Genomics, the study of human genes and chromosomes, has come a long way since Frederick Sanger and Walter Gilbert shared the 1980 Nobel Prize for concocting methods for DNA sequencing. Decades before their win, several renowned researchers helped advance genomic studies. James Watson and Francis Crick, for instance, proposed the double-helix structure of DNA in 1953. This breakthrough provided a foundational understanding of the molecule that carries genetic information. And of course, Rosalind Franklin’s X-ray diffraction images of DNA in 1952 contributed to Watson and Crick’s double-helix model.
Back then, genomics was mainly a field used for laboratory experimentation. Today, researchers employ genomic studies in medical research and applications, transforming our understanding of diseases, as well as opening doors to more precise diagnoses and targeted treatments.
For example, through genomic studies, scientists have discovered numerous genetic variations that can increase someone’s lifetime risk of developing breast cancer. Some of these mutations are hereditary, while others occur spontaneously. Understanding a person’s specific genetic profile can help identify whether they are at high risk for breast cancer and if they can benefit from increased screening or preventive measures like mastectomies.
The Role of Genetics in Breast Cancer
Read on for New Hope Unlimited’s overview of genetics as a breast cancer risk factor, covering topics such as hereditary versus sporadic forms of the disease, and the genes associated with breast cancer susceptibility.
How Do Genetics Lead to Breast Cancer?
A gene is the basic physical unit of inheritance. It comprises deoxyribonucleic acid (DNA), and all 46 chromosomes contain hundreds to thousands of genes. But what exactly is the connection between genes and breast cancer? Here’s a simple explanation:
All 20,000 to 25,000 genes in the human body carry instructions that control how cells behave, including how to grow and divide. Cancer develops when one or more genes in a cell mutate or change. Mutations are mistakes that occur during cell division, or they happen due to exposure to DNA-damaging agents (carcinogens) in the environment.
You inherited one set of genes from your biological father, and another set from your biological mother. If your parents have cancer genes, even if they never developed cancer themselves, they can still pass on these genes to you and your siblings, as can you to your children.
However, keep in mind that most malignant breast tumors happen by chance. Only about 5% to 10% are hereditary.
Understanding Hereditary vs. Sporadic Breast Cancer
Hereditary means breast cancer runs in your family. Sporadic breast cancer is more unexpected, as it occurs without a clear family history. These malignancies usually develop due to a combination of chance and environmental factors.
Types of Gene Mutations That Can Lead to Breast Cancer
Mutation in the following genes is associated with a heightened risk of breast cancer:
1. BRCA1 and BRCA2
A BRCA1 or BRCA2 gene mutation is the most common cause of hereditary breast cancer. In healthy cells, these genes help produce proteins necessary for repairing DNA damage. However, when the BRCA1 or BRCA2 gene has an error or alteration in its DNA sequence, abnormal cell growth can follow, potentially leading to cancer development. They begin working in tandem against you rather than for you, losing their tumor-suppressing abilities.
Here are additional facts about BRCA1 and BRCA2 mutations:
- If you inherited a mutated version of either the BRCA1 or BRCA2 gene from one of your parents, your risk of developing breast cancer is higher than others.
- If you carry one of these genetic mutations, you are more likely to get breast cancer at a younger age. You may also develop cancer in both breasts.
- Although rare, it is possible to have both a BRCA1 and BRCA2 mutation. It predominantly affects individuals of Ashkenazi Jewish descent, but it can also impact people from all racial or ethnic backgrounds. If you inherited both of these mutations, you have a 50% chance of passing them to your children.
- On average, a person with a mutation in either of these genes has a 7 in 10 chance of getting breast cancer by the age of 80. The higher the number of family members diagnosed with breast cancer, the higher the risk.
- These gene mutations also raise the risk of developing ovarian cancer and other types of malignant diseases.
- Men can get breast cancer, too. If they inherit these mutations, they are also more likely to develop prostate cancer.
Several other gene types can affect how your body responds to DNA damage. Some of them are also tumor suppressor genes, like BRCA, which can increase the risk of breast cancer and other diseases.
Other high-risk breast cancer genes include:
2. TP53 Gene (Tumor Protein P53)
The TP53 gene provides instructions for making a protein called tumor protein p53. This protein is a tumor suppressor, meaning it regulates cell division by preventing cells from growing and dividing in an uncontrolled manner. Mutations in the TP53 gene are associated with inherited breast cancers.
When functioning normally, the p53 protein helps prevent breast cancer by detecting DNA damage and arresting cell division to allow for DNA repair. If the DNA damage is beyond repair, p53 activates programs that cause cells to self-destruct. However, mutations in this gene lead to abnormal p53 protein that cannot perform critical functions properly. Inheriting the TP53 gene also raises the risk for other cancers, including sarcomas, adrenocortical carcinomas, and brain tumors.
