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Is Breast Cancer Hereditary In Females

What Are The Benefits Of Genetic Testing For Brca1 And Brca2 Variants

Hereditary Breast Cancer Genetics in 2019 – Brittany Bychkovsky, MD, MSc

There can be benefits to genetic testing, regardless of whether a person receives a positive or a negative result.

The potential benefits of a true negative result include a sense of relief regarding the future risk of cancer, learning that one’s children are not at risk of inheriting the family’s cancer susceptibility, and the possibility that special check-ups, tests, or risk-reducing surgeries may not be needed.

A positive test result may allow people to make informed decisions about their future health care, including taking steps to reduce their cancer risk.

Having Radiation To Your Chest

Women who were treated with radiation therapy to the chest for another cancer when they were younger have a significantly higher risk for breast cancer. This risk depends on their age when they got radiation. The risk is highest for women who had radiation as a teen or young adult, when the breasts were still developing. Radiation treatment in older women does not seem to increase breast cancer risk.

Evaluation Of Suspected Hereditary Predisposition To Breast Cancer

Individuals with a family and personal history suspicious for a familial syndrome should be referred to a genetic counselor for a comprehensive evaluation. Testing for mutations in cancer-associated genes is individually based, and requires a high index of suspicion for a particular gene based on the clinical situation. In general, when a family history is suggestive, it is best to test the individual with a cancer diagnosis, as this increases the probability of a positive test result. Standard clinical BRCA1 and BRCA2 testing has been carried out using PCR amplification and Sanger sequencing. For the Ashkenazi Jewish population, testing can be initially targeted to the three major founder mutations. In 2007, testing for large rearrangements was added for secondary analysis after research studies published that 6%18% of individuals who are BRCA mutation negative by sequencing can be explained by large insertions and deletions in the BRCA1 and BRCA2 genes using multiplex ligation-dependent probe amplification technology . If a mutation is identified, targeted testing can be done for other members of the family to assess risk. Possible outcomes of genetic testing are a true positive, a true negative , uninformative , or a variant of unknown significance . By definition, a VUS is a detected genetic change without a good description of any correlating clinical risk.

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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 , and chemoprevention.

Enhanced screening. Some women who test positive for harmful BRCA1 and BRCA2 variants may choose to start breast cancer screening at younger ages, have more frequent screening than is recommended for women with an average risk of breast cancer, or have screening with magnetic resonance imaging in addition to mammography.

No effective ovarian cancer screening methods are known. Some groups recommend transvaginal ultrasound, blood tests for the CA-125 antigen , and clinical examinations for ovarian cancer screening in women with harmful BRCA1 or BRCA2 variants. However, none of these methods appear to detect ovarian tumors at an early enough stage to improve long-term survival .

The benefits of screening men who carry harmful variants in BRCA1 or BRCA2 for breast and other cancers are not known. Some expert groups recommend that such men undergo regular annual clinical breast exams starting at age 35 . The National Comprehensive Cancer Network guidelines recommend that men with harmful germline variants in BRCA1 or BRCA2 consider having a discussion with their doctor about prostate-specific antigen testing for prostate cancer screening starting at age 40 .

Referral For Further Assessment

Breast Cancer (Hereditary Factors)

Your GP may refer you to a specialist family history clinic or regional genetics centre, depending on where you live.

These are specialist services that can assess your individual risk of developing breast cancer.

Being referred for an assessment does not necessarily mean youre at an increased risk.

Find out more about the family history risk assessment process, including who should be referred.

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Low Penetrant Breast Cancer Loci

A number of common breast cancer susceptibility loci have been associated with a slightly increased or decreased risk of breast cancer. These can follow the polygenic model, or can act synergistically with environmental factors or lifestyle, to account for a small fraction of familial breast cancer cases.

Most of these low-susceptibility loci have been highlighted through genome wide association studies and initially included a number of loci. In the final breast cancer assessment risk, six SNPs showed statistically significant association: MAP3K1, FGFR2, LSP1, TNRC19, and H19 .

Moreover, a particular SNP in CASP8 was identified to confer a slightly increased susceptibility in a candidate-gene study .

Although the actual contribution of low power, common susceptibility loci in hereditary breast cancer is debatable, the identification of such alleles can explain a subset of breast cancer cases.

What To Do If A Person Is Concerned About Their Risk

If a person is concerned that they may have inherited a breast cancer gene, they should speak with a doctor. A doctor may suggest for a person to undergo genetic counseling.

Genetic counseling involves a person speaking with a genetic counselor about their chances of developing breast cancer. Genetic counselors can also provide a person with resources and support.

