Identifying sequence variants contributing to hereditary breast and ovarian cancer in BRCA1 and BRCA2 negative breast and ovarian cancer patients

AbstractFamilies with breast and ovarian cancer are often tested for disease associated sequence variants in BRCA1 and BRCA2. Pathogenic sequence variants (PVs) in these two genes are known to increase breast and ovarian cancer risks in females. However, in most families no PVs are detected in these two genes. Currently, several studies have identified other genes involved in hereditary breast and ovarian cancer (HBOC). To identify genetic risk factors for breast and ovarian cancer in a Norwegian HBOC cohort, 101 breast and/or ovarian cancer patients negative for PVs and variants of unknown clinical significance (VUS) in BRCA1/2 were screened for PVs in 94 genes using next-generation sequencing. Sixteen genes were closely scrutinized. Nine different deleterious germline PVs/likely pathogenic variants (LPVs) were identified in seven genes in 12 patients: three in ATM, and one in CHEK2, ERCC5, FANCM, RAD51C, TP53 and WRN. Additionally, 32 different VUSs were identified and these require further characterization. For carriers of PV/LPV in many of these genes, there are no national clinical management programs in Norway. The diversity of genetic risk factors possibly involved in cancer development show the necessity for more knowledge to improve the clinical follow-up of this genetically diverse patient group.

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Facets of Conscientiousness and risk of dementia

Psychological Medicine ◽

10.1017/s0033291717002306 ◽

2017 ◽

Vol 48 (6) ◽

pp. 974-982 ◽

Cited By ~ 15

Author(s):

A. R. Sutin ◽

Y. Stephan ◽

A. Terracciano

Keyword(s):

Risk Factors ◽

Cognitive Impairment ◽

Personality Assessment ◽

Genetic Risk ◽

Cox Regression ◽

Genetic Risk Factors ◽

Self Control ◽

Standard Deviation Increase ◽

Study Participants

BackgroundMultiple studies have found Conscientiousness to be protective against dementia. The purpose of this study is to identify which specific aspects, or facets, of Conscientiousness are most protective against cognitive impairment and whether these associations are moderated by demographic factors and/or genetic risk.MethodsHealth and Retirement Study participants were selected for analysis if they completed the facets of Conscientiousness measure, scored in the range of normal cognitive functioning at the baseline personality assessment, and had at least one follow-up assessment of cognition over the up to 6-year follow-up (N = 11 181). Cox regression was used to test for risk of incident dementia and risk of incident cognitive impairment not dementia (CIND).ResultsOver the follow-up, 278 participants developed dementia and 2186 participants developed CIND. The facet of responsibility had the strongest and most consistent association with dementia risk: every standard deviation increase in this facet was associated with a nearly 35% decreased risk of dementia; self-control and industriousness were also protective. Associations were generally similar when controlling for clinical, behavioral, and genetic risk factors. These three facets were also independent predictors of decreased risk of CIND.ConclusionsThe present research indicates that individuals who see themselves as responsible, able to control their behavior, and hard workers are less likely to develop CIND or dementia and that these associations persist after accounting for some common clinical, behavioral, and genetic risk factors.

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Clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients

Breast Cancer Research and Treatment ◽

10.1007/s10549-015-3437-9 ◽

2015 ◽

Vol 152 (1) ◽

pp. 67-76 ◽

Cited By ~ 29

Author(s):

Christof Vulsteke ◽

Alena M. Pfeil ◽

Charlotte Maggen ◽

Matthias Schwenkglenks ◽

Ruth Pettengell ◽

...

Keyword(s):

Breast Cancer ◽

Risk Factors ◽

Cancer Patients ◽

Early Breast Cancer ◽

Genetic Risk ◽

Cardiac Toxicity ◽

Genetic Risk Factors ◽

Breast Cancer Patients

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Sequence variants of ACE, AGT, AT1R, and PAI-1 as genetic risk factors for vascular dementia

Neuroscience Letters ◽

10.1016/j.neulet.2006.03.035 ◽

2006 ◽

Vol 401 (3) ◽

pp. 276-279 ◽

Cited By ~ 15

Author(s):

Younyoung Kim ◽

Jin-Hyuck Kim ◽

Yu Jin Nam ◽

Yun Joong Kim ◽

Kyung-Ho Yu ◽

...

Keyword(s):

Risk Factors ◽

Vascular Dementia ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Sequence Variants ◽

Pai 1

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Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer disease brains

10.1101/2021.11.04.21265941 ◽

2021 ◽

Author(s):

Brenna C Novotny ◽

Maria-Victoria Fernandez ◽

Jorge Bahena ◽

John P Budde ◽

Kristy Bergmann ◽

...

