Non-BRCA1/BRCA2 High-Risk Familial Breast Cancers are Not Associated with a High Prevalence of BRCAness

Abstract Familial breast cancer is in most cases unexplained due to the lack of identifiable pathogenic variants in the BRCA1 and BRCA2 genes. Using genome sequencing, we first noted for non-BRCA1/BRCA2 tumours, only a small proportion (3/23) demonstrated features of BRCAness, with high HRDetect scores and concomitant somatic BRCA1 mutation or promoter hypermethylation to explain their BRCAness. Second, a small proportion (4/23) showed no features of BRCAness but had mutationally active tumours. Third, the remaining tumours lacked features of BRCAness and were mutationally quiescent. Only few families could be explained by pathogenic germline variants in other genes or polygenic risk score.

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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 ◽

10.3390/cancers12020378 ◽

2020 ◽

Vol 12 (2) ◽

pp. 378 ◽

Cited By ~ 2

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.20.01992 ◽

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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Identification of Recurrent Variants in BRCA1 and BRCA2 across Multiple Cancers in the Chinese Population

BioMed Research International ◽

10.1155/2020/6739823 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Yue Jiang ◽

Ting Tian ◽

Chengxiao Yu ◽

Wen Zhou ◽

Junzhe Yang ◽

...

Keyword(s):

Breast Cancer ◽

Hepatocellular Carcinoma ◽

Cervical Cancer ◽

Genetic Screening ◽

Chinese Population ◽

Familial Breast Cancer ◽

Cervical Cancer Patient ◽

Breast Cancer Cell Lines ◽

Brca1 And Brca2 ◽

Pathogenic Variants

BRCA1 and BRCA2 as important DNA repair genes have been thoroughly investigated in abundant studies. The potential relationships of BRCA1/2 pathogenic variants between multicancers have been verified in Caucasians but few in Chinese. In this study, we performed a two-stage study to screen BRCA1/2 pathogenic variants or variants of uncertain significance (VUS) with 7580 cancer cases and 4874 cancer-free controls, consisting of a discovery stage with 70 familial breast cancer cases and a subsequent validation stage with 7510 cases (3217 breast cancer, 1133 cervical cancer, 2044 hepatocellular carcinoma, and 1116 colorectal cancer). 48 variants were obtained from 70 familial breast cancer cases after BRCA1/2 exon detection, and finally, 20 pathogenic variants or VUS were selected for subsequent validation. Four recurrent variants in sporadic cases (BRCA1 c.4801A>T, BRCA1 c.3257del, BRCA1 c.440del, and BRCA2 c.7409dup) were identified and three of them were labeled Class 5 by ENIGMA. Two variants (BRCA1 c.3257del and c.440del) were specific in breast cancer cases, while BRCA2 c.7409dup and c.4307T>C were detected in two hepatocellular carcinoma patients and the BRCA1 c.4801A>T variant in one cervical cancer patient, respectively. Moreover, BRCA1 c.3257del was the most frequent variant observed in Chinese sporadic breast cancer and showed increased proliferation of BRCA1c.3257del-overexpressing triple-negative breast cancer cell lines (MDA-MB-231) in vitro. In addition to the known founder deleterious mutations, our findings highlight that the recurrently pathogenic variants in breast cancer cases could be taken as candidate genetic screening loci for a more efficient genetic screening of the Chinese population.

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

JNCI Cancer Spectrum ◽

10.1093/jncics/pkaa094 ◽

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.

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Long-Term Evaluation of Women Referred to a Breast Cancer Family History Clinic (Manchester UK 1987–2020)

Cancers ◽

10.3390/cancers12123697 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3697

Author(s):

Anthony Howell ◽

Ashu Gandhi ◽

Sacha Howell ◽

Mary Wilson ◽

Anthony Maxwell ◽

...

