Breast Cancer And Genetic Testing
At the current time, testing is available for BRCA gene mutations, as well as mutations ATM, CDH1, CHEK2, MRE11A, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, SEC23B, and TP53, with this area expected to expand dramatically in the near future.
Having these tests available, however, raises many questions. For example, who might have hereditary breast cancer and who should be tested? What should you do if you test positive for one of these genes?
Ideally, any testing should be done only with the guidance and help of a genetic counselor. There are two reasons for this.
One is that it can be devastating to learn that you carry a mutation that may increase your risk, and the guidance of someone who is aware of recommended management and screening is invaluable.
As noted earlier, some mutations confer a high risk and others a much lower risk. Some mutations might be of more concern earlier in life , whereas others might not require early screening. A genetic counselor can help you learn about what is currently recommended with regard to screening for your particular mutation while taking into account any other risk factors you might have.
The other reason genetic counseling is so important is that you may have a significant risk of developing breast cancer even if your tests are negative. There is much yet to learn, and a genetic counselor can help you look at your family history to see if you may carry a high risk despite negative testing, and plan screening accordingly.
How Are Gene Mutations Inherited
If you inherit a gene mutation for breast cancer, it means that you got it from one or both of your parents.
Many mutations, such as those found in the well-known BRCA1 and BRCA2 genes, are passed down in whatâs called an autosomal dominant pattern. This means that inheriting one bad gene from one parent may lead to an increased chance of disease.
If one of your parents has an autosomal dominant gene mutation, thereâs a 50% chance youâll inherit it. This is why we see the disease in many relatives, but not all of them.
What Is Hereditary Breast And Ovarian Cancer
A diagnosis of Hereditary Breast and Ovarian Cancer Syndrome is considered when there are multiple cases of breast cancer and/or ovarian cancer on the same side of the family. The chance that a family has HBOC increases in any of these situations:
1 or more women are diagnosed at age 45 or younger
There are breast and/or ovarian cancers in multiple generations on the same side of the family, such as having both a grandmother and an aunt on the fathers side both diagnosed with these cancers
A woman is diagnosed with a second breast cancer in the same or the other breast or has both breast and ovarian cancers
A male relative is diagnosed with breast cancer
There is a history of breast cancer, ovarian cancer, prostate cancer, and/or pancreatic cancer on the same side of the family
Having Ashkenazi Jewish ancestry
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What Are The Benefits Of Genetic Testing For Cancer
In genetic testing for cancer, knowledge may take away some anxiety or fear of the unknown. A person with an inherited cancer may receive specific cancer treatment because genetic testing showed they carry mutated genes linked to that cancer. Additionally, the person and their healthy family members carrying the same hereditary mutation can work with healthcare providers on ways to prevent cancer from happening. A person with inherited cancer can take steps so they dont pass their hereditary mutation on to their biological children.
What Makes A Cell Cancerous
Cancer is a disease characterized by a population of cells that grow and divide without respect to normal limits. These cancerous cells invade and destroy adjacent tissues, and they may spread throughout the body. The process by which normal cells are transformed into cancer cells is known as carcinogenesis. This process is also known as oncogenesis or tumorigenesis.
Nearly all cancers are caused by mutations in the DNA of abnormal cells. These mutations may be due to the effects of carcinogens, cancer-causing agents such as tobacco smoke, radiation, chemicals, or infectious agents. These carcinogens may act as an environmental âtrigger,â stimulating the onset of cancer in certain individuals and not others. Do all people who smoke get cancer? No. Can secondhand smoke increase a nonsmoking person’s chance of developing lung cancer? Yes. It also increases a nonsmoking person’s chance of developing heart disease.
Complex interactions between carcinogens and an individualâs genome may explain why only some people develop cancer after exposure to an environmental trigger and others do not. Do all cancers need an environmental trigger to develop? No. Cancer-causing mutations may also result from errors incorporated into the DNA during replication, or they may be inherited. Inherited mutations are present in all cells of the organism.
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Her2 And Its Inhibitors
In breast cancer, the overall HER2 mutation rate is ~1.6% . In a study by Bose et al., seven HER2 somatic mutations including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C, have been identified as activating mutations . Several patients with HER2 activating mutations are resistant to the reversible HER2 inhibitor lapatinib, but sensitive to the irreversible HER2 inhibitor neratinib. Neratinib as a dual inhibitor of HER2 and EGFR was approved by FDA in 2017. It has been shown that the HER2 L755S mutation results in an acquired resistance to lapatinib in breast cancer, which could be overcome by the neratinib . In another study, the HER2-T798I gatekeeper mutation in breast cancer patients with a AHER2-L869R mutation was identified as a mechanism of acquired resistance to neratinib . The trial of neratinib has also been conducted in colorectal cancer patients. The HER2 gene amplification and mutation in CRC can lead to the resistance of EGFR-targeted therapies cetuximab and panitumumab . A negative effect of neratinib monotherapy has recently been confirmed in 12 CRC patients with different tumors harboring HER2 mutations . There were no positive therapeutic response and the median PFS was only 1.8 months, indicating that monotherapy with neratinib is ineffective. The underlying mechanisms still require further investigations.