This type of counseling can also help a person decide if they would like to take part in genetic testing or not. Genetic testing involves checking a persons genetic profile for breast cancer-causing genes.

Genetic testing for cancer usually involves a person submitting a blood sample. However, other forms of genetic testing can use cell samples from a persons:

  • hair
  • anastrozole

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What You Need To Know

  • About 10% of breast cancers are related to inheritance of damaged genes, including breast cancer genes.
  • In addition to BRCA1 and BRCA2, other genes are associated with increased cancer risk, such as: PALB2, ATM, CHEK2, CDH1, STK11, PTEN, TP53 and NF1.
  • If you have inherited a damaged gene, the risk of developing breast cancer or other cancers can be as high as 80% depending on the specific gene and your family history.
  • Whether you get tested for genes that put you at risk for cancer is a personal decision, and should be considered carefully with the help of your doctor and family.
  • Regular monitoring and preventive surgery are options to discuss with your doctor if you are at risk for hereditary breast cancer.

Family History Of Breast Cancer And Inherited Genes

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Some people have a higher risk of developing breast cancer than the general population because other members of their family have had particular cancers. This is called a family history of cancer.

Having a mother, sister or daughter diagnosed with breast cancer approximately doubles the risk of breast cancer. This risk is higher when more close relatives have breast cancer, or if a relative developed breast cancer under the age of 50. But most women who have a close relative with breast cancer will never develop it.

UK guidelines help GPs to identify people who might have an increased risk of cancer due to their family history.

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Groups At Higher Risk For Hereditary Breast And Ovarian Cancer

You may have a higher risk for hereditary breast cancer if breast cancer or a BRCA gene mutation runs in your family.

Hereditary breast cancer means that breast cancer runs in your family, and could be caused by an inherited change in your genes. About 5% to 10% of breast cancers are hereditary.

You may have a higher risk for hereditary breast cancer if

  • Breast cancer runs in your family and/or
  • A BRCA gene mutation runs in your family.

Most hereditary breast cancers are caused by abnormal BRCA1 and BRCA2 genes. However, even if a BRCA1 or BRCA2 gene mutation does not run in the family, a strong family health history of breast cancer makes it more likely that a person will get breast cancer, possibly due to mutations in other genes. Mutations in several other genes also have been linked to breast and ovarian cancers.

The first step in assessing your risk is learning your family history and sharing this information with your health care provider to learn if genetic counseling and testing are right for you.

Pathological Characteristics Of Hereditary Breast Cancer

The majority of invasive breast cancers arising in BRCA1 and BRCA2 carriers are invasive ductal carcinomas . A higher frequency of BRCA1 tumors are classified as medullary carcinomas compared to sporadic tumors ., Medullary carcinomas are poorly differentiated, high-grade carcinomas with diffuse lymphocytic infiltrate but with a remarkably favorable prognosis, probably because of low incidence of lymph node metastasis. Notably, 11% of medullary carcinomas carry BRCA1 germline mutations. By contrast, excess of invasive lobular and tubular carcinomas has been reported for BRCA2 relative to BRCA1 tumors.,BRCA1 tumors are more frequently high-grade compared to sporadic tumors. They have a higher number of mitosis, and show a high frequency of necrotic areas and a higher proportion of continuous pushing margins and lymphocytic infiltration. All these features point toward a more aggressive tumor type., Most BRCA2 tumors are grade 2/3 with high mitotic rates. Continuous pushing margins are also characteristic of BRCA2 tumors.

In contrast to BRCA1 tumors, BRCA2 tumors seem to be more similar to sporadic tumors with relation to the expression of IHC markers. Most BRCA2 breast tumors show a luminal phenotype by overexpressing ER and PR and the cytokeratins CK8 and CK18.

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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.

Other Cancer Risks For People With Hboc

BRCA Testing in Young Cancer Patients

Anyone with mutations in the BRCA2 gene may be at an increased risk of other types of cancer, including melanoma and pancreatic, stomach, esophageal, and bile duct cancers.Mutations in other genes may be associated with an increased risk of developing breast and other cancers, including the Li-Fraumeni syndrome , Cowden syndrome, and others. The pattern of cancers in the family is often a clue to the specific gene that may explain the hereditary cancer for that family. Multigene panels are available for people with a strong personal and family history of cancer. Multigene panel tests include BRCA1 and BRCA2 and many other genes that increase the risk of breast, ovarian, and other cancers. If your BRCA1 and BRCA2 test was negative, then you may or may not have mutations in other genes. A newer type of testing, called next generation sequencing, massively parallel sequencing, or deep sequencing, has made testing for multiple genes at the same time faster and less expensive. If a genetic mutation is found, this could explain the cancers in a specific family and provide information about who is at risk and the appropriate types of monitoring and prevention/risk reduction methods.