Keyword(s):

Breast Cancer ◽

Family History ◽

Gene Families ◽

Mammographic Screening ◽

Good Prognosis ◽

Lifetime Risk ◽

Breast Cancers ◽

Moderate Risk ◽

Brca1 And Brca2 ◽

Pathogenic Variants

Clinics for women concerned about their family history of breast cancer are widely established. A Family History Clinic was set-up in Manchester, UK, in 1987 in a Breast Unit serving a population of 1.8 million. In this review, we report the outcome of risk assessment, screening and prevention strategies in the clinic and propose future approaches. Between 1987–2020, 14,311 women were referred, of whom 6.4% were from known gene families, 38.2% were at high risk (≥30% lifetime risk), 37.7% at moderate risk (17–29%), and 17.7% at an average/population risk who were discharged. A total of 4168 (29.1%) women were eligible for genetic testing and 736 carried pathogenic variants, predominantly in BRCA1 and BRCA2 but also other genes (5.1% of direct referrals). All women at high or moderate risk were offered annual mammographic screening between ages 30 and 40 years old: 646 cancers were detected in women at high and moderate risk (5.5%) with a detection rate of 5 per 1000 screens. Incident breast cancers were largely of good prognosis and resulted in a predicted survival advantage. All high/moderate-risk women were offered lifestyle prevention advice and 14–27% entered various lifestyle studies. From 1992–2003, women were offered entry into IBIS-I (tamoxifen) and IBIS-II (anastrozole) trials (12.5% of invitees joined). The NICE guidelines ratified the use of tamoxifen and raloxifene (2013) and subsequently anastrozole (2017) for prevention; 10.8% women took up the offer of such treatment between 2013–2020. Since 1994, 7164 eligible women at ≥25% lifetime risk of breast cancer were offered a discussion of risk-reducing breast surgery and 451 (6.2%) had surgery. New approaches in all aspects of the service are needed to build on these results.

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Analysis of the pathogenic variants of BRCA1 and BRCA2 using next-generation sequencing in women with familial breast cancer: a case–control study

BMC Cancer ◽

10.1186/s12885-019-5950-4 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Omar Alejandro Zayas-Villanueva ◽

Luis Daniel Campos-Acevedo ◽

José de Jesús Lugo-Trampe ◽

David Hernández-Barajas ◽

Juan Francisco González-Guerrero ◽

...

Keyword(s):

Breast Cancer ◽

Next Generation Sequencing ◽

Familial Breast Cancer ◽

Case Control Study ◽

Case Control ◽

Next Generation ◽

Brca1 And Brca2 ◽

Pathogenic Variants ◽

Generation Sequencing ◽

Control Study

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Breast conservation surgery and radiation for a patient with synchronous primary breast cancers and BRCA1/BRCA2 positivity: is mastectomy required?

Journal of Radiotherapy in Practice ◽

10.1017/s1460396911000021 ◽

2011 ◽

Vol 11 (1) ◽

pp. 62-65

Author(s):

Mark Trombetta ◽

Katherine Kotinsley ◽

Thomas B. Julian

Keyword(s):

Breast Conservation ◽

Genetic Mutation ◽

Breast Conservation Surgery ◽

Genetic Mutations ◽

Breast Cancers ◽

Brca1 And Brca2 ◽

Breast Preservation ◽

Conservation Surgery ◽

Brca1 Brca2

AbstractThe role of breast conservation in patients expressing BRCA1 and BRCA2 genetic mutations is controversial. A patient who was found to have bilateral synchronous breast cancers and expressed a BRCA genetic mutation was recently evaluated. The patient had a strong desire for breast preservation. This case and a review of the pertinent literature are presented to discuss the role of breast conservation and radiation in patients with BRCA1 or BRCA2 genetic mutations.

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

10.21203/rs.3.rs-470714/v1 ◽

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.

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Outcomes after breast cancer in an ethnically diverse cohort of high-risk patients: Differences in survival based on BRCA1/BRCA2 mutation status

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.21116 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 21116-21116

Author(s):