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An international team has completed the most comprehensive study of whole cancer genomes, significantly improving the fundamental understanding of cancer and indicating new directions for developing diagnostics and treatments.
The discoveries, published today in 23 papers in Nature and its affiliated journals, are an important step toward a map of all major cancer-causing mutations in the genome.
The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Project , a collaboration involving more than 1,300 scientists and clinicians from 37 countries, analyzed more than 2,600 whole genomes of 38 different tumor types the largest publicly available whole-genome dataset in the cancer genomics field. Fifty-two members of the Broad Institute of MIT and Harvard contributed to this research throughout the six-year long project.
Using the collected data, 16 working groups examined multiple aspects of cancer development, causation, progression, and classification, confirming previous findings and generating new knowledge about cancer biology, including identifying a large diversity of molecular processes that generate cancer-causing mutations. The Pan-Cancer Project also improved and developed new methods for analyzing cancer genomes.
Previous cancer genome studies focused on the 1 percent of the genome that codes for proteins, known as the exome. The Pan-Cancer Project explored the remaining 99 percent of the genome, which includes regions that regulate the activity of genes.
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How Do Mutations In Genes Cause Cancer
Genes are instructions made from DNA, which tell the cells in our bodies how to work. Every cell in our body contains genes that decide and control our body’s functions, growth and appearance. Each person has two copies of most genes, one inherited from their mother and one from their father.
In general, our genes enable our cells to function normally. However, sometimes the genes that were inherited have small changes, known as alterations or mutations. If one of our genes is altered or mutated, this can sometimes result in an increased risk of developing different illnesses compared to people who don’t have the genetic change.
A person with a gene mutation has a 50 per cent chance of passing it on to their children.
Ovarian Cancer And Other Cancers
BRCA1 and BRCA2 inherited gene mutations increase a womans risk of ovarian cancer, pancreatic cancer and melanoma .
BRCA1/2 mutations may also increase the risk of other cancers . However, data are limited, and these topics are still under study.
Learn about genetic testing.
For a summary of research studies on BRCA1 and BRCA2 inherited gene mutations and cancer, visit the Breast Cancer Research Studies section.
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What Results Would I Get From Genetic Testing For Cancer
Genetic tests can have several possible results: positive, true negative, uninformative negative or benign.
This test result means you have a genetic mutation thats linked to a specific inherited cancer. Positive results have different implications depending on why you were tested.
- If you have cancer, a positive test result confirms you have cancer because you inherited certain genetic mutations. Its important to remember that your test result doesnt mean your family members have the same mutation, that they must have genetic testing for cancer or that theyll develop cancer.
- If you had genetic testing because a family member has an inherited cancer, a positive test result means you have an increased risk of cancer. It doesnt mean youll develop cancer. If you have a positive test result, your genetic counselor will explain what the results mean. They or your healthcare provider may give you information on ways to lower your risk of developing cancer.
This result means the test didnt find a mutation associated with an increased risk of cancer. If you have cancer and your genetic test for a certain genetic mutation shows you dont carry that genetic mutation, it means your cancer isnt inherited. It also means your family members dont need to have genetic testing.
Variant of uncertain significance or VUS
Is There A Test For Hereditary Colon Cancer
Gene testing can identify individuals who carry the more common gene mutations associated with FAP or HPNCC, such as those listed above. However, these tests may not identify all gene mutations that cause FAP or HNPCC. In some families, additional mutations may be present that cause the FAP or HNPCC, which cannot be detected by the commonly used gene tests.
The test for FAP syndrome involves examining DNA in blood cells called lymphocytes , looking for mutations in the APC gene. No treatment to reduce cancer risk is currently available for people with APC mutations that are associated with FAP. But for those who test positive, frequent surveillance can detect the cancer at an early, more treatable stage. Because of the early age at which this syndrome appears, the test may be offered to children under the age of 18 if they have a parent known to carry the mutated APCgene.
Researchers hope that an easier test, which is currently experimental, will become available for common use in three to five years. This new test looks for cancer cells with the APC mutation in a stool sample.
Genetic testing for HNPCC involves looking for mutations in four of the five genes identified that are associated with HNPCC – MLH1, MSH2, MSH6, and PMS2.
Individuals in families at high risk of genetic predisposition may consider testing. Genetic counselors can help individuals make decisions regarding testing.
Additional Resources for Information on Hereditary Colon Cancer
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What Are The Names Of Cancer Genes
Genes with mutations linked to hereditary cancer riskCancerGenesBreast cancer in womenATM , BARD1 , BRCA1 , BRCA2 , BRIP1 , CHEK2 , CDH1 , NF1 , PALB2 , PTEN , RAD51C , RAD51D , STK11 , TP53Breast cancer in menBRCA1, BRCA2Colorectal cancerAPC, EPCAM ,Endometrial cancerBRCA1*, EPCAM5 more rowsFeb 8, 2022
How Changes In Genes Can Affect Cancer Risk
Some genes normally help control when our cells grow, divide to make new cells, repair mistakes in DNA, or cause cells to die when theyre supposed to. If these genes arent working properly, it can affect cancer risk. For example:
- Changes in genes that normally help cells grow, divide, or stay alive can lead to these genes being more active than they should be, causing them to become oncogenes. These genes can result in cells growing out of control.
