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Genes Associated With Breast Cancer

Support For Hereditary Breast Cancer

Rare gene mutation increases breast cancer risk

Just as people who have been diagnosed with breast cancer need support, those who carry genes that increase risk need support. Fortunately, there are organizations that focus specifically on supporting people in this situation.

One organization, FORCE, which is an acronym for Facing Our Risk of Cancer Empowered, offers a helpline, message board, and information for those who are facing hereditary cancer.

Other organizations and support communities are available to help people cope with the decisions related to a diagnosis of hereditary breast cancer.

The term previvor was coined by FORCE to describe people who are surviving a predisposition to breast cancer. If this is the situation you are facing, you are not alone, and using the hashtag #previvor, you can find many others on Twitter and other social media outlets.

Identification Of Clinical Significant Modules

Two approaches were used to identify modules associated with clinical information of breast cancer. First, module eigengenes were defined as the first principal component of each gene module and the expression of MEs was considered as a representative of all genes in a given module. The correlation between MEs and clinical trait was calculated to identify the clinical significant module. In addition, the gene significance was defined as mediated p-value of each gene in the linear regression between gene expression and the clinical traits. Then, the module significance were defined as the average GS of all the genes involved in the module.MS was measured to incorporate clinical information into the co-expression network. Module significance was defined as the average absolute gene significance measured for all genes in a given module.

What Are The Estimated Cancer Risks Associated With Hboc

Cancer risks for women with HBOC

  • Lifetime risk of breast cancer 45% to 75%

  • Lifetime risk of ovarian cancer

    • BRCA1 gene mutation 25% to 40%

    • BRCA2 gene mutation 10% to 20%

  • Developing a second breast cancer 20% to 40%

Cancer risks for men with HBOC

  • Lifetime risk of breast cancer

    • BRCA1 gene mutation 1% to 2%

    • BRCA2 gene mutation 6%

    • BRCA1 gene mutation some increased risk

    • BRCA2 gene mutation 20%

  • Men with a BRCA2 gene mutation have a significantly increased risk of developing more aggressive prostate cancer before age 65 and therefore screening should begin at age 40.

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Genes With Low Penetrance

3.5.1 MLH1, MSH2, MSH6, and PMS2

MLH1, MSH2, MSH6, and PMS2 encode DNA mismatch repair proteins responsible for DNA mismatch repair . Mutations in these genes can cause Lynch syndrome. Several studies have found that MMR gene mutations frequently exist in patients with BC , but the association between Lynch syndrome and BC is unclear .

With the widespread application of high-throughput sequencing, a large number of genes related to BC risk have been identified, such as BAP1, PPM1D, and ABRAXAS1 . However, their exact connection with BC and its penetrance remains unclear.

Familial Breast Cancer: Disease Related Gene Mutations And Screening Strategies For Chinese Population

Comprehensive integrated analysis of gene expression datasets ...
  • Department of Breast Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Background: About 5%10% of the breast cancer cases have a hereditary background, and this subset is referred to as familial breast cancer . In this review, we summarize the susceptibility genes and genetic syndromes associated with FBC and discuss the FBC screening and high-risk patient consulting strategies for the Chinese population.

Methods: We searched the PubMed database for articles published between January 2000 and August 2021. Finally, 380 pieces of literature addressing the genes and genetic syndromes related to FBC were included and reviewed.

Results: We identified 16 FBC-related genes and divided them into three types of genes according to their relative risk ratios. In addition, six genetic syndromes were found to be associated with FBC. We then summarized the currently available screening strategies for FBC and discussed those available for high-risk Chinese populations.

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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

  • Diagnose cancer

Having Certain Benign Breast Conditions

Women diagnosed with certain benign breast conditions may have a higher risk of breast cancer. Some of these conditions are more closely linked to breast cancer risk than others. Doctors often divide benign breast conditions into 3 groups, depending on how they affect this risk.

Non-proliferative lesions: These conditions dont seem to affect breast cancer risk, or if they do, the increase in risk is very small. They include:

  • Fibrosis and/or simple cysts
  • Other tumors

Mastitis is not a tumor and does not increase the risk of breast cancer.

Proliferative lesions without atypia : In these conditions theres excessive growth of cells in the ducts or lobules of the breast, but the cells dont look very abnormal. These conditions seem to raise a womans risk of breast cancer slightly. They include:

  • Usual ductal hyperplasia
  • Several papillomas
  • Radial scar

Proliferative lesions with atypia: In these conditions, the cells in the ducts or lobules of the breast tissue grow excessively, and some of them no longer look normal. These types of lesions include:

Breast cancer risk is about 4 to 5 times higher than normal in women with these changes. If a woman also has a family history of breast cancer and either hyperplasia or atypical hyperplasia, she has an even higher risk of breast cancer.

For more information, see Non-cancerous Breast Conditions.

Lobular carcinoma in situ

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Genetic Tests For Hereditary Cancer Syndromes

Genetic tests for mutations that cause hereditary cancer syndromes are usually requested by a persons doctor or other health care provider. Genetic counseling can help people consider the risks, benefits, and limitations of genetic testing in their particular situations.

