict the potential risk of patient’s family members. Presence of a harmful BRCA1/2 mutation
means that the patient’s offspring have 50% chances of inheriting those mutations. Likewise, siblings of the patient
positive for harmful BRCA1/2 mutation also have 50% chance of inheriting those mutations. Because of this it is
beneficial to consult the results with a genetic counsellor or health care provider to identify potentially high risk family
members.
Negative results: Negative BRCA test results means that no harmful BRCA1/2 mutation(s) detected in the patient’s DNA
sample. In this case patient’s risk of developing breast/ovarian cancer depends upon his/her personal medical history.
This results doesn’t completely rule out the possibility of patient to get breast/ovarian cancer. The presence of any novel
and rare mutations in BRCA1/2 genes for which there is no clinical information available can also contribute in the cancer
development. In addition, mutations in genes other than BRCA1/2 genes can also play role in breast/ovarian cancer
development.
Unknown significance: Presence of a variant with unknown significance means that there is no clinical data available to
define the pathogenicity of the variant. Due to lack of enough clinical evidences these variants are classified in a separate
category. In such cases, one should discuss the risk associated with such variant(s) with his/her healthcare provider or
genetic counselor to help make proper clinical decision.
What are recommended actions to manage the risk of developing cancer associated with positive BRCA test results?
Prior knowledge of a positive BRCA test results can be a useful tool for making proper informed decisions to prevent and
minimize the associated risk. Below are some of the recommended actions that can be taken to manage cancer risk in individuals
Castle Medical BRCA1/2 panel® FAQs
with harmful BRCA mutation according to National Cancer Institute and NCCN (National Comprehensive Cancer Network)
guidelines.
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Frequent screening: Women carrying harmful mutations are recommended to undergo clinical breast exam every 6-12
months beginning at the age of 25. In addition, annual MRI and mammogram should be done beginning at the age of
25 or younger. More frequent screening might detect the cancer in early stages where treatment is more likely to be
successful. For ovarian cancer there are no effective screening methods to reduce the risk of death associated.
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Pro-phyletic surgery: This method involves removal of the tissue that is at risk of developing cancer. Surgical removal
of both the breasts (bilateral prophylactic mastectomy) reduces the risk of breast cancer by at least 90 percent
(Hartmann, 1999) (Meijers-Heijboer, 2001). Similarly, removal of ovaries and fallopian tubes (bilateral prophylactic
salpingo-oophorectomy) reduces the risk of ovarian cancer by 90% and the risk of breast cancer by approximately 50%
(Guillem, 2006). It is important to note that getting a prophylactic surgery does not completely eliminate the risk of
developing cancer. Patient’s positive for BRCA1/2 test should consult their health care provider before making such
decisions.
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Chemoprevention: Chemoprevention therapy involves use of drugs to prevent or delay the progress of cancer in the
patients tested positive for BRCA1/2 genes. Tamoxifen is the anti-estrogen drug used to minimize the risk of breast
cancer. Studies have shown the effectiveness of tamoxifen in risk reduction in BRCA positive patients (King, 2001)
(Phillips, 2013) (Gronwald, 2006). Aromatase inhibitor drug, Exemestane has also been proven to be effective in
reducing the risk associated with the breast cancer (Goss, 2011). Oral contraceptives have shown to reduce the risk both
in general population as well as in women carrying BRCA1/2 mutations.
Additional Resources:
For more information about BRCA and associated cancer risk please visit the following links:
http://www.cancer.gov
http://www.facingourrisk.org
About Castle Medical:
Castle Medical, LLC is country’s one of the fastest-growing CAP and CLIA accredited national reference laboratory, located in
Smyrna, Georgia. Castle Medical seeks to “Bring truth and commonsense to healthcare” and has, thus, been dedicated in
revolutionizing health care services for last 5 years. Castle offers a wide range of clinical and molecular diagnostic tests. For
more information about Castle Medical please visit http://www.castlemedical.com/
References:
Antoniou. (2003). Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for
family history: a combined analysis of 22 studies. American Journal of Human genetics.
Chen, S. (2007). Meta-analysis of BRCA1 and BRCA2 penetrance. Journal of clinical oncology.
Cruz, C. (2011). Uveal Melanoma and BRCA1/BRCA2 Genes: A Relationship That Needs Further Investigation . Journal of Clinical Oncology.
Ferrone, C. (2009). BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. Journal of Clinical Oncology.
Finch, A. (2006). Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2
mutation. JAMA.
Goss, P. (2011). Exemestane for breast-cancer prevention in postmenopausal women. The New England journal of Medicine.
Gronwald, J. (2006). Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: An update. International Journal of Cancer.
Guillem, J. (2006). ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. Journal of Clinical
Oncology .
Hartmann, L. (1999). Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. New England Journal of
Medicine.
Castle Medical BRCA1/2 panel® FAQs
Howlader. (2012). SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations). National Cancer Institute.
Janavičius, R. (2010). Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control.
EPMA.
King, M. (2001). Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical
Adjuvant Breast and Bowel Project (NSABP–P1) Breast Cancer Prevention Trial. . JAMA.
Levy-Lahad. (2007). Cancer risks among BRCA1 and BRCA2 mutation carriers. British Journal of Cancer.
Meijers-Heijboer. (2001). Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. New England
Journal of Medicine.
N, H. (2012). SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations). National Cancer Institute.
Phillips, K. (2013). Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. Journal of Clinical Oncology.
Richards, S. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American
College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine.
Roy. (2011). BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nature Review Cancer.
Welcsh. (2001). BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Human Molecular Genetics.