Medical professionals often associate p53 with Li Fraumeni Syndrome, an inherited autosomal dominant disorder related to irregularities in the P53 gene. It is also referred to as the sarcoma, breast, leukemia, and adrenal gland (SBLA) cancer syndrome.
In a cohort study that evaluated 286 TP53+ individuals, cumulative cancer incidence was 50% by 46-years-old among TP53+ males and 31-years-old among females, as well as nearly 100% by 70-years-old for both. Cancer risk was also highest after age 20 for females, primarily due to malignant breast tumors. Among males, cancer risk was greater in childhood and later adulthood. As for females, the incidence by age 70 for breast cancer, brain cancer, soft tissue sarcoma (STS), and osteosarcoma were 54%, 6%, 15%, and 5%, respectively. In males, the cumulative incidence was 19%, 22%, and 11% for brain cancer, STS, and osteosarcoma. About 49% of the participants with one existing cancer developed at least another form of cancer after ten years.
3. CHEK2 (Checkpoint Kinase 2) Gene
The CHEK2 gene provides instructions for producing a protein called CHEK2, which helps limit the replication of genetically damaged cells. Mutations in CHEK2 are rare, but they double the risk of developing breast cancer, typically arising after age 40.
Similar to tumor-suppressor genes BRCA and TP53, when the CHEK2 gene mutates, it cannot perform its functions as intended. As a result, unrepaired DNA damage and uncontrolled cell growth can occur, which may lead to cancer.
Certain CHEK2 mutations significantly contribute to a higher risk of breast cancer. One of these mutations is the CHEK2*1100delC. Individuals who inherit it are 3.5 times more at risk of being diagnosed with breast cancer during their lifetime compared to the general population.
To quickly summarize, mutations in the BRCA1/2, TP53, and CHEK2 genes disrupt the cell cycle checkpoints and DNA repair mechanisms, which can lead to the development and growth of breast cancer cells, among other diseases. Identifying high-risk gene mutations through genetic testing can help determine your cancer risk and allow for increased screening and prevention strategies.
The aforementioned mutations are those that medical researchers have extensively investigated in relation to cancer. Below are mutations also suspected to raise cancer risks, although further research is necessary to support such claims.
4. ATM (Ataxia-Telangiectasia Mutated) Gene
ATM (ataxia-telangiectasia mutated) helps repair damaged DNA strands, thus maintaining the stability of the cell’s genetic information. Inherited ATM mutations can elevate the risk of certain diseases, potentially including breast cancer. The ATM gene can also cause neurodegenerative disorders, including lack of balance or dysfunctional walking patterns.
The ATM gene produces a protein kinase enzyme that helps activate the DNA damage response pathway. When DNA sustains damage, ATM stimulates other proteins that can either pause the cell cycle to allow time for repair, or initiate apoptosis (programmed cell death) if the damage is too extensive. Mutation in the ATM gene impairs this vital response mechanism.
Women who have a mutated form of the ATM gene face an estimated 20% to 60% heightened risk of developing breast cancer compared to the general population. Based on current scientific findings, female carriers of an ATM gene mutation may develop breast cancer at an earlier age than the median age of 62, and cancer may affect both breasts.
5. PALB2 (Partner and Localizer of BRCA2) Gene
PALB2 is an “anticancer” gene that produces a protein called partner and localizer of BRCA2 to repair damaged DNA. It helps protect against breast, ovarian, pancreatic, and prostate cancer.
When PALB2 mutates, unrepaired DNA damage accumulates over time and may cause cells to become cancerous. Men and women with a faulty PALB2 gene are more susceptible to breast and pancreatic cancer. In addition, men who inherit a defective PALB2 gene have a higher chance of developing prostate cancer, while women have an increased likelihood of developing ovarian cancer.
In one study published in The New England Journal of Medicine, researchers from 14 centers in eight countries examined data from 362 family members from 154 families. Each person had an abnormal PALB2 gene but did not have a faulty BRCA1 or BRCA2 gene. Here’s what they found:
- 229 out of the 311 women with a mutation in PALB2 had breast cancer. They concluded that the cancer risk of these women was 9.47 times higher than the average risk. The chances of developing breast cancer by age 50 and 70 were 14% and 35%, respectively.
- 7 out of 51 men with a mutation in the PALB2 gene had breast cancer.
