Support For Hereditary Breast Cancer
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.
Hereditary Leiomyomatosis And Renal Carcinoma
HLRCC is caused by faults in the FH gene. People with HLRCC have benign skin tumours , fibroids in the womb , and may have kidney cancer. Papillary renal cancer is the most common kidney cancer type in HLRCC, but other types, such as tubulo papillary renal cell cancer and collecting duct renal cell cancer, can develop. It is a very rare condition and the number of people with HLRCC is not known.
About The Medical Reviewer
Dr. Garber is the Chief of the Division for Cancer Genetics and Prevention at Dana-Farber Cancer Institute and a Professor of Medicine at Harvard Medical School. She also consults with the Pediatric Cancer Genetic Risk Program at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Dr. Garber conducts research in clinical cancer genetics, with a special focus in the genetics of breast cancer. She has played a major role in the development of national guidelines in cancer genetics. She is also a leader in research into the characteristics and treatment of triple negative or basal-like breast cancer, the most common form in women with BRCA1 mutations. Her translational research focuses on the evaluation of novel agents targeting DNA repair defects in breast cancer, including PARP inhibitors for treatment and prevention of breast cancer and other BRCA-associated cancers.Dr. Garber is a past president and current member of the Foundation Board of the American Association for Cancer Research . She serves on the National Cancer Advisory Board of the National Cancer Institute and was elected into the National Academy of Medicine in 2013. She also serves as the Chair of the Breast Cancer Research Foundation Scientific Advisory Board. She is an ASCO Statesman and a Fellow of the AACR Academy.
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How Is Hboc Inherited
Normally, each person has 2 copies of each gene in their bodys cells: 1 copy is inherited from a persons mother and 1 copy is inherited from a persons father. HBOC follows an autosomal dominant inheritance pattern. This means that a mutation needs to happen in only 1 copy of the gene for the person to have an increased risk of getting that disease. This means that a parent with a gene mutation may pass along a copy of their normal gene or a copy of the gene with the mutation. Therefore, a child who has a parent with a mutation has a 50% chance of inheriting that mutation. A sibling or parent of a person who has a mutation also has a 50% chance of having inherited the same mutation. However, if the parents test negative for the mutation , the risk to the siblings significantly decreases but their risk may still be higher than an average risk.
Expression Levels Of Key Genes In The Clinical Samples
We compared the mRNA and protein expression levels of 16 genes in clinical database. The result showed that the mRNA expression levels in TCGA were presented in Figure 6A–P. The highly expressed genes included AGPAT1, PCYT2, DGKZ, PLPP2, CEL, LYPLA1, GK, PLA2G2D, and low-expression genes have ENPP6, ADPRM, PAFAH1B1, SGMS2, CHPT1, SGPP1, CHKB, PCYT1A. In addition to the lack of PLA2G2D data in the HPA, the results showed the protein expression and distribution of the 15 genes that make up the signature in breast cancer and normal tissues . Compared with normal tissue, AGPAT1, PCYT2, PLPP2, LYPLA1 and GK Upregulated in breast cancer, ENPP6, ADPRM, PAFAH1B1, SGMS2, CHPT1, SGPP1, CHKB, PCYT1A downregulated in breast cancer, while GEL and DGKZ was not obvious.
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Figure 6 The mRNA expression level of 16 LMGs in TCGA. ADPRM expression AGPAT1 expression CEL expression DGKZ expression ENPP6 expression CHKB expression GK expression PCYT1A expression PAFAH1B1 expression PCYT2 expression PLA2G2D expression SGMS2 expression CHPT1 expression SGPP1 expression LYPLA1 expression PLPP2 expression. |
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Figure 7 Representative immunohistochemistry of 15 LMGs between breast cancer and normal tissues in the Human Protein Atlas database. |
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What Are The Estimated Cancer Risks Associated With Hboc
Cancer risks for women with HBOC
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Lifetime risk of breast cancer 45% to 75%
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Lifetime risk of ovarian cancer
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BRCA1 gene mutation 25% to 40%
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BRCA2 gene mutation 10% to 20%
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Developing a second breast cancer 20% to 40%
Cancer risks for men with HBOC
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Lifetime risk of breast cancer
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BRCA1 gene mutation 1% to 2%
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BRCA2 gene mutation 6%
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BRCA1 gene mutation some increased risk
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BRCA2 gene mutation 20%
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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.
