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Is All Breast Cancer Hereditary

Frequent Esr1 Point Mutations In Endocrine

Understanding the genetic risks of breast cancer

Advances in sequencing technologies have allowed more sensitive detection and thus insights into the landscape of ESR1 LBD point mutations in both primary and metastatic ER+ breast tumors. Three ESR1 mutations, Y537S, Y537N, and D538G were identified by next-generation sequencing in 14 out of 80 patient samples with endocrine-refractory, metastatic ER+ breast cancer. Notably, all breast tumors from patients that were found to harbor ESR1 LBD point mutations were treated with AIs. Interestingly, these alterations were not detected in matched primary samples and were also not detected in separate large sets of treatment naïve patients. Analysis of an independent ER negative cohort also failed to detect any ESR1 point mutations in the LBD. Although ESR1 mutations were found in 3% of primary samples in this population, alterations in Y537 and D538 residues of ESR1 were enriched in patients treated extensively with AIs. These results suggest that these ESR1 LBD mutations are acquired, or detected, in patients after treatment with endocrine therapy.

Is Breast Cancer Hereditary

Breast cancer is the second most common cancer in women in the United States, and with one in every eight women developing some form of invasive breast cancer in their lifetime,1 many people know at least one woman that has been diagnosed with the disease.

Genetic research has revealed that adverse mutations in a handful of different genes can greatly increase an individuals risk of developing breast cancer, and importantly, these hereditary forms of breast cancer can be passed from an affected parent to their child. Here, in recognition of Breast Cancer Awareness Month this October, we highlight the prevalence of hereditary breast cancer and how individuals can better assess their own hereditary cancer risk.

There are many different types of invasive breast cancer, or breast cancer that has spread beyond the site where it originally developed. The types of breast cancer differ in where the cancer originates, the appearance of and the presence or absence of hormone receptors on the cancer cells, and whether or not the cancer cells have too many copies of the HER2 gene. The types of invasive breast cancer and the percentage of diagnoses attributed to each type are listed below:

  • Invasive ductal carcinoma – 70-80%

Brca1 And Brca2 Genes

Everyone has BRCA1 and BRCA2 genes. BRCA stands for BReast CAncer gene. They are important genes that stop the cells in our body from growing and dividing out of control. Doctors call these tumour suppressor genes.

A fault in the BRCA1 or BRCA2 gene means that the cells can grow out of control. This can lead to cancer developing.

Faulty BRCA1 and BRCA2 genes are rare. Only around 1 in every 400 people have a faulty BRCA1 or BRCA2 gene.

Both men and women can have a faulty BRCA1 or BRCA2 genes. People who inherit faulty versions of these genes have an increased risk of developing different types of cancers. This includes:

  • breast cancer

  • pancreatic cancer

Also Check: Average Age Of Breast Cancer Onset

Ovarian Cancer And Other Cancers

BRCA1 and BRCA2 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.

For a summary of research studies on BRCA1 and BRCA2 mutations and cancer, visit the Breast Cancer Research Studies section.

Does Breast Or Ovarian Cancer Run In Your Family

Hereditary Cancers

If you have close relatives with breast or ovarian cancer, you may be at higher risk for developing these diseases. Does your family health history put you at higher risk? Would you benefit from cancer genetic counseling and testing?

Each year, about 250,000 women in the United States are diagnosed with breast cancer and more than 20,000 are diagnosed with ovarian cancer. About 3% of breast cancers and 10% of ovarian cancers result from inherited mutations in the BRCA1 and BRCA2 genes that are passed on in families. Inherited mutations in other genes can also cause breast and ovarian cancer, but BRCA1 and BRCA2 are the genes most commonly affected. 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. BRCA mutations also increase the likelihood of getting pancreatic cancer and, in men, high grade prostate cancer. Knowing your family health history can help you find out if you could be more likely to develop breast, ovarian, and other cancers. If so, you can take steps to prevent cancer or to detect it earlier when it may be more treatable.

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How Common Are Breast Cancer Gene Mutations

Breast cancer gene mutations arent common in the general population, Dr. Eng says, but they are common in people who have breast cancer. About 10% to 15% of people with breast cancer have one of the breast cancer gene mutations.

You can inherit these gene mutations from either of your biological parents, and the cancers theyre linked to can affect both men and women so consider all your relatives when thinking about your family history.

Risk Factors For Endometrial Cancer

Refer to the PDQ summary on Endometrial Cancer Prevention for information about risk factors for endometrial cancer in the general population.


Age is an important risk factor for endometrial cancer. Most women with endometrial cancer are diagnosed after menopause. Only 15% of women are diagnosed with endometrial cancer before age 50 years, and fewer than 5% are diagnosed before age 40 years. Women with Lynch syndrome tend to develop endometrial cancer at an earlier age, with the median age at diagnosis of 48 years.

