Characteristics of breast cancer in BRCA1/BRCA2 mutation carriers and non-carriersfrom a genetic counseling unit in Croatia

Breast cancer (BC) represents 25% of all malignancies in Croatian women, and in 18.8% of cases, it is diagnosed before the age of 50. Croatia launched BRCA testing of people at increased family risk. Hereditary BC is mainly caused by a pathogenic mutation in the BRCA1 or BRCA2 gene and is a significant risk factor for developing breast and ovarian cancer. The present study included 127 women diagnosed with BC, with a strong family history of BC and the known status of the germline mutations in the BRCA1/BRCA2 genes. The majority of women were BRCA1/2 mutation non-carriers, while 15.7% were BRCA1/2 mutation carriers, and 4% had a variant of unknown significance (VUS). BRCA1/2 mutation carriers were younger than non-carriers (median 38.5 years vs. 44 years) (P=.01) and had tumors of higher histological grade (P<.001). The intrinsic subtype of BC differs significantly depending on the type of mutation (P<.001). Triple-negative BC prevailed (87.5%) in BRCA1 mutation carriers, and 12.5% had a luminal B/HER2-negative BC. Four patients were BRCA2 mutation carriers, and two of them had luminal B/HER2-positive BC. Most BRCA1/2 non-carriers (69.2%) and all VUS-carriers have luminal B/HER2-negative BC. Our results show that BRCA1/2 mutation testing is essential for women with a family history burden. It is a piece of valuable information in breast cancer risk assessment and contributes to early diagnosis.

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A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Nature Communications ◽

10.1038/s41467-020-20496-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Juliette Coignard ◽

◽

Michael Lush ◽

Jonathan Beesley ◽

Tracy A. O’Mara ◽

...

Keyword(s):

Breast Cancer ◽

General Population ◽

Genome Wide Association Study ◽

Brca2 Mutation ◽

Risk Scores ◽

Genetic Modifiers ◽

Mutation Carriers ◽

Genotype Frequencies ◽

Genome Wide ◽

Brca1 Brca2

AbstractBreast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

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Primary multiple BRCA associated breast cancer and ovarian cancer (clinical case)

Medical Council ◽

10.21518/2079-701x-2020-9-248-257 ◽

2020 ◽

pp. 248-257

Author(s):

I. B. Kononenko ◽

A. V. Snegovoy ◽

Y. A. Bozhchenko ◽

D. N. Kravchenko ◽

Vladimir Yu. Selchuk ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Clinical Case ◽

Brca2 Mutation ◽

Cumulative Risk ◽

Brca2 Gene ◽

Left Breast ◽

Luminal A ◽

Uterine Tube ◽

Luminal B

Introduction. The study of mutation in BRCA1/2 genes was first initiated in the USA and Europe, and later in Russia. Statistics indicate that women with the BRCA1/BRCA2 mutation have a higher risk of breast and/or ovarian cancer than the general population. According to different authors, the average cumulative risk among BRCA1 carriers is 65% (range 44–78%) for breast cancer and 39% (range 18–54%) for ovarian cancer. For mutation carriers in the BRCA2 gene, the risk for breast cancer is 45–49%, while the risk for RNA is 11–18%. However, in patients already diagnosed with breast cancer or ovarian cancer, the risk of a second tumor persists throughout life and may remain high even in old age. Treatment of BRCA-associated breast cancer and/or ovarian cancer is almost the same as treatment for sporadic cancer, and includes surgical, radiation, and drug anticancer therapy. However, there are some features that need to be considered in clinical practice. Clinical case. In this article we present the clinical experience of the treatment of a 32-year-old patient with BRCA1-associated primary multiple synchronous breast cancer and metachronous uterine tube cancer. In July 2015, the patient was diagnosed with synchronous cancer of both breast (Luminal A right breast cancer and Luminal B left breast cancer). As part of a treatment and with the patient’s consent, a bilateral adnexectomy was performed. In the histological examination of the operating material, the uterine tube cancer was diagnosed in situ. From 16.03.2016 to the present time the patient receives adjuvant endocrinotherapy without signs of disease progression. Conclusion. This clinical case study presents the importance of a combined approach to the treatment and prevention of BRCAassociated cancer.