Keyword(s):

Risk Factors ◽

Alzheimer Disease ◽

Genetic Risk ◽

Autosomal Dominant ◽

Late Onset ◽

Disease Status ◽

Genetic Risk Factors ◽

Web Browser ◽

Pathogenic Variants ◽

Genetic Groups

The identification of multiple genetic risk factors for Alzheimer Disease (AD) provides evidence to support that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain, including information on treatment targets. In this study, we interrogate the metabolomic and lipidomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ϵ4 and TREM2 risk variant carriers, and non-carrier sporadic AD (sAD). We generated metabolomic and lipidomic data from parietal cortical tissue from 366 participants with AD pathology and 26 cognitively unimpaired controls using the Metabolon global metabolomics platform. We identified 133 metabolites associated with disease status (FDR q-value<0.05). In sAD brains these include tryptophan betaine (b=-0.57) and N-acetylputrescine (b=-0.14). Metabolites associated with sAD and ADAD include ergothioneine (b=-0.21 and -0.26 respectively) and serotonin (b=-0.34 and -0.58, respectively). TREM2 and ADAD showed association with α-tocopherol (b=-0.12 and -0.12) and CDP-ethanolamine (b=-0.13 and -0.10). β-citrylglutamate levels are associated with sAD, ADAD, and TREM2 compared to controls (b=-0.15; -0.22; and -0.29, respectively). Additionally, we identified a signature of 16 metabolites that is significantly altered between genetic groups (sAD vs. control p = 1.05x10-7, ADAD vs. sAD p = 3.21x10-5) and is associated with Braak tau stage and disease duration. These data are available to the scientific community through a public web browser (http://ngi.pub/Metabolomics). Our findings were replicated in an independent cohort of 327 individuals.

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Non-Coding Variants in BRCA1 and BRCA2 Genes: Potential Impact on Breast and Ovarian Cancer Predisposition

Cancers ◽

10.3390/cancers10110453 ◽

2018 ◽

Vol 10 (11) ◽

pp. 453 ◽

Cited By ~ 6

Author(s):

Elizabeth Santana dos Santos ◽

François Lallemand ◽

Leslie Burke ◽

Dominique Stoppa-Lyonnet ◽

Melissa Brown ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Predisposition ◽

Gene Promoters ◽

Breast And Ovarian Cancer ◽

Brca1 And Brca2 ◽

Coding Regions ◽

Pathogenic Variants ◽

Cancer Susceptibility Genes ◽

Donor And Acceptor ◽

The Impact

BRCA1 and BRCA2 are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to BRCA1/2 exons and intron/exon boundaries. Most identified pathogenic variants cause the partial or complete loss of function of the protein. However, it is becoming increasingly clear that variants in these regions only account for a small proportion of cancer risk. The role of variants in non-coding regions beyond splice donor and acceptor sites, including those that have no qualitative effect on the protein, has not been thoroughly investigated. The key transcriptional regulatory elements of BRCA1 and BRCA2 are housed in gene promoters, untranslated regions, introns, and long-range elements. Within these sequences, germline and somatic variants have been described, but the clinical significance of the majority is currently unknown and it remains a significant clinical challenge. This review summarizes the available data on the impact of variants on non-coding regions of BRCA1/2 genes and their role on breast and ovarian cancer predisposition.

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Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility

Cancers ◽

10.3390/cancers10100361 ◽

2018 ◽

Vol 10 (10) ◽

pp. 361 ◽

Cited By ~ 8

Author(s):

Rosalía Quezada Urban ◽

Clara Díaz Velásquez ◽

Rina Gitler ◽

María Rojo Castillo ◽

Max Sirota Toporek ◽

...

Keyword(s):

Ovarian Cancer ◽

High Risk ◽

Cancer Patients ◽

Cancer Susceptibility ◽

High Risk Group ◽

Cancer Genes ◽

Cancer Syndrome ◽

Breast And Ovarian Cancer ◽

Pathogenic Variants ◽

Recurrent Mutations

Hereditary breast and ovarian cancer syndrome (HBOC) represents 5–10% of all patients with breast cancer and is associated with high-risk pathogenic alleles in BRCA1/2 genes, but only for 25% of cases. We aimed to find new pathogenic alleles in a panel of 143 cancer-predisposing genes in 300 Mexican cancer patients with suspicion of HBOC and 27 high-risk patients with a severe family history of cancer, using massive parallel sequencing. We found pathogenic variants in 23 genes, including BRCA1/2. In the group of cancer patients 15% (46/300) had a pathogenic variant; 11% (33/300) harbored variants with unknown clinical significance (VUS) and 74% (221/300) were negative. The high-risk group had 22% (6/27) of patients with pathogenic variants, 4% (1/27) had VUS and 74% (20/27) were negative. The most recurrent mutations were the Mexican founder deletion of exons 9-12 and the variant p.G228fs in BRCA1, each found in 5 of 17 patients with alterations in this gene. Rare VUS with potential impact at the protein level were found in 21 genes. Our results show for the first time in the Mexican population a higher contribution of pathogenic alleles in other susceptibility cancer genes (54%) than in BRCA1/2 (46%), highlighting the high locus heterogeneity of HBOC and the necessity of expanding genetic tests for this disease to include broader gene panels.

