scholarly journals A novel BRCA1 duplication and new insights on the spectrum and frequency of germline large genomic rearrangements in BRCA1/BRCA2

2021 ◽  
Author(s):  
Ibrahim Sahin ◽  
Hanife Saat
Keyword(s):  
Breast Cancer ◽  
Clinical Results ◽  
Genomic Rearrangements ◽  
Breast Cancers ◽  
Cancer Syndrome ◽  
Large Genomic Rearrangements ◽  
Pathogenic Variants ◽  
Recurrent Mutations ◽  
History Of ◽  
Brca1 Brca2

Abstract Heritable breast cancers account for 5 to 10% of all breast cancers, and monogenic, highly penetrant genes cause them. Around 90% of pathogenic variants in BRCA1 and BRCA2 are observed using gene sequencing, with another 10% identified through gene duplication/deletion analysis, which differs across various communities. In this study, we performed a next-generation sequencing panel and MLPA on 1484 patients to explain the importance of recurrent germline duplications/deletions of BRCA1-2 and their clinical results and determine how often BRCA gene LGRs were seen in people suspected of hereditary breast and ovarian cancer syndrome. The large genomic rearrangements (LGRs) frequency was approximately 1% (14/1484). All the 14 mutations were heterozygous and detected in patients with breast cancer. BRCA1 mutations were more predominant (n = 8, 57.1%) than BRCA2 mutations (6, 42.9%). The most common recurrent mutations were BRCA2 exon three and BRCA1 exon 24 (23) deletions. To the best of our knowledge, BRCA1 5'UTR-exon11 duplication has never been reported before. Testing with MLPA is essential to identify patients at high risk. Our data demonstrate that BRCA1-2 LGRs should be considered when ordering genetic testing for individuals with a personal or family history of cancer, particularly breast cancer. Further research could shed light on BRCA1-2 LGRs' unique carcinogenesis roles.

scholarly journals Prevalence of Germline Pathogenic and Likely Pathogenic Variants in Patients With Second Breast Cancers

2020 ◽  
Vol 4 (6) ◽  
Author(s):  
Katharine A Yao K ◽  
Jacob Clifford ◽  
Shuwei Li ◽  
Holly LaDuca ◽  
Peter Hulick ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Race And Ethnicity ◽  
Statistical Tests ◽  
Diagnostic Testing ◽  
Breast Cancers ◽  
Breast Cancer Predisposition ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Predisposition Genes ◽  
Brca1 Brca2

Abstract Background Few studies have examined gene-specific associations with contralateral and/or second breast cancer (SBC). Methods The frequency of pathogenic and likely pathogenic (P/LP) variants in clinically actionable genes (BRCA1, BRCA2, PTEN, TP53, CHEK2, CDH1, ATM, PALB2, NBN, and NF1) was compared between women with a primary breast cancer (PBC) and SBC who underwent multigene panel testing at a single diagnostic testing laboratory. Race- and ethnicity-specific logistic regression burden tests adjusted for age at diagnosis of first breast cancer, histology, presence of first- or second-degree relatives with breast cancer, and prior testing for BRCA1/2 genes were used to test for associations with SBC. All statistical tests were 2-sided. Results The study was comprised of 75 550 women with PBC and 7728 with SBC. Median time between breast cancers for SBC was 11 (interquartile range = 6–17) years. Restricting to women tested for all actionable genes (n = 60 310), there were 4231 (7.8%) carriers of P/LP variants in actionable genes among the controls (PBC) compared with 652 (11.1%) women with SBC (P< .001). Among Caucasians, exclusive of Ashkenazi Jewish women, those carrying a P/LP variant in a clinically actionable gene were 1.44 (95% confidence interval [CI] = 1.30 to 1.60) times as likely to have SBC than noncarriers, after accounting for potential confounders. Among African American and Hispanic women, a P/LP variant in a clinically actionable gene was 1.88 (95% CI = 1.36 to 2.56) and 1.66 (9% CI = 1.02 to 2.58) times as likely to be associated with SBC, respectively (P < .001 and P = .03). Conclusion Women with P/LP variants in breast cancer predisposition genes are more likely to have SBC than noncarriers. Prospective studies are needed confirm these findings.

