21 Sep

BRCA Gene Mutations: Cancer Risk and Genetic Testing

ali Newsletter

What are BRCA1 and BRCA2?

BRCA1 (BReastCAncer gene 1) and BRCA2 (BReastCAncer gene 2) are genes that produce proteins that help repair damaged DNA, so when they have certain changes (mutations, harmful variant), cancer can develop.

Is it important to test for the presence of inherited harmful variants in BRCA1 or BRCA2 ?

People who inherit harmful variants in one of these genes have increased risks of several cancers—most notably breast and ovarian cancer.

The benefits of genetic testing outweigh any harm. Apart from the sense of relief from uncertainty and helping people make informed decisions about managing their health care, a true negative result can eliminate the need for unnecessary checkups and screening tests. A positive test result can direct a person toward available prevention, monitoring and treatment options.

How can a person who has inherited a harmful BRCA1 or BRCA2 gene variant reduce their risk of cancer?

Several options are available for reducing cancer risk in individuals who have inherited a harmful BRCA1 or BRCA2 variant. These include enhanced screening, risk-reducing surgery (sometimes referred to as prophylactic surgery), and chemoprevention.

11 situations should consider genetic testing for BRCA1 and BRCA2 variants

  • A personal history of breast cancer diagnosed before age 45
  • A personal history of breast cancer diagnosed before age 50 and a second primary breast cancer, one or more relatives with breast cancer, or an unknown or limited family medical history
  • A personal history of triple negative breast cancer diagnosed at age 60 or younger
  • A personal history of two or more types of cancer
  • A personal history of ovarian cancer
  • A personal history of male breast cancer
  • A personal history of breast cancer and one or more relatives with breast cancer diagnosed before age 50, two or more relatives diagnosed with breast cancer at any age, one or more relatives with ovarian cancer, one or more relatives with male breast cancer, or two or more relatives with prostate cancer or pancreatic cancer
  • A personal history of breast cancer and Ashkenazi (Eastern European) Jewish ancestry
  • A personal history of prostate cancer or pancreatic cancer with two or more relatives with BRCA-associated cancers
  • A history of breast cancer at a young age in two or more blood relatives, such as your parents, siblings or children
  • A relative with a known BRCA1 or BRCA2 mutation
  • One or more relatives with a history of cancer that would meet any of these criteria for gene testing.

Is there any treatment implications when having a harmful BRCA1 or BRCA2 variant for patients who have already developed cancer?

A class of drugs called PARP inhibitors, which block the repair of DNA damage, have been found to arrest the growth of cancer cells that have harmful BRCA1 or BRCA2 variants. Four PARP inhibitors—olaparib [Lynparza], rucaparib [Rubraca], niraparib [Zejula], and talazoparib [Talzenna]—are approved by the FDA to treat certain cancers bearing harmful variants in BRCA1 or BRCA2.

IS HRR TESTING AVAILABLE AT ALFA LAB?

Yes, by NGS technique in the genetic unit, too.

TEST INFO:

SAMPLE:3mL EDTA BLOOD
TAT:3 WKS
PRICE: 

REFERENCES:

  1. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2017, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2017/, based on November 2019 SEER data submission, posted to the SEER web site, April 2020.
  2. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 2017; 317(23):2402–2416. [PubMed Abstract]
  3. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. Journal of Clinical Oncology 2007; 25(11):1329–1333. [PubMed Abstract]
    https://www.mayoclinic.org
    1.  
21 Sep

The Basics on Hereditary Breast and Ovarian Cancer

ali Newsletter

If you are a woman with a family health history of breast or ovarian cancer, you may be more likely to get these cancers yourself. Collecting your family health history and sharing this information with your doctor can help you find out if you’re at higher risk. If so, you can take steps to lower your risk.

 

Each year, over 250,000 women in the United States learn that they have breast cancer and more than 20,000 find out that they have ovarian cancer. While most of these cancers happen by chance, some are hereditary, meaning that they are caused by genetic changes (called mutations) which are passed down in families.