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Male Breast Cancer: Surgical and Genetic Features and a Multidisciplinary Management Strategy

Breast Care ◽

10.1159/000501711 ◽

2019 ◽

Vol 15 (1) ◽

pp. 14-21 ◽

Cited By ~ 1

Author(s):

Francesca Pellini ◽

Eleonora Granuzzo ◽

Silvia Urbani ◽

Sara Mirandola ◽

Marina Caldana ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

High Risk ◽

Male Breast Cancer ◽

Brca2 Mutation ◽

Positive Family History ◽

Male Breast ◽

Mutation Carriers ◽

History Of ◽

Clinical Records

Background: Male breast cancer (MBC) is a rare disease with a rising incidence trend. The major risk factors related to MBC are a positive family history of breast cancer (BC) and BRCA1/2 mutations, which indicate a relevant genetic role. Methods: In this retrospective series, we enrolled 69 male patients presenting with male breast cancer (MBC) between 01/01/1992 and 31/12/2018, and 26 high-risk not-affected men presenting between 01/01/2016 and 31/12/2018. Participants’ electronic clinical records were reviewed. Patients’ data reported age at diagnosis, tumor characteristics, therapeutic management, and BRCA1/2 status as well as a family history of breast, ovarian, or prostate cancer (PCa) in first-degree relatives. Results: We analyzed 69 MBC patients. Median age was 64 years. The majority of tumors diagnosed were of an early TNM stage. The most frequent histological subtype was invasive ductal carcinoma (76.7%). Hormone receptors were positive in >90% of MBC cases. Nearly all patients underwent modified radical mastectomy or total mastectomy. Adjuvant endocrine therapy was delivered in 59.4%. Among MBC-affected patients, we recorded a high percentage of a positive family history of BC. Mutational analysis for the BRCA1/2 genes was performed in 17 MBC patients; 11.8% were carriers of BRCA2 pathogenic mutations. Among 26 healthy high-risk subjects included in this case series, 4 were BRCA1 mutation carriers and 9 were BRCA2 mutation carriers. Discussion: We evaluated the distribution of clinicopathological characteristics in MBC subjects and assessed the frequency of mutations in the BRCA genes in affected patients and healthy high-risk subjects, with the aim of proposing a surveillance program for BC and PCa.

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Study of the Carrier State for Five BRCA1/BRCA2 Deleterious Mutations in Bulgarian Women with Breast Cancer

Journal of Biomedical and Clinical Research ◽

10.1515/jbcr-2015-0109 ◽

2013 ◽

Vol 6 (2) ◽

pp. 100-105 ◽

Cited By ~ 1

Author(s):

Katia S. Kovacheva ◽

Zornica B. Kamburova ◽

Savelina L. Popovska ◽

Ivan N. Ivanov ◽

Maria N. Simeonova ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

Brca2 Gene ◽

Carrier State ◽

University Hospital ◽

Management Tool ◽

Deleterious Mutations ◽

Founder Mutations ◽

Bulgarian Population ◽

Brca1 Brca2

SummaryGenetic testing for BRCA 1/2 mutation is a well recognized medical management tool. Identification of healthy carriers of such mutations allows effective risk reduction procedures to be performed. There is no data reported on the founder mutations in the Bulgarian population. To evaluate the contribution of genetic factors to breast cancer (BC), we investigated the carrier state of Bulgarian women with BC for five common (according to BIC database) deleterious BRCA1/2 mutations. The list of patients diagnosed with BC between January 2011 and April 2012 was obtained from the Cancer Registry of University Hospital, Pleven. Eighty-two women with BC were interviewed and a pedigree was constructed of each of them. The patients were classified into seven categories, according to personal, disease and family history. Based on the preliminary prepared selection criteria and the personal family history, we defined a target group of 33 Bulgarian women with BC. They were screened for five deleterious mutations: 5382insC in BRCA1 and 6174delT, 6079del4, 8138del5, 5946delCT in BRCA2, by DNA sequencing. The genetic analysis detected none of the tested mutations. Two polymorphic variants were found in BRCA2 gene: c.5744C>T (rs4987117, SNP database) in exonl 1E in one patient and c.7806-14T>C (rs9534262, SNP database) in exonl7 in 22 patients. In conclusion, without basic information on the founder mutations in the population, the genetic screening for the specific mutations in a small group of tested patients is ineffective.

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Analysis of plasma proteome from BRCA1/BRCA2 mutation carriers as modifier risk factor of breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2010.28.15_suppl.1549 ◽

2010 ◽

Vol 28 (15_suppl) ◽

pp. 1549-1549

Author(s):

A. Custodio ◽

P. Pérez-Segura ◽

J. Zamorano ◽

A. López-Farrã ◽

E. Olivera ◽

...

Keyword(s):

Breast Cancer ◽

Risk Factor ◽

Brca2 Mutation ◽

Plasma Proteome ◽

Mutation Carriers ◽

Brca1 Brca2

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Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

British Journal of Cancer ◽

10.1038/sj.bjc.6605416 ◽

2009 ◽

Vol 101 (12) ◽

pp. 2048-2054 ◽

Cited By ~ 11

Author(s):

A Osorio ◽

◽

R L Milne ◽

G Pita ◽

P Peterlongo ◽

...