scholarly journals Prevalence of tumor genomic alternations in homologous recombination genes among Taiwanese breast cancers

2021 ◽  
Author(s):  
Chi-Cheng Huang ◽  
Chun-Yu Liu ◽  
Yi-Fang Tsai ◽  
Pei-Ju Lien ◽  
Yen-Shu Lin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
Missense Mutations ◽  
Breast Cancers ◽  
Cancer Syndrome ◽  
Pathogenic Variants ◽  
Clinical Benefits ◽  
Cancer Tissues

Abstract Purpose Deleterious BRCA1 / 2 mutations are among the most highly pathogenic variants in hereditary breast and ovarian cancer syndrome. PARP (poly ADP ribose polymerase) inhibitors selectively cause failure of single-strand but does not affect double-strand DNA break repair, and ant-tumor activity is observed in BRCA mutant breast cancers. Recently genes implicated into the homologous recombination repair (HRR) pathways are investigated extensively, as defective HRR genes may indicate potential clinical benefits from PARP inhibitors beyond BRCA1 / 2 mutations. Materials and Methods We evaluated the prevalence of BRCA1 / 2 mutations as well as alternations in HRR genes for Taiwanese breast cancers with targeted sequencing. Consecutive 648 breast cancer samples were assayed, and HRR genes by Heeke et al. and those interrogated in Talazoparib Beyond BRCA (TBB) trial were evaluated for prevalence from breast cancer tissues. Results Among 648 breast cancer samples, there were 18 truncating and 2 missense mutations in BRCA1 and 48 truncating and 2 missense mutations in BRCA2 , impacting 3% and 5% of study population (collectively altered in 6%) with co-occurrence of BRCA1 / 2 in 7 breast cancers. On the other hand, HRR genes defined by Heeke et al. were altered in 122 (19%) breast cancers while TBB interrogated genes (excluding BRCA1 / 2 ) were mutated in 107 (17%) patients. Beyond BRCA1/2 , the most prevalent HRR mutant genes came from ARID1A (7%), PALB2 (7%) and PTEN (6%). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples were impacted by at least one HRR gene. Conclusion The prevalence of high-penetrant BRCA1 / 2 mutations was far below one tenth of assayed samples while the prevalence of tumor DNA mutations in HRR pathways was much higher and approached one fifth among Taiwanese breast cancers. Further studies to evaluate the efficacy of PARP inhibitors in patients with defective HRR gene(s) are warranted to broaden the targeted population of synthetic lethality.

scholarly journals Risk of Contralateral Breast Cancer in Women with and without Pathogenic Variants in BRCA1, BRCA2, and TP53 Genes in Women with Very Early-Onset (<36 Years) Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 378 ◽  
Author(s):  
Zerin Hyder ◽  
Elaine F. Harkness ◽  
Emma R. Woodward ◽  
Naomi L. Bowers ◽  
Marta Pereira ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Family History ◽  
Contralateral Breast Cancer ◽  
Genomic Medicine ◽  
Contralateral Breast ◽  
Breast Cancers ◽  
Brca1 And Brca2 ◽  
North West ◽  
Pathogenic Variants ◽  
Brca1 Brca2

