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    Posted: Oct 07 2014 at 8:23am
Scientists uncover structure, mechanisms of BRCA2 protein

For the first time, researchers from the UK have created pictures of the BRCA2 protein. Mutations in the gene that encodes this protein are well known to increase the risk of breast and ovarian cancers. Uncovering the structure and mechanisms of the protein may pave the way for treatments targeting BRCA2 gene mutations, according to the investigators.

The research team, led by Prof. Xiaodong Zhang of the Department of Medicine at Imperial College London, publish their findings in the journal Nature Structural and Molecular Biology.

Around 45% of women who have a BRCA2 gene mutation will develop breast cancer by the time they are 70 years old, compared with 12% of women in the general population. While 1.4% of women in the general population will develop ovarian cancer at some point in their lives, this will happen for 11-17% of women with a BRCA2 gene mutation.

However, it has been challenging to develop treatments that target BRCA2 gene mutations.

Researchers know the BRCA2 protein plays a part in DNA repair. Any mutations in the gene that encodes the protein can hinder this repair process and causecancer. However, the mechanisms behind the DNA repair activity of BRCA2 and the structure of the protein have remained a mystery, until now.

Findings 'improve understanding of a fundamental cause of cancer'

The researchers were surprised to find that the BRCA2 proteins work in pairs, and each pair works with another protein called RAD51.

RAD51 molecules convene on strands of broken DNA with the help of the BRCA2 proteins. The RAD51 molecules then form filaments that look for matching DNA strands that will repair the broken DNA.

Furthermore, the researchers discovered that each pair of BRCA2 proteins attach to two sets of RAD51 molecules that point in opposing directions. They explain that this is so the RAD51 molecules can repair broken DNA strands that face either direction.

In addition, the team found that the BRCA2 proteins assist the RAD51 molecules in forming short filaments on numerous DNA regions. They say this may be to boost efficiency in finding matching DNA strands.

From their findings, Prof. Zhang and his team have created a set of pictures detailing the shape, structure and mechanisms of the BRCA2 protein.

Commenting on their discovery, Prof. Zhang says:

"This study improves our understanding of a fundamental cause of cancer. It's our first view of how the protein looks and how it works, and it gives us a platform to design new experiments to probe its mechanism in greater detail.

Once we have added more detail to the picture, we can design ways to correct defects in BRCA2 and help cells repair DNA more effectively to prevent cancer. We can also think about how to make the repair process less effective in cancer cells, so that they die."

http://www.medicalnewstoday.com/articles/283479.php?tw

DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jan 25 2018 at 7:12pm

New Data Brings Clarity to Rare BRCA2 Mutations

A study led by BCRF investigator Fergus Couch has shown that 54 BRCA2 variants of uncertain clinical significance are likely to be associated with an increased risk of breast or ovarian cancer.

Genetic testing for mutations in the BRCA1 and BRCA2 genes has dramatically improved our ability to understand risk of cancer in families with a high incidence of breast and ovarian cancers. However, in some cases patients receive a result known as VUS, short for genetic variants of uncertain significance. In these instances, researchers have yet to confirm whether these variants are harmless or cancer-causing, leaving no clear path to prevention or risk management. 

Distinguishing the pathogenic (cancer-causing) from non-pathogenic (harmless) variants in the BRCA genes is a critical hurdle in addressing these challenges and achieving precision prevention.

In an article published today in the American Journal of Human Genetics, Dr. Fergus Couch and his colleagues describe methods to classify BRCA2 VUS and quickly determine the potential risk they pose to those affected.

The study, supported in part by BCRF, is groundbreaking in its validation of a quick and reliable method to predict the clinical significance of BRCA2 VUS and could have immediate impact on how these specific variants are interpreted clinically for cancer surveillance and prevention.

“This method appears to be a very accurate way of identifying the VUS that influence BRCA2 activity and increase cancer risk as well as VUS that do not alter BRCA2 activity and are likely benign,” Dr. Couch explained. 

He cautioned however, “the method is not yet approved for clinical testing purposes, so for now these research results should not be used for clinical interpretation of VUS and management of patients.”

Dr. Couch and his team used functional tests and DNA sequence analysis to evaluate 139 BRCA2 VUS. They then combined these functional data with a statistical tool called VarCall that incorporates the functional information of the variant into an algorithm to assign it as likely to be pathogenic or neutral (no affect). Their rigorous study revealed 54 of the 139 VUS to be pathogenic – or likely to increase the risk of breast or ovarian cancer, while 73 of the variants were most likely not to pose any risk. Prior to the study, there were only 13 BRCA2 VUS classified as pathogenic.

Variants of Unknown Significance Explained

The rapid progression of DNA sequencing technologies that have made genetic testing possible have also uncovered many genetic variants of uncertain clinical significance, called VUS. These variants complicate cancer risk management, because neither doctors nor patients know how a particular VUS may impact individual breast or ovarian cancer risk.

“In separate studies, we have collaborated with other investigators to study VUS in the BRCA1 cancer predisposition gene, using a different test,” Dr. Couch said. “The BRCA1 test also appears to be a very accurate method for evaluating the influence of VUS on BRCA1 activity and for identifying VUS that may increase risk of cancer. Read the full press release from Mayo Clinic


https://www.bcrf.org/blog/new-data-brings-clarity-rare-brca2-mutations

DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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