R. Nanda ◽

D. Huo ◽

M. Cook ◽

L. Chen ◽

K. Hope ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Brca1 Mutation ◽

Brca2 Mutation ◽

Ethnically Diverse ◽

European Ancestry ◽

Rank Test ◽

Brca1 And Brca2 ◽

Brca2 Mutations ◽

Brca1 Brca2

21116 Background: Most studies of hereditary breast cancer report that BRCA1 associated tumors are characterized by high grade and hormone receptor negativity, while those associated with BRCA2 are more similar to sporadic cases. Several groups have demonstrated that BRCA1 mutations, but not BRCA2 mutations, are associated with reduced survival in women with breast cancer. These studies have primarily included women of European and Ashkenazi Jewish heritage. No study to date has assessed outcomes in an ethnically diverse cohort of high-risk individuals. Methods: High-risk individuals were identified through the University of Chicago Cancer Risk Clinic (UCCRC). Clinicopathologic data was collected on all patients with breast cancer who had undergone genetic testing and consented to inclusion in research protocols. Recurrence-free survival (RFS) and overall survival (OS) for BRCA1, BRCA2 and non-carriers was compared using the log-rank test. Hazard ratios (HR) and 95% Confidence Intervals (95% CI) were calculated from Cox proportional hazard models. Results: 280 patients from 258 families were studied. 67 were BRCA1 mutation positive, 36 were BRCA2 positive and 177 were non-carriers. 65% of patients were non-Hispanic non-Jewish whites, 15% African American, 15% Ashkanazi Jewish, 3% Hispanic and 2% Asian. At a median follow up of 5 years, 40 patients had relapsed and 22 had died. HRs (95% CI) for RFS of the BRCA1 and BRCA2 carriers relative to non-carriers were 1.6 (0.77–3.33) and 1.3 (0.55–3.09) respectively, when adjusted for year at diagnosis. The adjusted HRs (95% CI) for OS for the BRCA1 and BRCA2 carriers relative to non-carriers were 1.82 (0.48–3.02) and 0.67 (0.15–3.04), respectively. Conclusions: In this study of an ethnically diverse cohort of high-risk individuals, BRCA1 mutation carriers had a poorer outcome as compared to those with BRCA2 mutations or those without identifiable mutations in either gene, although this difference was not statistically significant. This observation is consistent with previous studies of women of predominantly Ashkenzi Jewish and European ancestry. This study was funded by the Falk Medical Research Trust, the Breast Cancer Research Foundation and the Entertainment Industry Fund. No significant financial relationships to disclose.

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Variations of DICER1 sequence in Chinese women with BRCA1/BRCA2 negative familial breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e12557 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e12557-e12557

Author(s):

Wenming Cao ◽

Yun Gao ◽

Hongjian Yang ◽

Shang-Nao Xie ◽

Xuli Meng ◽

...

Keyword(s):

Breast Cancer ◽

Familial Breast Cancer ◽

Genetic Model ◽

Germline Mutations ◽

Pleuropulmonary Blastoma ◽

Breast Cancers ◽

Deleterious Mutations ◽

Cancer Susceptibility Genes ◽

Increased Risk ◽

Brca1 Brca2

e12557 Background: Germline mutations in identified breast cancer susceptibility genes account for less than 20% of Chinese familial breast cancers. Dicer is an essential component of the microRNA producing machinery and germline mutations of DICER1 gene have been confirmed in familial pleuropulmonary blastoma, ovarian sex cord-stromal tumor and so on. Moreover, low expression of DICER1 is frequently detected in breast cancer. However, whether germline mutations of DICER1 occur in familial breast cancers remains unknown. Methods: 65 breast cancer probands from BRCA1/BRCA2 negative Chinese breast cancer families were used for screening of germline mutations in DICER1. In addition, 100 unrelated healthy females were enrolled as the controls. Polymerase chain reaction (PCR)-sequencing assay was employed to screen mutations in the entire coding regions and exon-intron boundaries of DICER1. Genotype and haplotype analyses were studied by widely available programs. Results: No deleterious mutations were identified in the 65 breast cancer probands. However, we found 12 germline variations and 4 of which were novel. In addition, the G allele frequency of rs2297730 (IVS12-91 A>G) was higher in familial breast cancer patients group than that in healthy controls group (OR = 1.873, 95% CI: 1.174-2.988, P = 0.008), and the A/G genotype were significantly associated with familial breast cancer (OR = 3.133; 95% CI: 1.562-6.287, P = 0.004). According to the minimum value of Akaike’s Information Criterion (AIC), the best genetic model was dominant. In addition, the haplotype GCGGAT was significantly associated with familial breast cancer (OR = 2.17, 95% CI: 1.20-3.91, P = 0.011). Conclusions: Although none of deleterious mutations were identified in the DICER1 gene, the current study provided a haplotype analysis of the DICER1 gene polymorphisms. We showed a significantly increased risk of BRCA1/BRCA2 negative familial breast cancer for DICER1 IVS12-91 A>G variant. It might be a potential risk marker for breast cancer in thus population.

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