Early age at diagnosis of breast cancer is a known risk factor for hereditary predisposition and some studies show a high risk of contralateral breast cancer in BRCA1 carriers diagnosed at very young ages. However, little is published on the risk of TP53 carriers. 397 women with breast cancer diagnosed <36 years of age were obtained from three sources: (i) a population-based study of 283 women diagnosed sequentially from 1980–1997 in North-West England, (ii) referrals to the Genomic Medicine Department at St Mary’s Hospital from 1990–2018, and (iii) individuals from (i) and the Family History Clinic at Wythenshawe Hospital South Manchester who tested negative for pathogenic variants (PV) in all three genes. Sequencing of BRCA1, BRCA2, and TP53 genes was carried out alongside tests for copy number for PV on all referred women. Rates of contralateral breast cancer were censored at death, last assessment, or risk-reducing mastectomy. In total, 47 TP53, 218 BRCA1, and 132 BRCA2 PV carriers were identified with breast cancer diagnosed aged 35 years and under, as well as a representative sample of 261 not known to carry a PV in BRCA1, BRCA2, and TP53. Annual rates of contralateral breast cancer (and percentage of synchronous breast cancers) were TP53: 7.03% (4.3%), BRCA1: 3.57% (1.8%), and BRCA2: 2.63% (1.5%). In non-PV carriers, contralateral rates in isolated presumed/tested non-carrier cases with no family history were 0.56%, and for those with a family history, 0.69%. Contralateral breast cancer rates are substantial in TP53, BRCA1, and BRCA2 PV carriers diagnosed with breast cancer aged 35 and under. Women need to be advised to help make informed decisions on contralateral mastectomy, guided by life expectancy from their index tumor.

Analysis of BRCA1 large genomic rearrangements to identify individuals at risk of breast cancer

2020 ◽  
Author(s):  
Noemí García-Magallanes ◽  
Alejandra Paola Martínez-Camberos ◽  
Emir Adolfo Leal-León ◽  
Verónica Judith Picos-Cárdenas ◽  
Enrique Johathan Romo-Martínez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Malignant Neoplasm ◽  
Brca1 Gene ◽  
Copy Number Variations ◽  
Genomic Rearrangements ◽  
Environmental Aspects ◽  
Single Nucleotide ◽  
Large Genomic Rearrangements ◽  
History Of ◽  
Amplification Assay

Abstract Background. Breast cancer (BC) is a malignant neoplasm in which genetic and environmental aspects contribute to its development. In many cases, pathogenic mutations in BRCA1 are caused by large genomic rearrangements such as copy number variations, a mechanism of gene inactivation that increases the risk of BC. Therefore, identifying women at high risk of BC through genetic testing is of great importance. This study aimed to identify large BRCA1 rearrangements in patients with early-onset or family history of BC. Methods. Peripheral blood from patients with (n= 38) and without (n= 30) BC was analyzed using the multiplex ligation-dependent probe amplification assay to detect large genomic rearrangements in BRCA1. Results. One patient with sporadic BC showed an ambiguous deletion in exon 12 of the BRCA1 gene. To validate this result, full sequencing of this region was performed. The mutation detected by MLPA resulted in a false positive, showing that large genomic rearrangements in BRCA1 were absent in all subjects. Moreover, in this same patient, we detected the presence of c.4308T>C (rs1060915) polymorphism. Conclusions. In our patients with BC, large genomic rearrangements in BRCA1 are held unaccountable for the development of the disease. We identified the presence of single nucleotide polymorphism, c.4308T>C (rs1060915), in a patient with sporadic BC.

scholarly journals Estrogens and Progestogens in Triple Negative Breast Cancer: Do They Harm?

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2506
Author(s):  
Mark van Barele ◽  
Bernadette A. M. Heemskerk-Gerritsen ◽  
Yvonne V. Louwers ◽  
Mijntje B. Vastbinder ◽  
John W. M. Martens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Hormone Replacement ◽  
Breast Cancers ◽  
Younger Women ◽  
Alternative Pathways ◽  
Increased Risk ◽  
History Of ◽  
Hormone Sensitive