6. PTEN (Phosphatase and Tensin Homolog) Gene
The PTEN gene regulates cell growth and division. Mutations in this gene have been associated with inherited cases of breast cancer. The gene provides directions for making an enzyme called phosphatase and tensin homolog, which helps regulate a cellular pathway known as the PI3K-AKT. This pathway controls cell proliferation, growth, and survival. When the PTEN gene undergoes abnormal changes and can no longer regulate PI3K-AKT as designed, uncontrolled cell growth and division can occur, increasing the risk of breast cancer development. In many cases, a rare inherited disorder (Cowden syndrome) characterized by numerous noncancerous growths called hamartomas contributes to this increased risk. Still, mutations in the PTEN gene account for a small fraction of breast cancer cases.
7. STK11 (Serine/Threonine Kinase 11) Gene
The STK11 gene, also known as LKB1, carries instructions and provides information for producing a tumor suppressor called protein kinase enzyme. STK11 mutations are passed down from generation to generation in an autosomal dominant fashion. In other words, only one copy of the altered gene is sufficient to increase the risk of developing breast cancer.
Those who inherit a mutated copy of STK11 from their biological mother or father have a 32% to 54% lifetime risk of developing breast cancer compared to 12.5% for the average risk women. Moreover, they are at risk of developing cervical cancer (10% compared to less than 1%), endometrial cancer (10% compared to 3%), and a rare form of ovarian cancer known as Sertoli cell tumor. Among men, they have a 10% lifetime risk of acquiring a rare type of testicular cancer known as Sertoli cell tumor as opposed to less than 1% for most men. Both sexes with a faulty STK11 gene are also at risk for cancers of the colon, rectum, pancreas, stomach, small intestine, and lung.
8. CDH1 (E-Cadherin 1) Gene
The CDH1 gene provides instructions for making E-cadherin, a protein that helps cells stick together and form specialized tissues during development. Mutations in the CDH1 gene reduce or eliminate the production of functional E-cadherin, which disrupts the connections between cells. This weakening of cell-to-cell adhesion may cause cells to proliferate abnormally and migrate to other parts of the body, which can lead to cancer development.
Individuals with a mutated copy of CDH1 in each cell have a condition called hereditary diffuse gastric cancer syndrome. People with this condition have a high lifetime risk of developing diffuse gastric cancer and lobular breast cancer.
In 2021, a cohort study published in JAMA Network examined 283 individuals with mutations in the CDH1 gene. The participants were mainly White females with a median age of 48. They were from 151 families and were categorized based on family history of breast and/or gastric cancer: hereditary lobular breast carcinoma or HLBC (15.5%), hereditary diffuse gastric cancer or HDGC (16.2%), and mixed (68.2%) groups. The majority of HLBC patients undergoing risk-reducing gastrectomy exhibited occult gastric adenocarcinoma on pathology. Similarly, most asymptomatic HDGC patients had occult gastric cancer. Carriers of CDH1 variants without a family history of gastric cancer showed high rates of occult gastric cancer, suggesting a highly penetrant gastric phenotype regardless of family history. These findings are pertinent for counseling families with CDH1 variants linked to HLBC.
9. NF1 (NeuroFibromin 1) Gene
The NF1 gene creates the protein neurofibromin, which helps regulate cell growth. Mutated, this gene results in a loss of neurofibromin, allowing cells to grow uncontrolled.
A meta-analysis published in the journal of Hereditary Cancer in Clinical Practice emphasized the heightened breast cancer risk in individuals with neurofibromatosis, especially among young women. According to the researchers, increased awareness and attention to breast cancer risk in the younger population is crucial. Disseminating information to the general public and primary healthcare providers can help ensure adherence to the NCCN breast cancer screening guidelines.
Further reading: Ultimate Guide to Getting Screened for Breast Cancer
The Bottom Line on Inherited Gene Defects and Breast Cancer Incidence
Mutations or changes in the tumor suppressor genes can have drastic effects on breast cancer development and progression. These genes normally help regulate cell division and growth; when mutated, they no longer function as they should. Consequently, abnormal cells proliferate unchecked, sometimes forming malignant tumors.
Born female or male, knowing whether you inherited a gene mutation can help you understand your risk for breast cancer and other diseases.
Your Reminder to Undergo Genetic Counseling and Testing
Genetic testing can help you and your healthcare team identify inherited mutations in the BRCA1 and BRCA2 genes, or in genes such as TP53, STK11, and others discussed above. Testing is an option if you have breast cancer, survived it, or have a strong family history. However, remember that not every person needs genetic testing. You must talk with your doctor and analyze the good versus bad before proceeding.
If you or a loved one have been diagnosed with breast cancer or another malignancy, you likely want access to every possible treatment option. While traditional approaches like chemotherapy, radiation, and surgery remain the standard of care, alternative cancer care can improve your health and well-being with less harmful, non-toxic techniques. If you want to explore these options, contact New Hope Unlimited today. We offer a range of complementary and integrative therapies designed to target the root cause of malignant tumors.