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Risks For Breast Cancer

A risk factor is something that increases the risk of developing cancer. It could be a behaviour, substance or condition. Most cancers are the result of many risk factors. But sometimes breast cancer develops in women who dont have any of the risk factors described below.

Most breast cancers occur in women. The main reason women develop breast cancer is because their breast cells are exposed to the female hormones estrogen and progesterone. These hormones, especially estrogen, are linked with breast cancer and encourage the growth of some breast cancers.

Breast cancer is more common in high-income, developed countries such as Canada, the United States and some European countries. The risk of developing breast cancer increases with age. Breast cancer mostly occurs in women between 50 and 69 years of age.

Breast Cancer Risk And Breast Awareness

You may feel reassured to know that only a small number of breast cancers are due to having a significant family history.

However, breast cancer is still the most common cancer in women in the UK.

One in seven women in the UK will develop breast cancer in their lifetime.

Its important to be breast aware. This means:

  • Checking your breasts regularly, so you know what looks and feels normal for you
  • Contacting your GP if you notice a breast change thats new or unusual

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What Can You Do If You Are Concerned About Your Risk

If your doctor decides that your family health history makes you more likely to get breast, ovarian, and other cancers, he or she may refer you for genetic counseling. Even if your doctor doesnt 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 recommendationsExternalexternal icon, you should consider talking to your doctor about starting mammography screening in your 40s.

The genetic counselor can use your family health history information to determine your possible cancer risks and whether you might consider genetic testing to find out if you have a BRCA1, BRCA2, or other mutation. In some cases, the genetic counselor might recommend genetic testing using a panel that looks for mutations in several genes in addition to BRCA1 and BRCA2. Genetic testing is most useful if first performed on someone in your family who has had breast or ovarian cancer. If this relative has a BRCA1, BRCA2, or other mutation, then their close relatives can be offered testing for that mutation. If they do not have a BRCA1, BRCA2 or other mutation, then their relatives may not need to be tested. BRCA genetic counseling and testing is often, but not always, covered without cost sharing by many health plans under the Affordable Care Act.

Breast Cancer Screening For Women With A Strong Family History Of Breast Or Ovarian Cancer

Is Population Testing for Hereditary Breast and Ovarian Cancer Worthwhile?

There are special breast cancer screening guidelines for women with a strong family history of breast or ovarian cancer.

If you have a greater than 20 percent lifetime risk of breast cancer based mainly on your family history of breast or ovarian cancer, the National Comprehensive Cancer Network recommends you get a :

  • Clinical breast exam every 6-12 months, but not before age 21
  • Mammogram every year, starting 10 years younger than the youngest breast cancer case in your family, but not before age 30
  • Breast MRI every year, starting 10 years younger than the youngest breast cancer case in your family, but not before age 25

Learn more about breast cancer screening recommendations for men at higher risk.

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Reproductive History Estrogen Is The Main Hormone Associated With Breast Cancer Estrogen Affects The Growth Of Breast Cells Experts Believe That It Plays An Important Role In The Growth Of Breast Cancer Cells As Well The Type Of Exposure And How Long Cells Are Exposed To Estrogen Affects The Chances That Breast Cancer Will Develop

Early menarche

The start of menstruation is called menarche. Early menarche is when menstruation starts at an early age . Starting your period early means that your cells are exposed to estrogen and other hormones for a greater amount of time. This increases the risk of breast cancer.

Late menopause

Menopause occurs as the ovaries stop making hormones and the level of hormones in the body drops. This causes a woman to stop menstruating. If you enter menopause at a later age , it means that your cells are exposed to estrogen and other hormones for a greater amount of time. This increases the risk for breast cancer. Likewise, menopause at a younger age decreases the length of time breast tissue is exposed to estrogen and other hormones. Early menopause is linked with a lower risk of breast cancer.

Late pregnancy or no pregnancies

Pregnancy interrupts the exposure of breast cells to circulating estrogen. It also lowers the total number of menstrual cycles a woman has in her lifetime.

Women who have their first full-term pregnancy after the age of 30 have a slightly higher risk of breast cancer than women who have at least one full-term pregnancy at an earlier age. Becoming pregnant at an early age reduces breast cancer risk.

The more children a woman has, the greater the protection against breast cancer. Not becoming pregnant at all increases the risk for breast cancer.


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