Effective medical options are available for women at risk for hereditary breast and ovarian cancer that can make them less likely to get these cancers. Because of this, all women should learn about their family health history of breast and ovarian cancer to know if they could be at risk for hereditary breast and ovarian cancer.

The first step to find out if you are at risk is to collect your family health history of breast and ovarian cancer and share this information with your doctor. If your family health history shows that you could be at risk for hereditary breast and ovarian cancer, your doctor may refer you for genetic counseling and genetic testing.

The BRCA1 and BRCA2 Genes

The genes most commonly affected in hereditary breast and ovarian cancer are the breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes. About 3% of breast cancers (about 7,500 women per year) and 10% of ovarian cancers (about 2,000 women per year) result from inherited mutations in the BRCA1 and BRCA2 genes.

Normally, the BRCA1 and BRCA2 genes protect you from getting certain cancers. But some mutations in the BRCA1 and BRCA2 genes prevent them from working properly, so that if you inherit one of these mutations, you are more likely to get breast, ovarian, and other cancers. However, not everyone who inherits a BRCA1 or BRCA2 mutation will get breast or ovarian cancer.

Everyone has two copies of the BRCA1 and BRCA2 genes, one copy inherited from their mother and one from their father. Even if a person inherits a BRCA1 or BRCA2 mutation from one parent, they still have the normal copy of the BRCA1 or BRCA2 gene from the other parent. Cancer occurs when a second mutation happens that affects the normal copy of the gene, so that the person no longer has a BRCA1 or BRCA2 gene that works properly. Unlike the inherited BRCA1 or BRCA2 mutation, the second mutation would not be present throughout the person’s body, but would only be present in the cancer tissue.

Breast and ovarian cancer can also be caused by inherited mutations in genes other than BRCA1 and BRCA2. This means that in some families with a history of breast and ovarian cancer, family members will not have mutations in BRCA1 or BRCA2, but can have mutations in one of these other genes. These mutations might be identified through genetic testing using multigene panels, which look for mutations in several different genes at the same time.

You and your family members are more likely to have a BRCA1 or BRCA2 mutation if your family has a strong history of breast or ovarian cancer. Family members who inherit BRCA1 and BRCA2 mutations usually share the same mutation. If one of your family members has a known BRCA1 or BRCA2 mutation, other family members who get genetic testing should be checked for that mutation.

If you are concerned that you could have a BRCA1, BRCA2, or other mutation related to breast and ovarian cancer, the first step is to collect your family health history of breast and ovarian cancer and share this information with your doctor.

Family Health History and the BRCA1 and BRCA2 genes

Breast and ovarian cancers that run in families can be caused by genetic changes, or mutations, most commonly in the BRCA1 and BRCA2 genes. You can use the My Family Health Portrait tool to collect your family health history of breast, ovarian, and other cancers and share this information with your doctor. Your personal and family health history information can help your doctor decide whether to refer you for genetic counseling to find out if genetic testing might be right for you. It’s important to know that not everyone who inherits a BRCA1 or BRCA2 mutation will get breast or ovarian cancer. Also, not all inherited forms of breast or ovarian cancer are due to mutations in the BRCA1 and BRCA2 genes.

Can men get breast cancer? Men and BRCA-related cancers

Although breast cancer is much more common in women, men with BRCA1 or BRCA2 mutations are more likely to get breast cancer than other men. In addition, men with BRCA mutations are more likely to get high grade prostate cancer. Both men and women with BRCA mutations are more likely to get pancreatic cancer.

