Decreased Parp Trapping Through Disruption Of Parp1 And Parg Proteins
PARP proteins act as a catalyst to modify proteins by covalent addition of PAR chainsthis process is known as PARylation . When DNA is damaged, PARP1 is the main protein involved in most cellular PARylation . A good predictor for cytotoxicity is the capacity of the different inhibitors to trap PARP proteins on damaged chromatin. PARP1 is the most abundant PARP protein in cells, and it accounts for more than 90% of cellular PARylation . As a result, PARP1 mutations that reduce the trapping of the protein on DNA induce PARP inhibitors resistance even in HR-deficient cells . Additionally, PAR glycohydrolase reverses PARylation and is responsible for the degradation of PAR chains . Therefore, PARG works in the same way as PARP inhibitors by preventing PAR accumulation. A study performed on genetic screening of BRCA2-deficient mice cell lines has identified loss of PARG as another cause for PARP inhibitors resistance .
About The Medical Reviewer
Dr. Mark Pomerantz is a medical oncologist at the Dana-Farber Cancer Institute. Dr. Pomerantz received his undergraduate degree from Yale University and his medical degree from Stanford University. He trained in Internal Medicine at Brigham and Women’s Hospital in Boston, Massachusetts. He then pursued a fellowship in Medical Oncology at the Dana-Farber Cancer Institute in Boston. Dr. Pomerantz received his post-doctoral training in cancer genetics with Dr. Matthew Freedman at the Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT. He is on faculty at the Dana-Farber Cancer Institute in the Lank Center for Genitourinary Oncology.
Lowering Risk Of Death
There are two different management approaches for people with BRCA2 mutations, both of which are designed to reduce the chance that a person will die from one of the cancers of risk:
- Early detection: Early detection is the process of trying to find a cancer which has formed at the earliest stage possible. With many cancers, we know that survival is higher when its found at an early stage than if it is discovered at a later stage . With early detection, the goal is to find cancer before it would otherwise cause the symptoms that would lead to its discovery. We dont have methods to detect all cancers at these early stages, and the tests we do have are not perfect. For example, despite having had a normal mammogram, some women are diagnosed with breast cancer shortly thereafter.
- Risk reduction: Risk reduction strategies work to reduce the risk that a cancer will develop in the first place. They are designed to prevent cancer from occurring. Methods of reduction may include surgery or medications .
Most approaches to a genetic predisposition to cancer include either screening or risk reduction, but there is one test that can do both. Colonoscopy can be used to detect colon cancer in the earliest stages. It can also be used to reduce the risk of a person getting cancer if a pre-cancerous polyp is found and removed before it becomes malignant.
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Somatic Mutations In Ddr Genes
In addition to germline mutations, somatic mutations also drive prostate carcinogenesis especially into the advanced stages . Oncogenes or inactivation of tumor suppressor genes can lead to uncontrolled tumor growth. The TSG p53 is commonly mutated in prostate cancer 1020% of primary and up to 42% of advanced prostate cancer . Similarly, the TSG PTEN mutations are found in 27% of primary and up to 60% of metastatic prostate cancer . The AR is a specific oncogene especially implicated in prostate cancer as AR-directed transcription allows growth of the tumor in all stages of prostate cancer . These somatic mutations are present in DNA repair pathwaysRobinson et al. found 23% of mCRPC had somatic DDR mutations . BRCA1/2 and ATM accounted for nearly 20% of these and were found more frequently in mCRPC. Furthermore, loss of BRCA2 was found in 12.7% of cases and 90% displayed biallelic loss . Abida et al. also found that somatic BRCA2 mutations were exhibited in tumors early on that then progressed to metastatic disease .
Researchers Urge Prostate Cancer Screening For Men With Brca Gene Defects
- By Charlie Schmidt, Editor, Harvard Medical School Annual Report on Prostate Diseases
Prostate cancer screening with the prostate-specific antigen test has been criticized for flagging too many slow-growing tumors that might never be life-threatening.