Family history including inherited cancer genes

Although the hyperestrogenic state is the most common predisposing factor for endometrial cancer, family history also plays a significant role in a womans risk for disease. Approximately 3% to 5% of uterine cancer cases are attributable to a hereditary cause, with the main hereditary endometrial cancer syndrome being Lynch syndrome, an autosomal dominant genetic condition with a population prevalence of 1 in 300 to 1 in 1,000 individuals.

Reproductive history

Reproductive factors such as multiparity, late menarche, and early menopause decrease the risk of endometrial cancer because of the lower cumulative exposure to estrogen and the higher relative exposure to progesterone.


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Some Facts About Breast Cancer

  • Breast cancer is one of the most common cancers in the world.
  • In the UK about 1 in 8 women develop breast cancer at some stage of their lives.
  • The biggest risk factor for developing breast cancer is increasing age. Most cases develop in women over the age of 50.
  • Of women who do develop breast cancer, most do not have a strong family history of the disease. However, some women do come from families where breast cancer occurs more often than usual .
  • If breast cancer is detected in an early stage, there is a good chance of a cure. X-ray testing of the breast can detect breast cancer at an early stage.

What Should I Do If I Am Concerned

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If you are concerned about a history of breast cancer in your family you should see your GP. They will want to take a family history. Before seeing your GP, it is a good idea to try to find out who in your family has been diagnosed with breast cancer , at what age they were diagnosed and their exact blood relationship to you.

Your GP will wish to know any relevant details about first- and second-degree relatives .

  • First-degree relatives are mother, father, daughters, sons, sisters, or brothers.
  • Second-degree relatives are grandparents, grandchildren, aunts, uncles, nieces, nephews, half-sisters and half-brothers.

On the basis of the family history, it is usually possible for your GP to assess your risk as either near-normal, moderate, or high. If your risk is moderate or high then, if you wish, you may be referred to a doctor who is a specialist for further assessment and counselling.

For details of the factors used to assess the risk, see the website of the National Institute for Health and Care Excellence under Further reading & references, below. It has produced guidelines which doctors can refer to when assessing the risk of breast cancer for individual women.

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Genetics Of Hereditary Cancer

Cancer is one of the leading causes of death worldwide and hereditary tumor diseases account for about 5-10% of all cancers. If the genetic modification which predisposes the tumor disease is known, it can be directly detected using a patient sample, as all cells of the organism carry the same genetic modification. Carriers are heterozygous and remain asymptomatic until the second intact allele is spontaneously inactivated by another variant . If this occurs in tumor suppressor genes, leads to uncontrolled cell growth and the development of a malignant cell clone. However, spontaneously occurring variants can also lead to the activation of growth factors , which also leads to uninhibited cell proliferation. In most cases, the risk of developing a tumor during the course of life is very high for carriers of a germline variant. Carriers should be offered frequent screening checks, preventive surgical measures if necessary and psycho-oncological care.

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 and primary peritoneal cancer , 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 and prostate cancer . Both men and women with harmful BRCA1 or BRCA2 variants are at increased risk of pancreatic cancer, although the risk increase is low .

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 . 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.

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Genes Mutations And Cancer

Cancer is a disease in which cells grow out of control. This happens because of changes in some of the genes inside cells. Genes are pieces of DNA that control how cells make the proteins the body needs to function, as well as how cells are kept in balance. Your genes affect things such as hair color, eye color, and height. They can also affect your chance of getting certain diseases, such as cancer.

Nearly every cell in your body has all of the genes you were born with. Although all cells have the same genes, different cells may use different genes. For example, muscle cells use different genes than skin cells use. The genes that the cell doesnt need are turned off and not used. The genes that the cell is using are activated or turned on.

An abnormal change in a gene is called a mutation. Mutations in a gene can affect how it functions. For example, a mutation might stop a gene from working. Or it might keep a gene turned on all the time . Either way, these can cause problems inside the cell.

Gene mutations can be either inherited or acquired.

Many family cancer syndromes are caused by inherited mutations in tumor suppressor genes. These are genes that normally keep cells under control by slowing down how often they divide , repairing DNA mistakes, or telling cells to die at the right time.

For more information about gene changes that can lead to cancer, see Genes and Cancer.

Inheriting Certain Gene Changes

Genetics of Breast Cancer

About 5% to 10% of breast cancer cases are thought to be hereditary, meaning that they result directly from gene changes passed on from a parent.

BRCA1 and BRCA2: The most common cause of hereditary breast cancer is an inherited mutation in the BRCA1 or BRCA2 gene. In normal cells, these genes help make proteins that repair damaged DNA. Mutated versions of these genes can lead to abnormal cell growth, which can lead to cancer.