You can inherit BRCA1, BRCA2, and other mutations from your mother or your father, so be sure to include information from both sides of your family when collecting your family health history. Include information on your parents, sisters, brothers, children, grandparents, aunts, uncles, nieces, nephews, and grandchildren. Include information about your ancestry, if you know it. BRCA1 and BRCA2 mutations are more common in people with Ashkenazi Jewish or Eastern European ancestry. Tell your doctor if you are concerned about your family health history, especially if you or your close relatives have or had any of the following:

  • Breast cancer, especially at a younger age (age 50 or younger)
  • Ovarian, peritoneal or fallopian tube cancer
  • Triple negative breast cancer (Triple negative cancers are a type of breast cancer that lack estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2)
  • Cancer in both breasts
  • Breast cancer in a male relative
  • Pancreatic cancer
  • Metastatic or high grade prostate cancer
  • Multiple cancers in the family, including breast, ovarian, high grade prostate, or pancreatic cancer
  • Ashkenazi or Eastern European Jewish ancestry
  • A known BRCA1 or BRCA2 mutation in the family
If Your Family Health History of Breast Cancer is Average or Moderate Risk

Most women with a family health history of breast cancer don’t need genetic counseling for breast and ovarian cancer. Most women have family health histories that mean they are at average risk. Some women with breast cancer in their families will have a moderate risk.

If your family health history of breast cancer is average or moderate risk, you probably won’t need genetic counseling and testing for hereditary breast and ovarian cancer. One exception is if you have a moderate risk family health history and Ashkenazi or Eastern European Jewish ancestry. BRCA1 and BRCA2 mutations are more common in women of Ashkenazi or Eastern European Jewish ancestry. This means that women of Ashkenazi or Eastern European Jewish ancestry are more likely to have a BRCA1 or BRCA2 mutation than women of other ancestries with similar family health histories. Thus, a family health history that would be considered moderate risk for most women might be considered strong risk for you because of your Ashkenazi or Eastern European Jewish ancestry.

Even if your doctor doesn’t recommend genetic testing and counseling, your family health history of breast cancer can affect when you start mammography screening. If you are a woman with a parent, sibling, or child with breast cancer, you are at higher risk for breast cancer. Based on current recommendationsexternal icon, you should consider talking to your doctor about starting mammography screening in your 40s.

If your Family Health History of Breast or Ovarian Cancer is Strong Risk

If you are a woman with a strong risk family health history, you are more likely to have a mutation in BRCA1 or BRCA2 than women with average or moderate risk family health histories. Thus, you are more likely to benefit from genetic counseling and testing for mutations in BRCA1 and BRCA2. To learn more about risk for breast or ovarian cancer based on family health history, see family health history risk categories.

If You Have a Personal History of Breast or Ovarian Cancer

If you have a personal history of ovarian, fallopian tube, or primary peritoneal cancer, some current guidelines recommend that you have genetic counseling and testing. If you have a personal history of breast cancer, genetic counseling and testing may or may not be recommended for you, depending on your age of diagnosis, type of breast cancer, presence of certain other cancers or cancer in both breasts, ancestry, and family health history of breast, ovarian, and other cancers.

Learn more about genetic counseling for hereditary breast and ovarian cancer.

The BRCA1 and BRCA2 genes

The breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes are the genes most commonly affected in hereditary breast and ovarian cancer. Normally, the BRCA1 and BRCA2 genes protect you from getting certain cancers. But certain mutations in the BRCA1 and BRCA2 genes prevent them from working properly, so that if you inherit one of these mutations, you are more likely to get breast, ovarian, and other cancers. You and your family members are more likely to have a BRCA1 or BRCA2 mutation if your family has a strong history of breast or ovarian cancer. Because BRCA1 and BRCA2 mutations are inherited, family members with BRCA1 or BRCA2 mutations usually share the same mutation

21 Sep

BRCA FAQs

ali Newsletter

The BRCA gene test is a blood test that uses DNA analysis to identify harmful changes (mutations) in either one of the two breast cancer susceptibility genes — BRCA1 and BRCA2.

A BRCA genetic test looks for changes, known as mutations, in genes called BRCA1 and BRCA2. A mutation in a BRCA1 or BRCA2 gene can cause cell damage that may lead to cancer. 

Women with a mutated BRCA gene have a higher risk of getting breast or ovarian cancer. Men with a mutated BRCA gene are at a higher risk for getting breast or prostate cancer. Not everyone who inherits a BRCA1 or BRCA2 mutation will get cancer.