But some men have inherited gene defects that boost their risk of developing prostate cancers that can be quite aggressive. Is PSA screening particularly well-suited for these genetically defined groups? New research suggests the answer is yes.
In November, a team of British scientists released highly anticipated findings from a study of PSA screening in men with defects in a pair of important genes called BRCA1 and BRCA2. Better known for increasing the odds of breast and ovarian cancer in women, BRCA gene defects are also risk factors for aggressive prostate cancer in men. Cells with defective BRCA genes have a compromised ability to repair the DNA damage they sustain routinely every day. As that damage accumulates, those cells become prone to forming tumors.
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Inheritance Of Prostate Cancer Risk
Many types of epidemiologic studies strongly suggest that prostate cancer susceptibility genes exist in the population. Analysis of longer follow-up of the monozygotic and dizygotic twin pairs in Scandinavia concluded that 58% of prostate cancer risk may be accounted for by heritable factors. Additionally, among affected MZ and DZ pairs, the time to diagnosis in the second twin was shortest in MZ twins . This is in agreement with a previous U.S. study that showed a concordance of 7.1% between DZ twin pairs and a 27% concordance between MZ twin pairs. A Swedish study also found concordance with disease aggressiveness defined as Gleason score greater than 6, clinical stage greater than T2, N1, M1, and PSA greater than 10 .
The first segregation analysis was performed in 1992 using families from 740 consecutive probands who had radical prostatectomies between 1982 and 1989. The study results suggested that familial clustering of disease among men with early-onset prostate cancer was best explained by the presence of a rare autosomal dominant, highly penetrant allele. Hereditary prostate cancer susceptibility genes were predicted to account for almost half of early-onset disease . In addition, early-onset disease has been further supported to have a strong genetic component from the study of common variants associated with disease onset before age 55 years.
References
How Do Brca Genes Affect Prostate Cancer Risk
Around 10% of all prostate cancers are linked to inherited gene changes. These are called hereditary cancers. The BRCA genes boost your odds of developing hereditary prostate cancer, especially the BRCA2 gene.
If you have a BRCA2 mutation, most studies show you may have around a 20% to 40% chance of developing prostate cancer over your lifetime. For some people, research shows the odds may be as high as 60%.
To put that in perspective, someone without this mutation has about a 16% chance of developing prostate cancer at some point in their life.
Cancer affects everyone in a different way. And many people who inherit a BRCA2 mutation wonât ever develop prostate cancer. But compared with people without this gene change, studies show that those with the variant are more likely to:
- Have an aggressive form of prostate cancer
- Develop prostate cancer before age 65
- Have cancer that comes back after treatment
- Die for reasons related to prostate cancer
Thereâs some evidence that people with a BRCA2 mutation who have advanced, or metastatic, disease may respond better to certain prostate cancer treatments. That includes PARP Inhibitors. But we need more research to know which treatment works best for this group.
If you have a BRCA1 mutation, your lifetime odds of prostate cancer may not go up very much or at all.
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The Breast Cancer Genes Impact On Prostate Cancer Risk
Until recently, genetic testing for prostate cancer was not recognized by national guidelines for insurance to cover. The Ohio State clinic is one of only a few such dedicated clinics in the United States. Since her clinic launched in the fall of 2018, Byrne has seen hundreds of men with prostate cancer for genetic testing.Since prostate and breast cancers are both common in the population, the risk for hereditary prostate cancer is just as concerning as it is for breast cancer. It is important knowledge for people to have, as it can guide treatment options and help family members understand their risk, Byrne says. Recent guidance and medical policy changes instituted by the National Comprehensive Cancer Network and other medical governance organizations have improved both access and financial coverage of genetic counseling related to prostate cancer. Its not just about inherited risk from female to female or male to male. BRCA status can impact risk of sons from mothers, daughters from fathers and vice versa, Byrne adds. If a mother is BRCA-positive, her daughters should know this to understand their risk for ovarian, breast and pancreatic cancer, melanoma, and sons should know this for pancreatic, prostate cancer, male breast cancer and melanoma.