A genetic counselor, doctor, or other health care professional trained in genetics can help an individual or family understand their test results and explain the possible implications of test results for other family members.

People considering genetic testing should understand that their results may become known to other people or organizations that have legitimate, legal access to their medical records, such as their insurance company or employer, if their employer provides the patients health insurance as a benefit. Legal protections are in place to prevent genetic discrimination, including the Genetic Information Nondiscrimination Act of 2008 and the Privacy Rule of the Health Information Portability and Accountability Act of 1996.

The page on Genetic Testing for Inherited Cancer Susceptibility Syndromes has more information on what tests are available and who may want to consider them.

Familial Atypical Multiple Mole Melanoma Syndrome

How Genes Influence Breast Cancer Risk

FAMMM is a syndrome that increases your risk of developing melanoma skin cancer. People with FAMMM tend to have large numbers of moles or moles that are unusual. They also have at least one close relative with a diagnosis of melanoma. A close relative is a parent, brother or sister, or child.

Scientists think that FAMMM is linked to a fault in the CDKN2A gene. It may also increase your risk of developing pancreatic cancer. But doctors need more research to find out for sure.

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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.

Screening Strategies For Fbc

FBC is characterized by familial aggregation, and family members of patients with FBC have a higher lifetime risk of disease than the general population . Generally, the screening processes for high-risk groups of FBC are as follows: professional genetic counselors use screening tools to identify potentially diseased members of the family women who have a positive screening result receive genetic counseling to decide whether to perform advanced genetic counseling or BRCA genetic testing and finally, early monitoring and physical examination of these high-risk groups are carried out to achieve early detection and treatment . This set of procedures is utilized in some countries however, due to the differing FBC gene mutations among ethnic and geographical groups, when applied to the Chinese population, this procedure needs to be modified to meet the differing needs of this specific population .

3.8.1 Genetic Counseling

Genetic counseling is a counseling process for relatives who have genetic diseases or are at risk of infection to provide disease occurrence and early detection or prophylactic intervention methods. Genetic counseling can prevent genetic diseases and provide insight regarding reproductive options and should be conducted by a well-trained professional counselor. The professional counselor conducts family investigation and analysis by evaluating the proband in the family and estimating the possibility of the disease in the offspring.

3.8.2 Genetic Testing

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Results Have The Potential To Improve Breast Cancer Screening And Risk Assessment In All Women

Today, BCRF investigator Dr. Fergus Couch published the results of the first large, multi-center study to improve the accuracy of breast cancer risk assessment for women without a family history of the disease in the New England Journal of Medicine. Fellow BCRF investigators Drs. Christine Ambrosone, Katherine Nathanson, Susan Domchek, and Jeffrey Weitzel were part of the collaborative, multi-institution study team.

Investigators analyzed germline DNA from 32,247 women with breast cancer and 32,544 unaffected womenall participants in the Cancer Risk Estimates Related to Susceptibility consortiumto derive this important data.

We started this project about four years ago, because we realized that all the genetic risk estimates for breast cancer were focused on BRCA1 and BRCA2 genes when there are now 12 genes that are accepted to be predisposing for breast cancer, Dr. Couch said. The BRCA1 and BRCA2 studies were in high-risk patientsthose with a family history or early onset of the disease. There were no genetic risk estimates for women that didn’t have such a family history or young age of onset.

The need for accurate estimates of gene mutations

New insights into gene mutation frequencies

The impact of this new data

As Dr. Couch noted, the data obtained from this study is going to be very valuable going forward, as people will then embark upon risk management strategies and understand their personal risk.

Combinations Of Polymorphisms In Different Genes

HER genes and breast cancer

One study examined the four polymorphisms in the CYP1A1 gene and the GSTM1 and GSTT1 polymorphisms. None of these polymorphisms, either separately or combined, was associated with increased breast cancer risks. Others analysed a combination of the m2 polymorphism in the CYP1A1 gene and the GSTM1 polymorphism and again no associations were found. One study examined the m1 polymorphisms in the CYP1A1 gene and the polymorphisms in the CYP17 and COMT genes. The presence of at least two putative high risk genotypes was associated with an increased risk of breast cancer .

In conclusion, in a few studies with small sample sizes, combinations of polymorphisms were examined.

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Zinc Ring Finger Domain

The RING motif, a Zn finger found in eukaryotic peptides, is 4060 amino acids long and consists of eight conserved metal-binding residues, two quartets of cysteine or histidine residues that coordinate two zinc atoms. This motif contains a short anti-parallel beta-sheet, two zinc-binding loops and a central alpha helix in a small domain. This RING domain interacts with associated proteins, including BARD1, which also contains a RING motif, to form a heterodimer. The BRCA1 RING motif is flanked by alpha helices formed by residues 822 and 8196 of the BRCA1 protein. It interacts with a homologous region in BARD1 also consisting of a RING finger flanked by two alpha-helices formed from residues 3648 and 101116. These four helices combine to form a heterodimerization interface and stabilize the BRCA1-BARD1 heterodimer complex. Additional stabilization is achieved by interactions between adjacent residues in the flanking region and hydrophobic interactions. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression.