HOW is BRCA genetic MUTATION tested?

BRCA gene mutation is tested by the next generation sequencing technique. A massively parallel sequencing technology that offers ultra-high throughput, scalability, and speed. The technology is used to determine the order of nucleotides in entire genomes or targeted regions of DNA or RNA.

WHY it's done?

Mutations in either breast cancer gene — BRCA1 or BRCA2 — significantly increase the risk of: Breast cancer, Male breast cancer, Ovarian cancer, Prostate cancer, Pancreatic cancer, Melanoma.

Test is useful for:

  • Evaluation for patients with a personal or family history suggestive of hereditary breast and ovarian cancer (HBOC) syndrome
  • Establishing a diagnosis of HBOC syndrome allowing for targeted cancer surveillance based on associated risks
  • Identifying variants within genes known to be associated with increased risk for HBOC syndrome allowing for predictive testing of at-risk family members
  • Therapeutic eligibility including poly adenosine diphosphate-ribose polymerase (PARP) inhibitors in select cancer types

So, test is done to have a plan for tomorrow if the patient is at risk, OR test is considered to be done for the aim of precision medicine for these cancers.

WHO should consider BRCA gene testing?

A candidate for genetic testing — is a patient who has:

    • A personal history of breast cancer diagnosed before age 45
    • A personal history of breast cancer diagnosed before age 50 and a second primary breast cancer, one or more relatives with breast cancer, or an unknown or limited family medical history
    • A personal history of triple negative breast cancer diagnosed at age 60 or younger
    • A personal history of two or more types of cancer
    • A personal history of ovarian cancer
    • A personal history of male breast cancer
    • A personal history of breast cancer and one or more relatives with breast cancer diagnosed before age 50, two or more relatives diagnosed with breast cancer at any age, one or more relatives with ovarian cancer, one or more relatives with male breast cancer, or two or more relatives with prostate cancer or pancreatic cancer
    • A personal history of prostate cancer or pancreatic cancer with two or more relatives with BRCA-associated cancers
  • A relative with a known BRCA1 or BRCA2 mutation

 

What other cancers are linked to harmful variants in BRCA1 and BRCA2?

  • Harmful variants in BRCA1 and BRCA2 increase the risk of several additional cancers. In women, these include fallopian tube cancer (6) and primary peritoneal cancer (7), both of which start in the same cells as the most common type of ovarian cancer. 
  • Men with BRCA2 variants, and to a lesser extent BRCA1 variants, are also at increased risk of breast cancer (8) and prostate cancer (9). Both men and women with harmful BRCA1 or BRCA2 variants are at increased risk of pancreatic cancer, although the risk increase is low (10).

In addition, certain variants in BRCA1 and BRCA2 can cause subtypes of Fanconi anemia, a rare syndrome that is associated with childhood solid tumors and development of acute myeloid leukemia (11). The mutations that cause these Fanconi anemia subtypes have a milder effect on protein function than the mutations that cause breast and ovarian cancer. Children who inherit one of these variants from each parent will develop Fanconi anemia.

21 Sep

BRCA1&2 GENETIC TEST INFORMATION

ali Newsletter

Identification of a pathogenic variant may assist with diagnosis, prognosis, clinical management, familial screening, and genetic counseling for hereditary breast and ovarian cancer syndrome.

TECHNIQUE USED

This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 2 genes associated with hereditary breast and ovarian cancer syndrome: BRCA1 and BRCA2.

METHOD NAME

Sequence Capture and Targeted Next-Generation Sequencing followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing.

REPORTING NAME

BRCA1/2 Full Gene Analysis

SPECIMEN REQUIRED

Specimen Type: Whole blood
Container/Tube:
Preferred: Lavender top (EDTA) or yellow top (ACD)
Acceptable: Any anticoagulant
Specimen Volume: 3 mL
Specimen Stability Information: Ambient (preferred) 4 days/Refrigerated
Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere
with testing.