Triple-negative breast cancers (TNBC) occur more frequently in younger women and do not express estrogen receptor (ER) nor progesterone receptor (PR), and are therefore often considered hormone-insensitive. Treatment of premenopausal TNBC patients almost always includes chemotherapy, which may lead to premature ovarian insufficiency (POI) and can severely impact quality of life. Hormone replacement therapy (HRT) is contraindicated for patients with a history of hormone-sensitive breast cancer, but the data on safety for TNBC patients is inconclusive, with a few randomized trials showing increased risk-ratios with wide confidence intervals for recurrence after HRT. Here, we review the literature on alternative pathways from the classical ER/PR. We find that for both estrogens and progestogens, potential alternatives exist for exerting their effects on TNBC, ranging from receptor conversion, to alternative receptors capable of binding estrogens, as well as paracrine pathways, such as RANK/RANKL, which can cause progestogens to indirectly stimulate growth and metastasis of TNBC. Finally, HRT may also influence other hormones, such as androgens, and their effects on TNBCs expressing androgen receptors (AR). Concluding, the assumption that TNBC is completely hormone-insensitive is incorrect. However, the direction of the effects of the alternative pathways is not always clear, and will need to be investigated further.

scholarly journals Novel and Recurrent BRCA1/BRCA2 Germline Mutations in Patients with Breast /Ovarian Cancer: A Series from the South of Tunisia

2020 ◽  
Author(s):  
Dorra Ben Ayed-Guerfali ◽  
Wala Ben Kridis-Rejab ◽  
Nihel Ammous-Boukhris ◽  
Wajdi Ayadi ◽  
Slim Charfi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Risk ◽  
Germline Mutations ◽  
Brca Mutations ◽  
Mutation Carriers ◽  
Counseling And Testing ◽  
Recurrent Mutations ◽  
Tunisian Patients ◽  
History Of ◽  
Brca1 Brca2

Abstract Background: The incidence of breast/ovarian cancer is increasing in Tunisia especially in young women and mostly those with family history. However, the spectrum of BRCA mutations remains little explored in Tunisian patients in particular in the southern region. Methods: We sequenced the entire coding regions of BRCA1and BRCA2 genes using Next Generation Sequencing (NGS) in 134 selected patients with breast/ovarian cancer. Results: Among the 134 patients, 19 (14.17%) carried pathogenic mutations (10 are BRCA1 mutation carriers and 9 are BRCA2 mutation carriers) that are mainly frameshisft indel (76.9%). Interestingly, 5 out of the 13 variants (38.46%) were found at least twice in unrelated patients, as the c.1310-1313 delAAGA in BRCA2 and the c.5030_5033 delCTAA that has been identified in 4/98 BC patients and in 3/15 OC patients from unrelated families with strong history of cancer. Besides recurrent mutations, 6 variant (4 in BRCA1 and 2 in BRCA2) were not reported previously. Furthermore, 3 unrelated patients carried the VUS c.9976A>T, (K3326*) in BRCA2 exon 27. BRCA carriers correlated significantly with tumor site (p=0.029) and TNBC cases (p=0.008). In the groups of patients (31-40 y and 41-50 y), BRCA1 mutations occurred more frequently in patients with OC than those with BC, and conversely BRCA2 carriers are mostly affected with BC (p=0.001 and p=0.044 respectively).Conclusions: The overall frequency of the BRCA germline mutations was 14.17% in patients with high risk of breast /ovarian cancer. We identified recurrent mutations as the c.1310_1313 delAAGA in BRCA2 gene and the c.5030_5033 delCTAA in BRCA1 gene that were found in 4% and 20% of familial BC and OC respectively. Our data will contribute in the implementation of genetic counseling and testing for families with high-risk of breast/ovarian cancer.

scholarly journals Expanding the search for germline pathogenic variants for breast cancer. How far should we go and how high should we jump? The missed opportunity!