Rare Genetic Syndromes With Increased Breast Cancer Risk

The Tp53 gene and Li-Fraumeni syndrome

Inactivating mutations in the Tp53 gene have been found in many tumour types including breast cancer. Li-Fraumeni syndrome is an autosomal dominant disorder, caused by germline mutations in the Tp53 gene. This syndrome is characterised by an increased risk of soft tissue and osteosarcomas, leukaemias, brain tumours, adrenocortical carcinomas, and breast cancers. The risk of developing breast cancer before the age of 45 is 18-fold higher for affected females as compared to the general population. The excess is greatest below the age of 20 and declines with increasing age for breast cancer after the age of 45 = 1.8). Germline mutations in the Tp53 gene have been estimated to account for less than 1% of breast cancer cases. However, somatic mutations in the Tp53 gene are reported in 19-57% of human breast cancers and LOH is found in 30-42%. There is no association between somatic Tp53 mutations and LOH at the Tp53 locus, suggesting that one inactivated allele may be sufficient for breast cancer development. Hypermethylation of the promoter region of the Tp53 gene does not play a role in breast cancers.

The ATM gene and ataxia telangiectasia

A recent study of 138 Austrian hereditary breast and ovarian cancer patients without BRCA1 and BRCA2 mutations showed functionally significant ATM germline mutations in at least 8.7% of the HBOC patients. The penetrance for one of the mutations was estimated to be 85% at age 60.

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Nucleic Acids Isolation From Tumor Samples

Breast biopsies were stored at 70 °C until their analysis. For DNA extraction, 200 mg of tissue was disrupted with mortar in the presence of liquid nitrogen. The frozen powder was transferred to a 1.5 ml tube, and 750 l of lysis buffer was added and incubated for 1 h at 60 °C with agitation. Then, RNase was added to each sample, mixed carefully, and set at 37 °C for 30 min. Samples were kept at room temperature for 5 min, and then 200 l of protein precipitation solution , and 0.49 M potassium acetate solution) were added. Samples were vortexed vigorously and kept on ice for 5 min. Samples were centrifugated at 16,000×g for 4 min to pellet debris and proteins. Supernatants were separated and collected in a clean tube. Then, 600 l of 100% isopropyl alcohol was added and mixed carefully. Samples were centrifugated as described above. DNA pellet was washed three times with 70% ethanol. Finally, ethanol residues were eliminated, 100 l of resuspension buffer was added, and DNA samples were kept at 20 °C until further analysis.

Questions To Ask The Health Care Team

Understanding the genetic risks of breast cancer

If you are concerned about your risk of cancer, talk with your health care team. It can be helpful to bring someone along to your appointments to take notes. Consider asking your health care team the following questions:

  • What is my risk of developing breast cancer and ovarian cancer?

  • What is my risk for other types of cancer?

  • What can I do to reduce my risk of cancer?

  • What are my options for cancer screening?

If you are concerned about your family history and think your family may have HBOC, consider asking the following questions:

  • Does my family history increase my risk of breast cancer, ovarian cancer, or other types of cancer?

  • Should I meet with a genetic counselor?

  • Should I consider genetic testing?

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Multiple Endocrine Neoplasia Type 1 And 2

MEN is a rare inherited condition in which tumours develop in different parts of the body. There are 2 types, MEN1 and MEN2.

People with MEN1 usually develop tumours in the pancreas, parathyroid gland and pituitary gland. Tumours can also develop in the:

  • bowel

  • adrenal glands

The tumours can be non cancerous or cancerous .

MEN2 is caused by a fault in the RET gene. MEN2 can cause a type of thyroid cancer called medullary thyroid cancer. People with MEN2 also have an increased risk of developing adrenal gland tumours.

Brca1 And Brca2 Genetic Mutations

Most inherited cases of breast cancer are associated with mutations in two genes: BRCA1 and BRCA2 .

Everyone has BRCA1 and BRCA2 genes. The function of the BRCA genes is to repair cell damage and keep breast, ovarian, and other cells growing normally. But when these genes contain mutations that are passed from generation to generation, the genes don’t function normally and breast, ovarian, and other cancer risk increases. BRCA1 and BRCA2 mutations may account for up to 10% of all breast cancers, or 1 out of every 10 cases.

Having a BRCA1 or BRCA2 mutation doesn’t mean you will be diagnosed with breast cancer. Researchers are learning that other mutations in pieces of chromosomes called SNPs may be linked to higher breast cancer risk in women with a BRCA1 mutation as well as women who didn’t inherit a breast cancer gene mutation.

Women who are diagnosed with breast cancer and have a BRCA1 or BRCA2 mutation often have a family history of breast cancer, ovarian cancer, and other cancers. Still, most people who develop breast cancer did not inherit a genetic mutation linked to breast cancer and have no family history of the disease.

You are substantially more likely to have a genetic mutation linked to breast cancer if:

If one family member has a genetic mutation linked to breast cancer, it does not mean that all family members will have it.

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