Brca1/2 Mutations In Pancreatic Cancer
Pancreatic cancer is a disease with poor prognosis and low survival rates worldwide. Its mortality compares strikingly with its incidence. In the UK in 2011, there were 8,773 diagnosed cases and a mortality rate of 8,320 . Through analysis of the literature it was found that both BRCA1 and BRCA2 mutations are associated with the incidence of pancreatic cancer and that BRCA2 mutation poses an increased risk for developing pancreatic cancer . Furthermore environmental and genetic factors have been proposed as causes of the pancreatic cancer with the genetic factor of particular importance believed to be the BRCA2 gene .
It is clear that BRCA1/2 mutations are evident in many familial breast-pancreas cancer families and that carriers of the BRCA2 mutation have an increased risk of developing pancreatic cancer . Nonetheless, the degree to which family history of pancreatic cancer influences the likelihood of detecting a BRCA1/2 mutation in an individual with breast cancer is less clear . Perhaps, differences in population samples can account for conflicting results within studies making it difficult to make a connection. Furthermore, the use of different analysis models within studies can lead to variations in mutation prevalence.
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How Can A Person Who Has Inherited A Harmful Brca1 Or Brca2 Gene Variant Reduce Their Risk Of Cancer
Several options are available for reducing cancer risk in individuals who have inherited a harmful BRCA1 or BRCA2 variant. These include enhanced screening, risk-reducing surgery , and chemoprevention.
Enhanced screening. Some women who test positive for harmful BRCA1 and BRCA2 variants may choose to start breast cancer screening at younger ages, have more frequent screening than is recommended for women with an average risk of breast cancer, or have screening with magnetic resonance imaging in addition to mammography.
No effective ovarian cancer screening methods are known. Some groups recommend transvaginal ultrasound, blood tests for the CA-125 antigen , and clinical examinations for ovarian cancer screening in women with harmful BRCA1 or BRCA2 variants. However, none of these methods appear to detect ovarian tumors at an early enough stage to improve long-term survival .
The benefits of screening men who carry harmful variants in BRCA1 or BRCA2 for breast and other cancers are not known. Some expert groups recommend that such men undergo regular annual clinical breast exams starting at age 35 . The National Comprehensive Cancer Network guidelines recommend that men with harmful germline variants in BRCA1 or BRCA2 consider having a discussion with their doctor about prostate-specific antigen testing for prostate cancer screening starting at age 40 .
Implications For Male Brca1/2 Mutation Carriers
Kim et al. report that in most BRCA1/2 testing programmes less than 10 % of the individuals tested are men, yet there is an equal gender distribution in the population of male and female BRCA1/2 mutation carriers. It is argued that BRCA1/2 mutation screening may be of greater relevance to females as the risks of cancer are greatly elevated in female BRCA1/2 mutation carriers compared to male , however the findings of this review highlight that there are cancer risks for male carriers of BRCA1/2 mutations therefore screening has relevance for men in their own right, rather than just to inform risk for relatives.
Several motivation factors prompt individuals to undergo genetic screening. In a study by Daly et al. 23 of 26 participants cited concern for their offspring as their main motivation to undergo screening. Concerns about transmitting a mutated gene to daughters appeared to be a major motivating factor. Results reported by Hallowell et al. generated similar findings and found that all men underwent genetic testing with the intention of providing information for their children.
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How Do I Know If I Need To Get Tested
While there is still much we do not know about prostate cancer, certain segments of the population are believed to be at an increased risk for carrying a BRCA1 or BRCA2 mutation. Individuals with a first or second degree relative who has been diagnosed with breast cancer before the age of 50 are thought to be at an increased risk for carrying the gene mutation. Additional risk factors include:
- Having a father or brother with prostate cancer.
- Two first- or second-degree relatives with breast, pancreatic, or prostate cancer.
- People of Ashkenazi Jewish descent.
It is important to remember that you will not necessarily develop prostate cancer even if you fall into one or more of these categories, or even if you test positive for a BRCA mutation.