Construction Of A Lipid
First, the expression level of lipid metabolism genes was extracted from the total gene expression list. If a gene appeared more than once in the same sample, the limma of Bioconductor R package was utilized for averaging operations.8 Second, the limma was utilized to identify differentially expressed lipid-metabolism-associated genes between breast cancer tissue samples and normal breast tissue samples. The false discovery rate threshold was set at FDR < 0.05 for DE-LMGs calling. To establish the lipid metabolism-related risk model, univariate Cox regression analysis was performed on the lipid metabolism-related genes. A total of 18 prognostic related differential genes were obtained by the intersection of DE-LMGs and prognostic genes. Heatmaps of the 18 genes were plotted using the heatmap R package. The mutation rates of prognostic DE-LMGs were analyzed by the cBioPortal for Cancer Genomics online website .9 The OncoPrint schematic was constructed in cBioPortal to directly reflect the mutation of 817 BRCA patients. A proteinprotein interaction network of proteins encoded by all overlapping DE-LMGs with prognostic value was visualized using String .10
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Screening And Prevention Strategies
| Addressed in general terms and other guidelines referenced | Addressed in general terms and other guidelines referenced |
| Genetic Counseling: Addressed |
References
Other Genes And Future Perspectives
Over 80 other breast cancer susceptibility genes and loci have been identified in the past few years, but again none have entered clinical practice either because of the difficulty in interpreting results from sequencing analyses or because the RR associated with the mutated alleles is so low that there is at best limited clinical relevance . Only one low-penetrance variant was specifically associated with ILC in a pooled, post hoc analysis of 36 casecontrol studies .
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Functional Enrichment And Pathway Analysis
BC patients were divided into the high- and low-risk groups based on the median risk score, Gene Ontology 12 and Kyoto Encyclopedia of Genes and Genomes 13 pathway enrichment analyses for all selected DEGs between the two risks. Cohorts were performed with the clusterProfiler package in BioConductor using |log2FC|1 and FDR < 0.05 as thresholds. Then, we determined the scores of 16 tumor-infiltrating immune cells and 13 immune-related functions for samples by ssGSEA. Bioconductor R package GSVA was used to compare ssGSEA enrichment scores for immune cells and immune-related pathways between the two groups .14 Finally, correlations between the risk signature and the key immune regulators, PD-L1 and PD-L2 were evaluated.
Brca1 And Brca2 Genes
In 1990, DNA linkage studies on large families with the above characteristics identified the first gene associated with breast cancer. Scientists named this gene “breast cancer 1” or BRCA1 . BRCA1 is located on chromosome 17. Mutations in the gene are transmitted in an autosomal dominant pattern in a family.
Since it was clear that not all breast cancer families were linked to BRCA1, studies continued and in 1994, scientists discovered another gene , and named it BRCA2. BRCA2 is located on chromosome 13. Mutations in this gene are also transmitted in an autosomal dominant pattern in a family.
Both BRCA1 and BRCA2 are tumor suppressor genes that usually have the job of controlling cell growth and cell death. Everyone has two BRCA1 and two BRCA2 genes . When a person has one altered or mutated copy of either the BRCA1 or BRCA2 gene, their risk for various types of cancer increases.
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BRCA1 Mutation |
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BRCA2 Mutation |
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BRCA2 Mutation
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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.
Putting It All Togetherpolygenic Risk Scores
Individually, SNPs have quite small effect sizes and may not be informative for evaluating risk of developing breast cancer. However, the recent OncoArray study suggested that all of the breast cancer susceptibility markers to date explain up to 18% of familial relative risk . Thus, combining these common variants together may provide some insight into individual risks of breast cancer. While the first 7 breast cancer susceptibility SNPs were shown to have little influence on risks predicted by the National Cancer Institute Breast Cancer Risk Assessment Tool , subsequent studies using polygenic risk scores based on larger numbers of SNPs have successfully demonstrated an ability to stratify or individualize breast cancer risk in a number of populations .
In 2016, Dite and colleagues evaluated models combining a PRS based on 77 breast cancer susceptibility SNPs and clinical breast cancer risk prediction models including BOADICEA, BRCAPRO, BCRAT, and IBIS . This study suggested that including the PRS improved breast cancer prediction in women younger than 50 years by more than 20%. Beginning in August 2017, Myriad Genetics, a commercial genetic testing laboratory, incorporated 82 SNPs on the MyRisk multi-gene panel. The resulting Breast Cancer riskScore that includes results from the 82 SNPs and the TyrerCuzick model predicts a woman’s 5-year and lifetime risk of developing breast cancer .
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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
- Mild hyperplasia
- Epithelial-related calcifications
- 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 don’t look very abnormal. These conditions seem to raise a womans risk of breast cancer slightly. They include:
- Usual ductal hyperplasia
- Fibroadenoma
- 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
Brca1 And Brca2 Inherited Gene Mutations
Like other inherited gene mutations, BRCA1 and BRCA2 gene mutations are rare in the general population. In the U.S., about 1 in 400 people have a BRCA1/2 mutation .
Prevalence varies by ethnic group. Among Ashkenazi Jewish men and women, about 1 in 40 have a BRCA1/2 mutation .
Learn more about BRCA1/2 mutations.
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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 .
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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