  • If you have inherited a mutated copy of either gene from a parent, you have a higher risk of breast cancer.
  • On average, a woman with a BRCA1 or BRCA2 gene mutation has up to a 7 in 10 chance of getting breast cancer by age 80. This risk is also affected by how many other family members have had breast cancer.
  • Women with one of these mutations are more likely to be diagnosed with breast cancer at a younger age, as well as to have cancer in both breasts.
  • Women with one of these gene changes also have a higher risk of developing ovarian cancer and some other cancers.
  • In the United States, BRCA mutations are more common in Jewish people of Ashkenazi origin than in other racial and ethnic groups, but anyone can have them.

Other genes: Other gene mutations can also lead to inherited breast cancers. These gene mutations are much less common, and most of them do not increase the risk of breast cancer as much as the BRCA genes.

Inherited mutations in several other genes have also been linked to breast cancer, but these account for only a small number of cases.

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Whole Exome Sequencing Reveals Unique Mutations In Ethiopian Breast Tumors

We performed DNA sequencing on three tumors and healthy tissue from matched patients. Each of the three tumors were identified as ER+ using immunohistochemical subtyping. We identified mutations in 615 genes across all three patients, unique to the tumor tissue . Two patients had a mutation in a different spot in the BRCA2 gene, which is not surprising based on the number of variants of uncertain significance in BRCA2 .

Additionally, data from this population shows that patients with a family history were more likely to be ER-than patients without a family history , suggesting that many of these patientsâ cancers are due to somatic mutations. We also searched for mutations in genes related to breast cancer aggression, subtype, and progression. Gene ontology enrichments showed MSigDB Oncogenic categories related to KRAS, PTEN, and EGFR signaling , demonstrating that at least some of the somatic variants in population are in the same pathways as other ER + tumors in other populations .

GSEA enrichments of the SNPs found across the Ethiopian patient tumors.

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Who Should Be Offered Genetic Testing

These are general guidelines to identify patients at high risk for HBOC. You should consider referring your patient to your local genetics centre or hereditary cancer program for further assessment if s/he has a family or personal history of:

Breast cancer diagnosis at a young age

Ovarian cancer at any age

Male breast cancer

Multiple primaries in the same individual e.g. bilateral breast cancer , breast and ovarian cancer

Breast cancer diagnosis AND a family history of two or more additional HBOC- related cancers, including breast, ovarian, prostate and pancreatic cancer

High risk ethnicity and a personal and/or family history of breast, ovarian or pancreatic cancer

Triple negative breast cancer diagnosed < age 60

OR if s/he has a personal

Probability of 10% or higher to carry a BRCA mutation

Eligibility criteria for genetic testing vary among organizations. In general, criteria are based on clinical features that increase the likelihood of a hereditary cancer susceptibility syndrome.

If possible, testing is first offered to the affected individual in the family at highest risk to carry a mutation in order to maximize the likelihood of detecting a mutation. For example, this might be the youngest individual with breast cancer in a family with multiple cases of breast and ovarian cancer.

See the GEC-KO point of care tool which can be used in your practice to help identify patients that would benefit from referral to genetics or your local hereditary cancer program.

Read Also: Chemotherapy For Brca2 (breast Cancer)

How Are Gene Mutations Inherited

The way that you inherit a mutation for hereditary breast cancer depends on the specific gene that affects the disease in you.

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 your parent has an autosomal dominant gene mutation, thereâs a 50% chance youâll inherit it.

Ethiopian Women Present With Aggressive Er1 Breast Cancer At A Young Age

What is Hereditary Breast and Ovarian Cancer Syndrome?

Through discussions with surgeons and oncologists at the Black Lion Hospital in Addis Ababa, we were alerted to the fact that Ethiopian women are diagnosed at a much younger age than women of European descent. A recent study found that the overall mean age at diagnosis was 43 years old, and 40% of patients were under 40 years old . Amongst this cohort, patients with Luminal B breast cancer had the youngest median age at diagnosis at 35, followed by Her2-enriched at 41, Triple negative at 46, and Luminal A at 47. The age of diagnosis across breast cancer subtypes is consistently younger for those born in Africa compared to those born in the US . Also, at the time of diagnosis, Ethiopian patients had a significantly higher chance of having a higher-grade pathology compared to White and African Americans, across all subtypes . Second, a recent study from Jemal and Fedewa demonstrated that breast cancer cases in East Africa are more likely to be ER+ compared to West African or African American cases .

a) Data from world health organization on mortality data across populations from Ethiopia , Ghana , Nigeria and US . b) Data adapted from Jemal and Fedewa on age of diagnosis of breast cancer across relevant subpopulations . c) Proportion of ER+ breast cancer patients from the same reference.

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