Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants

2021 ◽  
Author(s):  
Gorka Ruiz de Garibay ◽  
Ignacio Fernandez‐Garcia ◽  
Sylvie Mazoyer ◽  
Flavia Leme de Calais ◽  
Pietro Ameri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Pathogenic Variants ◽  
Altered Regulation ◽  
Exon 11 ◽  
Brca1 Exon

scholarly journals Analysis of Italian BRCA1/2 Pathogenic Variants Identifies a Private Spectrum in the Population from the Bergamo Province in Northern Italy

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 532
Author(s):  
Gisella Figlioli ◽  
Arcangela De Nicolo ◽  
Irene Catucci ◽  
Siranoush Manoukian ◽  
Bernard Peissel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Disease Risk ◽  
Northern Italy ◽  
Genetic Isolate ◽  
National Population ◽  
Pathogenic Variants ◽  
High Breast Cancer Risk

Germline pathogenic variants (PVs) in the BRCA1 or BRCA2 genes cause high breast cancer risk. Recurrent or founder PVs have been described worldwide including some in the Bergamo province in Northern Italy. The aim of this study was to compare the BRCA1/2 PV spectra of the Bergamo and of the general Italian populations. We retrospectively identified at five Italian centers 1019 BRCA1/2 PVs carrier individuals affected with breast cancer and representative of the heterogeneous national population. Each individual was assigned to the Bergamo or non-Bergamo cohort based on self-reported birthplace. Our data indicate that the Bergamo BRCA1/2 PV spectrum shows less heterogeneity with fewer different variants and an average higher frequency compared to that of the rest of Italy. Consistently, four PVs explained about 60% of all carriers. The majority of the Bergamo PVs originated locally with only two PVs clearly imported. The Bergamo BRCA1/2 PV spectrum appears to be private. Hence, the Bergamo population would be ideal to study the disease risk associated with local PVs in breast cancer and other disease-causing genes. Finally, our data suggest that the Bergamo population is a genetic isolate and further analyses are warranted to prove this notion.

scholarly journals Implementation of interventions targeting the uptake of genetic testing services for breast cancer risk: protocol for a systematic review

BMJ Open ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. e031727
Author(s):  
Subash Thapa ◽  
Anja Leppin ◽  
Rikke Kristensen ◽  
Mette Just Bonde ◽  
Arja R Aro
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Cochrane Library ◽  
Intervention Level ◽  
Pathogenic Variants ◽  
Implementation Outcomes ◽  
Intervention Description

IntroductionThe timely identification of breast cancer-related pathogenic variants can help to identify the risk of potential disease development and determine healthcare choices. However, the uptake rate of genetic testing services for breast cancer risk remains low in many countries. Interventions targeting the uptake of these services among individuals potentially at risk for inherited breast cancer are often complex and have multiple components, and are therefore difficult to implement, replicate and disseminate to new contexts. Our aim is to systematically review studies targeting the uptake of genetic testing services for breast cancer risk and critically assess the quality of implementation outcomes and the reporting of intervention descriptions.Methods and analysisPubMed, CINAHL, PsycINFO, Embase, Cochrane Library and all Campbell Coordinating Group databases will be searched for intervention studies that target individuals' participation in breast cancer genetic testing programmes. Papers published in English within the time period from January 2005 until October 2019 will be considered for inclusion. Titles, abstracts and full papers will be screened for eligibility by two pairs of reviewers independently. For data analysis and synthesis, study-level and intervention-level characteristics will be abstracted. We will present all implementation outcomes that are mentioned in each of the studies and register the number of studies that do not at all look at or report implementation outcomes. The quality of implementation will be checked using a 5-point rubric item, and the quality and completeness of reporting of intervention description will be evaluated using the 12-item Template for Intervention Description and Replication (TIDieR).Ethics and disseminationEthical approval is not required to conduct this review. Review findings will be disseminated to academic and non-specialist audiences via peer-reviewed academic journals and presented at appropriate conferences, workshops and meetings to policymakers, practitioners and organisations that work with our population of interest.PROSPERO registration numberCRD42018105732.

scholarly journals Rare and potentially pathogenic variants in hydroxycarboxylic acid receptor genes identified in breast cancer cases

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Cierla McGuire Sams ◽  
Kasey Shepp ◽  
Jada Pugh ◽  
Madison R. Bishop ◽  
Nancy D. Merner
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Treatment Strategies ◽  
The Cancer Genome Atlas ◽  
Acid Oxidation ◽  
Loss Of Function ◽  
Cancer Proliferation ◽  
Hydroxycarboxylic Acid ◽  
Pathogenic Variants