Keyword(s):

Breast Cancer ◽

Brca2 Mutation ◽

Brca1 And Brca2 ◽

Mutation Carriers ◽

Risk Modifier ◽

Brca1 Brca2

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Correlation of breast cancer risk in European BRCA2 mutation carriers with birth cohort.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.1537 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 1537-1537

Author(s):

Muy-Kheng Maria Tea ◽

Regina Kroiss ◽

Daniela Muhr ◽

Christine Fuerhauser-Rappaport ◽

Teresa M. U. Wagner ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Risk ◽

Birth Cohort ◽

Brca2 Mutation ◽

Molecular Genetic ◽

Brca2 Gene ◽

Cancer Gene ◽

Mutation Carriers ◽

Study Population ◽

Breast Cancer Gene

1537 Background: Mutations in the Breast Cancer Gene 1 (BRCA1) and Breast Cancer Gene 2 (BRCA2) lead to an elevated risk of developing breast (BC) and ovarian cancer (OC). However, risk estimates vary, depending on the study population. Furthermore, there are indications that birth cohort can influence the cancer risk. We investigated the risks for BC and OC associated with BRCA2 mutations in a cohort of female mutation carriers of a genetically heterogeneous central European population who were identified by molecular genetic testing in our institute. Methods: This study included 171 Caucasian women from Austria who underwent genetic counseling and where molecular genetic analysis identified a mutation in the BRCA2 gene at the Medical University of Vienna, Division of Senology, in Austria. A total of 57 healthy and 114 affected BRCA2-carriers were detected. The risk was estimated using the product limit method. The log rank test was used to compare different strata. Results: The risk of developing cancer to age 70 was found to be 85% for BC (95% CI 77–93%) and 31% for OC (95% CI 16–46%) in our BRCA2 study population. Female BRCA2-carriers born in 1958 or later were at a significantly higher risk of developing BC (p<0.001; 88% vs. 46% to age 40) but not of OC (p is not significant; 0% vs. 2% to age 40) compared to mutation carriers born earlier. Conclusions: We conclude that female BRCA2 mutation carriers should also be counseled about their cohort-dependent cancer risk, especially for breast cancer. Further research about variables that may affect cancer risk like lifestyle-related factors should be considered.

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Detecting BRCA2 Protein Truncation in Tissue Biopsies to Identify Breast Cancers That Arise in BRCA2 Gene Mutation Carriers

Journal of Clinical Oncology ◽

10.1200/jco.2008.20.5211 ◽

2009 ◽

Vol 27 (24) ◽

pp. 3894-3900 ◽

Cited By ~ 5

Author(s):

Patrice Watson ◽

Rita Lieberman ◽

Carrie Snyder ◽

Vanessa J. Clark ◽

Henry T. Lynch ◽

...

Keyword(s):

Breast Cancer ◽

Brca2 Mutation ◽

Brca2 Gene ◽

Wild Type Allele ◽

Breast Cancers ◽

Wild Type ◽

Type Allele ◽

Mutation Carriers ◽

Brca2 Protein ◽

Protein Truncation

Purpose Mutations in the BRCA2 gene are dominantly inherited but cause cancers when the wild-type allele has loss of heterozygosity (LOH) within the cancer. Because most disease-associated BRCA2 mutations are protein-truncating mutations, a test for truncated BRCA2 proteins should identify most BRCA2 hereditary cancers. Methods We have developed a tissue truncation test to identify truncated BRCA2 proteins in breast cancer tissue biopsies in vivo that does not use amplification or genetic manipulations. N-terminal and C-terminal antibodies are used to visualize protein truncation by demonstrating that the beginning of the protein is present but the end (ie, terminus) is absent. Results A quantitative C-terminal immunostaining score or a C-terminal to N-terminal truncation ratio correctly classified 20 of 21 breast cancers arising in BRCA2 mutation carriers and 57 of 58 cancers arising outside the context of a multiple-case breast cancer family. This represents a sensitivity of 95% and a specificity of 98%. Because of the presence of C-terminal BRCA2 protein and atypical clinical features of the misclassified cancer in a BRCA2 mutation carrier, we performed polymerase chain reaction and sequence analyses on this cancer. The results showed continued presence of the BRCA2 wild-type allele in the cancer, which indicated that intact BRCA2 protein was present in this cancer. Conclusion This immunohistochemistry-based test (which takes only 4 hours) appears to identify BRCA2 hereditary cancer with high accuracy. The test also appears to diagnose the biochemical loss of BRCA2 protein in cancers (ie, BRCA2-mutant genotype), which will usually but not always agree with the presence of a germline BRCA2 mutation found by susceptibility testing by DNA sequencing of blood samples.

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