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Hikmat Abdel-Razeq
Keyword(s):  
Breast Cancer ◽  
Brca1 And Brca2 ◽  
Healthy Women ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
History Of ◽  
Risk Reducing ◽  
Current Guidelines ◽  
Missed Opportunity

Since the identification of BRCA1 and BRCA2 genes 3 decades ago, genetic testing and genetic counseling have become an integral part of routine clinical practice. The risk of breast cancer among carriers of germline pathogenic variants, like BRCA1 and BRCA2, is well established. Risk-reducing interventions, including bilateral mastectomies and salpingo-oophorectomies are both effective and have become more acceptable. Many researchers and professional societies view current guidelines as restrictive and may miss many at-risk women, and are calling to expand testing to include all patients with breast cancer, regardless of their personal or family history of cancer, while others are calling for wider adoption to even include all healthy women at age 30 or older. This review will address expanding testing in two directions; horizontally to include more patients, and even healthy women, and vertically to include more genes using next-generation sequencing-based multi-gene panel testing.

scholarly journals Influence of Germline BRCA Genotype on the Survival of Patients with Triple-Negative Breast Cancer

2021 ◽  
Vol 1 (3) ◽  
pp. 140-147
Author(s):  
Cynthia Villarreal-Garza ◽  
Ana S. Ferrigno ◽  
Alejandro Aranda-Gutierrez ◽  
Paul H. Frankel ◽  
Nora H. Ruel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Point Mutations ◽  
Treatment Resistance ◽  
Cancer Center ◽  
Breast Cancers ◽  
Entire Cohort ◽  
Pathogenic Variants ◽  
Mutational Status

The presence of BRCA pathogenic variants (PV) in triple-negative breast cancer (TNBC) is associated with a distinctive genomic profile that makes the tumor particularly susceptible to DNA-damaging treatments. However, patients with BRCA PVs can develop treatment resistance through the appearance of reversion mutations and restored BRCA expression. As copy-number variants (CNV) could be less susceptible to reversion mutations than point mutations, we hypothesize that carriers of BRCA CNVs may have improved survival after treatment compared with carriers of other BRCA PVs or BRCA wild-type. Women diagnosed with stage I–III TNBC at ≤50 years at a cancer center in Mexico City were screened for BRCA PVs using a recurrent PV assay (HISPANEL; 77% sensitivity). Recurrence-free survival (RFS) and overall survival (OS) were compared according to the mutational status. Among 180 women, 17 (9%) were carriers of BRCA1 ex9–12del CNVs and 26 (14%) of other BRCA PVs. RFS at ten years for the whole cohort was 79.2% [95% confidence interval (CI), 72.3–84.6], with no significant differences according to mutational status. 10-year OS for the entire cohort was 85.3% (95% CI, 78.7–90.0), with BRCA CNV carriers demonstrating numerically superior OS rates other PV carriers and noncarriers (100% vs. 78.6% and 84.7%; log-rank P = 0.037 and P = 0.051, respectively). This study suggests that BRCA1 ex9–12del CNV carriers with TNBC may have a better OS, and supports the hypothesis that the genotype of BRCA PVs may influence survival by limiting treatment resistance mediated by reversion mutations among CNV carriers. Significance: Large CNV BRCA carriers in a cohort of young Mexican patients with TNBC had superior OS rates than carriers of other BRCA pathogenic variants (i.e., small indels or point mutations). We hypothesize that this is due to the resistance of CNVs to reversion mutations mediating resistance to therapy. If validated, these findings have important prognostic and clinical treatment implications for BRCA-associated breast cancers.

Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score

2021 ◽  
pp. JCO.20.01992
Author(s):  
Chi Gao ◽  
Eric C. Polley ◽  
Steven N. Hart ◽  
Hongyan Huang ◽  
Chunling Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
General Population ◽  
Association Studies ◽  
Polygenic Risk Score ◽  
Genome Wide Association Studies ◽  
Polygenic Risk ◽  
First Degree Relatives ◽  
Pathogenic Variants ◽  
Predisposition Genes ◽  
Brca1 Brca2

PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

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