Currently, there are no preventative treatments for individuals who have a BRCA1 or BRCA2 mutation. However, knowing there is a mutation in the family may prompt your primary care physician to recommend prostate screenings more frequently or at an earlier age.
If a tumor does develop, these additional tests may provide insight into certain vulnerabilities of the cancer and opportunities for specialized, targeted therapies.
Cancer Screening And Medical Management
A personalized cancer risk management program can be developed for individuals known to be at increased cancer risk due to a mutation in BRCA1 or BRCA2. You and your doctors will ultimately decide what plan makes the most sense for you. Cancer risk management generally includes the following categories:
- Intensive screening to increase the chances of early detection, should cancer develop.
- Prophylactic or risk reducing surgical removal of breast tissue.
- Chemoprevention, which is taking a medicine shown to lower the chances of developing cancer.
For men with BRCA1 or BRCA2 mutations, medical management typically begins at age 35. Your oncologist or primary care physician can help shape your specific screening plan.
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What The Brca Gene Means For Men And Families
Many of us have heard of the BRCA1 and BRCA2 genes since they are the most well-known gene links to breast cancer. But, did you know that men have a BRCA gene, too? In recent years, researchers have been working to better understand the BRCA gene, how a mutation in the BRCA gene might play a role in a cancer diagnosis, the similarities between breast cancer and prostate cancer, and how a BRCA gene mutation might influence prostate cancer treatment.
Understanding genetics, family history, and other risk factors can be helpful in navigating a cancer diagnosis especially in breast cancer, ovarian cancer, and prostate cancer.
New Drugs Approved For Advanced Brca
- By Charlie Schmidt, Editor, Harvard Medical School Annual Report on Prostate Diseases
Defective BRCA genes are well known for their ability to cause breast and ovarian cancers in women. But these same gene defects are also strong risk factors for aggressive prostate cancer in men. About 10% of men with metastatic prostate cancer meaning cancer that is spreading away from the prostate test positive for genetic mutations in BRCA genes. Fortunately, these cancers can be treated with new types of personalized therapies.
In May, the FDA approved two new drugs specifically for men with BRCA-positive metastatic prostate cancer that has stopped responding to other treatments. One of the drugs, called rucaparib, was approved on May 15. The other one, olaparib, was approved on May 19.
Both drugs work by shutting down the cancer cells ability to fix its DNA. Like all cells in the body, cancer cells are bombarded every day by free radicals, low-level radiation, and other stressors that cause DNA damage. BRCA genes ordinarily fix that damage so that cells can function normally and survive. But if the genes are defective, then the damage piles up. BRCA-positive tumors get around that problem by deploying an alternate DNA repair gene called PARP. Rucaparib and olaparib both inhibit PARP, leaving cancer cells without any way to fix their increasingly mangled DNA eventually the cells die.
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Mutations In Brca And Other Dna Repair Genes As A Potential Target For Platinum
Specific treatment strategies for patients with somatic and/or germline mutations in DNA repair genes could be obtained from research in other tumor types frequently associated with these events such as breast and ovarian cancers. Platinum-based chemotherapy has been proven to be an effective treatment for BRCA1 and BRCA2 mutated breast and ovarian cancers as these compounds generate DNA cross-links that cannot be easily resolved with an impaired homologous recombination . In standard protocols for prostate cancer, platinum-based chemotherapy is only used when neuroendocrine differentiation has occurred as phase III trials in mCRPC failed to show any benefit in unselected population . However, several retrospective reports have suggested that BRCA2 mutated prostate cancer may be highly sensitive to this therapy . In a retrospective analysis of 141 men with mCRPC treated at the Dana Farber Cancer Institute between 20012015 with at least two doses of carboplatin and docetaxel, the treatment demonstrated benefits for patients with germline BRCA2 mutations . Six out of the eight BRCA2 carriers identified presented a > 50% PSA decline within 12 weeks of initiating this regimen when compared to 23 of 133 of non-carriers . A > 50% PSA decline was associated with a more prolonged survival . Several studies are ongoing to evaluate the role of platinum-based chemotherapy for patients with DNA repair defects.