- Genes that normally help keep cell division under control or cause cells to die at the right time are known as tumor suppressor genes. Changes that turn off these genes can result in cells growing out of control.
- Some genes normally help repair mistakes in a cells DNA. Changes that turn off these DNA repair genes can result in the buildup of DNA changes within a cell, which might lead to them growing out of control.
DNA changes that create oncogenes or that turn off tumor suppressor genes or DNA repair genes might lead to cancer, although typically it takes several gene changes before a cell becomes a cancer cell. To learn more, see Oncogenes, Tumor Suppressor Genes, and DNA Repair Genes.
Gene changes can also play a role in other conditions that might impact cancer risk. For example, some gene variants can affect body weight. People with extra body weight are more likely to get some types of cancer, so these variants might also indirectly affect cancer risk.
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What Are The Genetic Causes Of Breast Cancer
- PALB2 After BRCA1 and BRCA2, PALB2 is currently the third most prevalent breast cancer gene.
- CHEK2 Checkpoint Kinase 2, or CHEK2, creates a protein that helps suppress tumor growth.
- CDH1 CDH1, or CaDHerin 1, is a tumor suppression gene that helps groups of cells stick together to form organized tissues.
What Are Acquired Mutations
Unlike hereditary mutations, acquired mutations occur at some point during a lifespan. These mutations arent present at birth, and only present in some cells. Because they occur in somatic cells, any cell of the body other than reproductive cells, acquired mutations may be called somatic variants. These cant be passed down to offspring.
So, how do they occur? These mutations may occur when the person is exposed to something in the environment. For example, the suns damaging ultraviolet rays may harm DNA, causing changes that lead to skin cancer. Cigarette smoke, radiation, viruses and diet may also lead to acquired mutations that may affect cancer risk. Other acquired mutations may occur randomly as the cells divide, with no identifiable cause.
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Challenges In Understanding Cancer Genetics
Researchers have learned a lot about how cancer genes work. But many cancers are not linked with a specific gene. Cancer likely involves multiple gene mutations. Moreover, some evidence suggests that genes interact with their environment. This further complicates our understanding of the role genes play in cancer.
Researchers continue to study how genetic changes affect cancer development. This knowledge has led to improvements in cancer care, including early detection, risk reduction, the use of targeted therapy, and survival.
Further studying cancer genetics may help doctors find better ways to:
Predict a persons risk of cancer
What Do Brca1 And Brca2 Genetic Test Results Mean
BRCA1 and BRCA2 mutation testing can give several possible results: a positive result, a negative result, or a variant of uncertain significance result.
Positive result. A positive test result indicates that a person has inherited a known harmful variant in BRCA1 or BRCA2 and has an increased risk of developing certain cancers. However, a positive test result cannot tell whether or when the tested individual will develop cancer. Some people who inherit a harmful BRCA1 or BRCA2 variant never develop cancer.
A positive test result may also have important implications for family members, including future generations.
- Both men and women who inherit a harmful BRCA1 or BRCA2 variant, whether or not they develop cancer themselves, may pass the variant to their children. Each child has a 50% chance of inheriting a parents variant.
- All blood relatives of a person who has inherited a harmful BRCA1 or BRCA2 variant are at some increased risk of having the variant themselves. For example, each of that persons full siblings has a 50% chance of having inherited the variant as well.
- Very rarely, an individual may test positive for a harmful variant not inherited from either parent. This is called a de novo variant. Such a variant is one that arose in a germ cell of one of the parents and is present in all the cells of the person who grew from that cell. The children of someone with a de novo variant are at risk of inheriting the variant.
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The Risks Of Inherited Gene Mutations
Women who inherit the mutated BRCA1 gene have a 55% to 65% risk of breast cancer by age 70. Women with mutated BRCA2 have about a 45% risk. Men with a BRCA mutation are also at a higher risk of breast cancer.
Transgender and gender expansive people can also inherit these gene mutations. If youâre part of this community, you should consider that top surgery, which removes breast tissue, doesnât completely remove this risk.
Either mutation brings a higher risk of getting breast cancer at a younger age .
People who have a mutated BRCA1 or BRCA2 gene have a higher risk of a second primary breast cancer, too. Bilateral breast cancer is also more common in women who carry a BRCA1 or BRCA2 gene.
Breastcancer.org: âGenetics,â âResearchers Identify 110 Genes Associated With Breast Cancer,â âRisk of Developing Breast Cancer,â âTypes of Genetic Tests,â âHER2 Status.â
Journal of Cancer Education: âWhat Black Women Know and Want to Know About Counseling and Testing for BRCA1/2.â
National Institutes of Health, Genetics Home Reference: âBreast Cancer,â âPIK3CA gene.â
MedlinePlus: âAutosomal dominant.â
Mayo Clinic: âAutosomal dominant inheritance pattern,â âBRCA gene test for breast and ovarian cancer risk.â
National Comprehensive Cancer Network.