scholarly journals BRCA1 and Metastasis: Outcome of Defective DNA Repair

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 108
Author(s):  
Rehna Krishnan ◽  
Parasvi S. Patel ◽  
Razqallah Hakem
Keyword(s):  
Dna Repair ◽  
Individual Cell ◽  
Brca1 Mutation ◽  
Breast Cancers ◽  
Wild Type ◽  
Brca1 And Brca2 ◽  
Potential Impact ◽  
The Individual ◽  
Defective Dna Repair ◽  
Inherited Mutations

Heritable mutations in BRCA1 and BRCA2 genes are a major risk factor for breast and ovarian cancer. Inherited mutations in BRCA1 increase the risk of developing breast cancers by up to 72% and ovarian cancers by up to 69%, when compared to individuals with wild-type BRCA1. BRCA1 and BRCA2 (BRCA1/2) are both important for homologous recombination-mediated DNA repair. The link between BRCA1/2 mutations and high susceptibility to breast cancer is well established. However, the potential impact of BRCA1 mutation on the individual cell populations within a tumor microenvironment, and its relation to increased aggressiveness of cancer is not well understood. The objective of this review is to provide significant insights into the mechanisms by which BRCA1 mutations contribute to the metastatic and aggressive nature of the tumor cells.

Immunohistochemical Expression of DNA Repair Proteins in Familial Breast Cancer Differentiate BRCA2-Associated Tumors

2005 ◽  
Vol 23 (30) ◽  
pp. 7503-7511 ◽  
Author(s):  
Emiliano Honrado ◽  
Ana Osorio ◽  
José Palacios ◽  
Roger L. Milne ◽  
Lydia Sánchez ◽  
...  
Keyword(s):  
Dna Repair ◽  
Brca1 Mutation ◽  
Tissue Microarrays ◽  
Nuclear Antigen ◽  
Breast Cancers ◽  
Brca1 And Brca2 ◽  
Final Study ◽  
Familial Tumors ◽  
Immunohistochemical Studies ◽  
Associated Tumors

Purpose Morphologic and immunohistochemical studies of familial breast cancers have identified specific characteristics associated with BRCA1 mutation-associated tumors when compared with BRCA2 and non-BRCA1/2 tumors, but have not identified differences between BRCA2 and non-BRCA1/2 tumors. Because BRCA1 and BRCA2 genes participate in the DNA repair pathway, we have performed an immunohistochemical study with markers related to this pathway to establish the profile of the three groups. Materials and Methods We have studied two tissue microarrays that include 103 familial and 104 sporadic breast tumors, with a panel of DNA repair markers including ATM, CHEK2, RAD51, RAD50, XRCC3, and proliferating cell nuclear antigen. Results We found more frequent expression of CHEK2 in BRCA1 and BRCA2 tumors than in non-BRCA1/2 and sporadic tumors. We found absence of nuclear expression and presence of cytoplasmic expression of RAD51 in BRCA2 tumors that differentiate them from other familial tumors. We validated these results with a new series of patient cases. The final study with 253 familial patient cases (74 BRCA1, 71 BRCA2, 108 non-BRCA1/2), and 288 sporadic patient cases, has allowed us to confirm our preliminary results. Because BRCA2 tumors present a specific immunohistochemical profile for RAD51 and CHEK2 markers that is different from non-BRCA1/2 tumors, we have built a multivariate model with these markers that distinguish both tumors with an estimated probability of at least 76%. Conclusion Our results suggest that BRCA2 tumors demonstrate more cytoplasmic and less nuclear RAD51 staining, and increased CHEK2 staining. This pattern may distinguish BRCA2 from familial non-BRCA1/2 tumors.

Homologous Recombination Deficiency in Breast Cancer: A Clinical Review

2017 ◽  
pp. 1-13 ◽  
Author(s):  
Wendie D. den Brok ◽  
Kasmintan A. Schrader ◽  
Sophie Sun ◽  
Anna V. Tinker ◽  
Eric Yang Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Significant Proportion ◽  
Clinical Use ◽  
Breast Cancers ◽  
Repair Pathway ◽  
Wild Type ◽  
Brca1 And Brca2 ◽  
Homologous Recombination Deficiency ◽  
Brca1 Brca2

BRCA1 and BRCA2 germline mutation–associated breast cancers are known to be deficient in the process of homologous recombination and often respond favorably to drugs targeting this important DNA repair pathway. There is emerging evidence that a significant proportion of patients with BRCA1/ BRCA2 wild-type breast cancer are also deficient in homologous recombination, and it is hypothesized that these patients may derive similar benefit from drugs targeting this pathway. Current research has focused on the development of a companion diagnostic to identify these sporadic BRCA-like tumors. This review outlines the various approaches that researchers have taken to predict homologous recombination deficiency as part of correlative biomarker work in various studies and clinical trials in breast cancer. As some of these tests of homologous recombination deficiency move closer to clinical use, understanding the approach and limitations of each is of relevance to clinicians who treat patients with breast cancer.