Abstract Background Three genes clustered together on chromosome 12 comprise a group of hydroxycarboxylic acid receptors (HCARs): HCAR1, HCAR2, and HCAR3. These paralogous genes encode different G-protein coupled receptors responsible for detecting glycolytic metabolites and controlling fatty acid oxidation. Though better known for regulating lipid metabolism in adipocytes, more recently, HCARs have been functionally associated with breast cancer proliferation/survival; HCAR2 has been described as a tumor suppressor and HCAR1 and HCAR3 as oncogenes. Thus, we sought to identify germline variants in HCAR1, HCAR2, and HCAR3 that could potentially be associated with breast cancer risk. Methods Two different cohorts of breast cancer cases were investigated, the Alabama Hereditary Cancer Cohort and The Cancer Genome Atlas, which were analyzed through nested PCRs/Sanger sequencing and whole-exome sequencing, respectively. All datasets were screened for rare, non-synonymous coding variants. Results Variants were identified in both breast cancer cohorts, some of which appeared to be associated with breast cancer BC risk, including HCAR1 c.58C > G (p.P20A), HCAR2 c.424C > T (p.R142W), HCAR2 c.517_518delinsAC (p.G173T), HCAR2 c.1036A > G (p.M346V), HCAR2 c.1086_1090del (p.P363Nfs*26), HCAR3 c.560G > A (p.R187Q), and HCAR3 c.1117delC (p.Q373Kfs*82). Additionally, HCAR2 c.515C > T (p.S172L), a previously identified loss-of-function variant, was identified. Conclusions Due to the important role of HCARs in breast cancer, it is vital to understand how these genetic variants play a role in breast cancer risk and proliferation and their consequences on treatment strategies. Additional studies will be needed to validate these findings. Nevertheless, the identification of these potentially pathogenic variants supports the need to investigate their functional consequences.

scholarly journals Development and Validation of a Clinical Polygenic Risk Score to Predict Breast Cancer Risk

2020 ◽  
pp. 585-592 ◽  
Author(s):  
Elisha Hughes ◽  
Placede Tshiaba ◽  
Shannon Gallagher ◽  
Susanne Wagner ◽  
Thaddeus Judkins ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Cancer History ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Breast Cancer Susceptibility Genes

PURPOSE Women with a family history of breast cancer are frequently referred for hereditary cancer genetic testing, yet < 10% are found to have pathogenic variants in known breast cancer susceptibility genes. Large-scale genotyping studies have identified common variants (primarily single-nucleotide polymorphisms [SNPs]) with individually modest breast cancer risk that, in aggregate, account for considerable breast cancer susceptibility. Here, we describe the development and empirical validation of an SNP-based polygenic breast cancer risk score. METHODS A panel of 94 SNPs was examined for association with breast cancer in women of European ancestry undergoing hereditary cancer genetic testing and negative for pathogenic variants in breast cancer susceptibility genes. Candidate polygenic risk scores (PRSs) as predictors of personal breast cancer history were developed through multivariable logistic regression models adjusted for age, cancer history, and ancestry. An optimized PRS was validated in 2 independent cohorts (n = 13,174; n = 141,160). RESULTS Within the training cohort (n = 24,259), 4,291 women (18%) had a personal history of breast cancer and 8,725 women (36%) reported breast cancer in a first-degree relative. The optimized PRS included 86 variants and was highly predictive of breast cancer status in both validation cohorts ( P = 6.4 × 10−66; P < 10−325). The odds ratio (OR) per unit standard deviation was consistent between validations (OR, 1.45 [95% CI, 1.39 to 1.52]; OR 1.47 [95% CI, 1.45 to 1.49]). In a direct comparison, the 86-SNP PRS outperformed a previously described PRS of 77 SNPs. CONCLUSION The validation and implementation of a PRS for women without pathogenic variants in known breast cancer susceptibility genes offers potential for risk stratification to guide surveillance recommendations.

scholarly journals Blood Arsenic Levels as a Marker of Breast Cancer Risk among BRCA1 Carriers

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3345
Author(s):  
Wojciech Marciniak ◽  
Tomáš Matoušek ◽  
Susan Domchek ◽  
Angelo Paradiso ◽  
Margherita Patruno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Breast Cancers ◽  
Lifetime Cancer Risk ◽  
Pathogenic Variants ◽  
Inherited Susceptibility ◽  
Increased Risk

An important group of breast cancers is those associated with inherited susceptibility. In women, several predisposing mutations in genes involved in DNA repair have been discovered. Women with a germline pathogenic variant in BRCA1 have a lifetime cancer risk of 70%. As part of a larger prospective study on heavy metals, our aim was to investigate if blood arsenic levels are associated with breast cancer risk among women with inherited BRCA1 mutations. A total of 1084 participants with pathogenic variants in BRCA1 were enrolled in this study. Subjects were followed from 2011 to 2020 (mean follow-up time: 3.75 years). During that time, 90 cancers were diagnosed, including 67 breast and 10 ovarian cancers. The group was stratified into two categories (lower and higher blood As levels), divided at the median (<0.85 µg/L and ≥0.85 µg/L) As level among all unaffected participants. Cox proportional hazards models were used to model the association between As levels and cancer incidence. A high blood As level (≥0.85 µg/L) was associated with a significantly increased risk of developing breast cancer (HR = 2.05; 95%CI: 1.18–3.56; p = 0.01) and of any cancer (HR = 1.73; 95%CI: 1.09–2.74; p = 0.02). These findings suggest a possible role of environmental arsenic in the development of cancers among women with germline pathogenic variants in BRCA1.

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