LIMITATIONS

If the patient has had an allogeneic hematopoietic stem cell transplant or a recent heterologous blood transfusion, results may be inaccurate due to the presence of donor DNA.
If the patient has had an allogeneic hematopoietic stem cell transplant or a recent heterologous blood transfusion, results may be inaccurate due to the presence of donor DNA. Call Alfa Laboratories for instructions for testing patients who have received a bone marrow transplant.

CLINICAL & INTERPRETIVE

USEFUL FOR

Evaluation for patients with a personal or family history suggestive of hereditary breast and ovarian cancer (HBOC) syndrome
Establishing a diagnosis of HBOC syndrome allowing for targeted cancer surveillance based on associated risks
Identifying variants within genes known to be associated with increased risk for HBOC syndrome allowing for predictive testing of at-risk family members
Therapeutic eligibility including poly adenosine diphosphate-ribose polymerase (PARP) inhibitors in select cancer types

TESTING ALGORITHM

For more information see Breast, Gynecological and Prostate Cancer Testing Algorithm

CLINICAL INFORMATION

Hereditary breast and ovarian cancer (HBOC) syndrome is an autosomal dominant hereditary cancer syndrome associated with germline variants in the BRCA1 or BRCA2 genes.
Variants within BRCA1 and BRCA2 account for the majority of hereditary breast and ovarian cancer families.(1,2) However, there are additional genes that are known to be associated with hereditary breast and ovarian cancer syndromes.
HBOC syndrome is predominantly characterized by early-onset breast cancer and ovarian cancer. Individuals with breast and ovarian cancer are also at increased risks for prostate, pancreatic, and male breast cancers. Some individuals develop multiple primary or bilateral cancers.(1,2)
Individuals with biallelic pathogenic variants in BRCA1 and BRCA2 are at risk for Fanconi anemia, an autosomal recessive bone marrow failure syndrome. Of note, there are several other genes known to cause Fanconi anemia.(1)

The National Comprehensive Cancer Network and the American Cancer Society provide recommendations regarding the medical management of individuals with HBOC syndrome.(2-4)

REFERENCE VALUES
An interpretive report will be provided.
INTERPRETATION

All detected variants are evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(5)
Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

CAUTIONS

Clinical Correlations
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.
If testing was performed because of a clinically significant family history, it is often useful to first test an affected family member. Detection of a reportable variant in an affected family member would allow for more informative testing of at-risk individuals.

Technical Limitations
Next-generation sequencing may not detect all types of genomic variants. In rare cases, false-negative or false-positive results may occur. The depth of coverage may be variable for some target regions; assay performance below the minimum acceptable criteria or for failed regions will be noted. Given these limitations, negative results do not rule out the diagnosis of a genetic disorder. If a specific clinical disorder is suspected, evaluation by alternative methods can be considered.
There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. Confirmation of select reportable variants will be performed by alternate methodologies based on internal laboratory criteria.
This test is validated to detect 95% of deletions up to 75 base pairs (bp) and insertions up to 47 bp. Insertions/deletions (indels) of 40 or more bp, including mobile element insertions, may be less reliably detected than smaller indels.

Deletion/Duplication Analysis
This analysis targets single and multi-exon deletions/duplications; however, in some instances single exon resolution cannot be achieved due to isolated reduction in sequence coverage or inherent genomic complexity. Balanced structural rearrangements (such as translocations and inversions) may not be detected.

This test is not designed to detect low levels of mosaicism or to differentiate between somatic and germline variants. If there is a possibility that any detected variant is somatic, additional testing may be necessary to clarify the significance of results.

For detailed information regarding gene specific performance and technical limitations, see Method Description or contact our laboratory genetic testing unit at ———————— .

RECLASSIFICATION OF VARIANTS POLICY

At this time, it is not standard practice for the laboratory to systematically review previously classified variants on a regular basis. The laboratory encourages health care providers to contact the laboratory at any time to learn how the classification of a particular variant may have changed over time.

VARIANT EVALUATION

Evaluation and categorization of variants is performed using published American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations as a guideline. Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Variants classified as benign or likely benign are not reported.