scholarly journals How to measure homologous recombination deficiency in ovarian cancer

2017 ◽  
Vol 5 (1) ◽  
pp. 15-20 ◽  
Author(s):  
Claudia Marchetti ◽  
Iain A. McNeish
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Somatic Mutations ◽  
Parp Inhibitors ◽  
Important Advance ◽  
Brca1 And Brca2 ◽  
Homologous Recombination Deficiency ◽  
Repair Pathways ◽  
Defective Dna Repair ◽  
Important Therapeutic Target

Defective DNA repair via homologous recombination (HR) is common in ovarian high grade serous carcinomas, and homologous recombination deficiency (HRD) represents an important therapeutic target in epithelial ovarian cancers (EOCs). The development of poly(ADP ribose) polymerase (PARP) inhibitors (PARPi) has been an important advance in the treatment of HR-deficient EOCs with the potential to change daily clinical practice. However, while germline and somatic mutations in BRCA1 and BRCA2 are still the most important mechanisms of HRD, alterations in other DNA repair pathways might also contribute to defective HR. In this review, we focus on current and emerging approaches for identifying and targeting HR-deficient EOCs, and discuss the challenges associated with these approaches.

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

2021 ◽  
Author(s):  
Lars Andersen ◽  
Martin Larsen ◽  
Helen Davies ◽  
Andrea Degasperi ◽  
Henriette Nielsen ◽  
...  
Keyword(s):  
Small Proportion ◽  
Familial Breast Cancer ◽  
Brca1 Mutation ◽  
Promoter Hypermethylation ◽  
Polygenic Risk Score ◽  
Breast Cancers ◽  
Brca1 And Brca2 ◽  
Pathogenic Variants ◽  
High Prevalence ◽  
Brca1 Brca2

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.

Childhood adversity studies as an antidote to the predominance of neo-liberal thinking in the field of mental health

2020 ◽  
Vol 29 (4) ◽  
pp. 556-563
Author(s):  
Adam Burley
Keyword(s):  
Mental Health ◽  
Childhood Adversity ◽  
Sole Source ◽  
Point Of View ◽  
Early Adversity ◽  
Potential Impact ◽  
The Individual

This is a personal and reflective piece written from a clinician's point of view on the influence that the developing awareness around the consequences of childhood adversity has had upon the discussions, thinking and practice across the areas in which they are working. It seeks to argue that the increased understanding and recognition of the potential impact of early adversity can not only enhance and deepen the understanding of an individual's difficulties, but can serve to inform how services respond in a way that takes account of this. It suggests that the research and literature on childhood adversity can offer a route map away from a model of mental health that focuses predominantly on the individual as the sole source of interest.

scholarly journals Weighing in on heart failure: the potential impact of bariatric surgery

2021 ◽  
Author(s):  
Tanuka Datta ◽  
Andrew J. Lee ◽  
Rachel Cain ◽  
Melissa McCarey ◽  
David J. Whellan
Keyword(s):  
Heart Failure ◽  
Bariatric Surgery ◽  
Weight Loss ◽  
Cardiovascular System ◽  
Economic Burden ◽  
Treatment Strategies ◽  
It Impacts ◽  
Potential Impact ◽  
The Individual ◽  
Physiologic System

AbstractObesity is a growing worldwide epidemic with significant economic burden that carries with it impacts on every physiologic system including the cardiovascular system. Specifically, the risk of heart failure has been shown to increase dramatically in obese individuals. The purpose of this review is to provide background on the individual burdens of heart failure and obesity, followed by exploring proposed physiologic mechanisms that interconnect these conditions, and furthermore introduce treatment strategies for weight loss focusing on bariatric surgery. Review of the existing literature on patients with obesity and heart failure who have undergone bariatric surgery is presented, compared, and contrasted.

scholarly journals GENE-16. CLINICALLY AGGRESSIVE MENINGIOMAS ARE CHARACTERIZED BY MUTATIONAL SIGNATURES ASSOCIATED WITH DEFECTIVE DNA REPAIR AND MUTATIONS IN CHROMATIN REMODELING GENES

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi106-vi106
Author(s):  
Sylvia Kurz ◽  
Benjamin Liechty ◽  
Stephen Kelly ◽  
Varshini Vasudevaraja ◽  
Ramona Bledea ◽  
...  
Keyword(s):  
Dna Repair ◽  
Chromatin Remodeling ◽  
Mutational Signatures ◽  
Defective Dna Repair
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