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Variants in Miro1 Cause Alterations of ER-Mitochondria Contact Sites in Fibroblasts from Parkinson’s Disease Patients

Journal of Clinical Medicine ◽

10.3390/jcm8122226 ◽

2019 ◽

Vol 8 (12) ◽

pp. 2226 ◽

Cited By ~ 9

Author(s):

Clara Berenguer-Escuder ◽

Dajana Grossmann ◽

Franҫois Massart ◽

Paul Antony ◽

Lena F. Burbulla ◽

...

Keyword(s):

Risk Factors ◽

Calcium Homeostasis ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Calcium Handling ◽

Contact Sites ◽

Pathogenic Variants ◽

Associated Proteins ◽

Cellular Phenotypes ◽

And Function

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD-associated proteins are involved in mitochondrial quality control, e.g., PINK1, Parkin, and LRRK2, which were recently identified as regulators of mitochondrial-endoplasmic reticulum (ER) contact sites (MERCs) linking mitochondrial homeostasis to intracellular calcium handling. In this context, Miro1 is increasingly recognized to play a role in PD pathology. Recently, we identified the first PD patients carrying mutations in RHOT1, the gene coding for Miro1. Here, we describe two novel RHOT1 mutations identified in two PD patients and the characterization of the cellular phenotypes. Methods: Using whole exome sequencing we identified two PD patients carrying heterozygous mutations leading to the amino acid exchanges T351A and T610A in Miro1. We analyzed calcium homeostasis and MERCs in detail by live cell imaging and immunocytochemistry in patient-derived fibroblasts. Results: We show that fibroblasts expressing mutant T351A or T610A Miro1 display impaired calcium homeostasis and a reduced amount of MERCs. All fibroblast lines from patients with pathogenic variants in Miro1, revealed alterations of the structure of MERCs. Conclusion: Our data suggest that Miro1 is important for the regulation of the structure and function of MERCs. Moreover, our study supports the role of MERCs in the pathogenesis of PD and further establishes variants in RHOT1 as rare genetic risk factors for neurodegeneration.

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Non-BRCA1/2 Variants Detected in a High-Risk Chilean Cohort With a History of Breast and/or Ovarian Cancer

Journal of Global Oncology ◽

10.1200/jgo.18.00163 ◽

2019 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Christina Adaniel ◽

Francisca Salinas ◽

Juan Manuel Donaire ◽

Maria Eugenia Bravo ◽

Octavio Peralta ◽

...

Keyword(s):

Ovarian Cancer ◽

Genetic Testing ◽

High Risk ◽

Genetic Predisposition ◽

Cancer Syndrome ◽

Breast And Ovarian Cancer ◽

Brca1 And Brca2 ◽

Pathogenic Variants ◽

Cancer Program ◽

Genetic Test Results

PURPOSE Little is known about the genetic predisposition to breast and ovarian cancer among the Chilean population, in particular genetic predisposition beyond BRCA1 and BRCA2 mutations. In the current study, we aim to describe the germline variants detected in individuals who were referred to a hereditary cancer program in Santiago, Chile. METHODS Data were retrospectively collected from the registry of the High-Risk Breast and Ovarian Cancer Program at Clínica Las Condes, Santiago, Chile. Data captured included index case diagnosis, ancestry, family history, and genetic test results. RESULTS Three hundred fifteen individuals underwent genetic testing during the study period. The frequency of germline pathogenic and likely pathogenic variants in a breast or ovarian cancer predisposition gene was 20.3%. Of those patients who underwent testing with a panel of both high- and moderate-penetrance genes, 10.5% were found to have pathogenic or likely pathogenic variants in non- BRCA1/2 genes. CONCLUSION Testing for non- BRCA1 and -2 mutations may be clinically relevant for individuals who are suspected to have a hereditary breast or ovarian cancer syndrome in Chile. Comprehensive genetic testing of individuals who are at high risk is necessary to further characterize the genetic susceptibility to cancer in Chile.

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