Abstract
DNA repair deficient (HRD) homologous recombination (HR) breast cancers have been shown to be sensitive to targeted DNA repair therapies. Increasing evidence suggests that sporadic breast cancers without BRCA1/BRCA2 mutations may also be HRD. We developed the RAD51 ex vivo functional assay to identify HRD in primary breast cancer. An integrated approach of methylation, gene expression and whole exome sequencing was used to determine the etiology of HRD. HRD functional breast cancers showed genomic features of lacking a competent HR, including major state transitions and specific mutation signatures. Somatic and/or genetic germline changes resulting in biallelic loss of HR gene function supported functional HRD in 89% of cases and were observed in only one of the 15 HR competent strains tested. These findings indicate the importance of comprehensive genetic evaluation of biallelic changes in the HR pathway to provide a precision medicine approach to patient selection for targeted therapies for tumor-specific DNA repair defects.
| Original language | English |
|---|---|
| Pages (paragraphs) | 165-177 (view, other). |
| Page number | 13 |
| Every day | Pathology Journal |
| Tom | 242 |
| Issue number | 2 |
| Two | |
| country | Published -June 2017 |
| Posted outside | Sim |
Keywords
- BRCAness
- DNA repair
- no homologous recombination
- mutation
- WORK51
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Mutter , RW , Riaz , N , Ng , CKY , Delsite , R , Piscuoglio , S , Edelweiss , M , Martelotto , LG , Sakr , RA , King , TA , Giri , DD , Drobnjak , M , Brogi , E. , Bindra , R. , Bernheim , G. , Lim , RS , Blecua , P. , Desrichard , A. , Higginson , D. , Towers , R. , … Powell , SN (2017.).Biallelic changes in DNA repair genes underlie homologous recombination DNA repair defects in breast cancer.Pathology Journal,242(2), 165-177.https://doi.org/10.1002/path.4890
MUTTER, Robert W.; Riaz, Nadeem; Ng, Charlotte K.Y. to anotherBiallelic changes in DNA repair genes underlie homologous recombination DNA repair defects in breast cancer. Em:Pathology Journal. 2017; Volume 242, No. 2. pp. 165-177 (view, other).
@article{df0265e64296413d9f1c3855fb823675,
title = "Biallelic changes in DNA repair genes underlie homologous recombination DNA repair defects in breast cancer",
abstract = "DNA repair deficient (HRD) breast cancers by homologous recombination have been shown to be sensitive to targeted DNA repair therapies. Growing evidence indicates that sporadic breast cancers without BRCA1/BRCA2 mutations may also be HRD. We have developed the ex vivo RAD51 test functional to identify HRD primary breast cancers An integrated approach of methylation, gene expression and whole exome sequencing was used to determine the aetiology of HRD Functional HRD breast cancers exhibited genomic features of HR deficiency, including a large transition ladder state and specific mutation signatures Somatic and genetic changes /or germline that result in loss of function of biallelic HR genes support functional HRD in 89% of cases and were observed in only one of the 15 HR competent strains tested underscore the importance of comprehensive genetic evaluation of biallelic changes in the HR pathway to ensure a precision medicine approach for selecting patients for therapies targeting tumor-specific DNA repair defects.”
keywords = "BRCAness, DNA repair, defective homologous recombination, mutation, RAD51",
author = "Mutter, {Robert W.} i Nadeem Riaz i Ng, {Charlotte K.Y.}, Rob Delsite, Salvatore Piscuoglio, Marcia Edelweiss i Martelotto, {Luciano G.}, Sakr, {Rita A.} i King, {Tari A.}, Giri, {Dilip D.}, Maria Drobnjak, Eddie Brogi, Ranjit Bindra, Giana Bernheim, Lim, {Raymond S.}, Peter Black, Alexis Desrichard, Dan Higginson, Russell Towers, Ruomu Jiang and William Lee i Britta Weigelt and Reis-Filho, George S. and Powell, Simon N.
note="Funding Information: We would like to thank Mesruh Turkekul and Katia Monova for their help with the immunohistochemical staining. They were funded in part by Geoffrey Beene Cancer Center. The SP part was funded by Susan G Komen Postdoctoral Fellowship (PDF14298348 ) RWM is funded by Mayo Clinic P50 CA116201 Breast Cancer SPORE and the American Society for Radiation Oncology. Publisher's copyright: Copyright {\textcopyright}2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.",
again = "2017",
month = June,
doi = "10.1002/path.4890",
language = "English",
volume = "242",
pages = "165--177",
novine = "Journal of Pathology",
issn = "0022-3417",
redaktor = "John Wiley and Sons Ltd",
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Mutter, RW, Riaz, N, Ng, CKY, Delsite, R, Piscuoglio, S, Edelweiss, M, Martelotto, LG, Sakr, RA, King, TA, Giri, DD, Drobnjak, M, Brogi, E, Bindra, Bernheim , G , Lim , RS , Blecua , P , Desrichard , A , Higginson , D , Towers , R , Jiang , R , Lee , W , Weigelt , B , Reis-Filho , JS & Powell , SNBiallelic changes in DNA repair genes underlie homologous recombination DNA repair defects in breast cancer',Pathology Journal, St. 242, no. 2, pp. 165-177 (view, other).https://doi.org/10.1002/path.4890
Biallelic changes in DNA repair genes underlie homologous recombination DNA repair defects in breast cancer.Mutter, Robert W.; Riaz, Nadeem; Ng, Charlotte K.Y. me second
Em:Pathology Journal, Volume. 242, Number 2, 06/2017, pp. 165-177 (view, other).
search result:Contribution to the magazine›Article›peer review
VI - Wed
T1 – Biallelic changes in DNA repair genes underlie homologous recombination DNA repair defects in breast cancer
AU-Mutter, Robert W.
AU - Riaz, Nadeem
AU — author, Charlotte K.Y.
AU - Delsite, Rob
AU - Piscuoglio, Salvatore
AU - Runolist, Marcia
AU-Martelotto, Luciano G.
AU-Sakr, Rita A.
AU - king, division.
AU-Giri, Dilip D.
AU – Drobnjak, Maria
AU - Brogi, Edi
AU - Bindra, Ranjit
AU - Bernheim, Giana
AU-Lim, Raymond S.
AU - Blecua, Pedro
AU - Desrichard, Alexis
AU-Higginson, Dan
AU – Torres, Russell
UA - Jiang, Ruomu
AU - Lee, William
AU - Weigelt, Britta
AU – Reis-Filho, Jorge S.
AU – Powell, Simon N.
N1 - Funding Information: We would like to thank Mesruh Turkekulu and Katia Monova for their help with immunohistochemical staining. The core sequencing facility is supported by the Cancer Center Support Grant from the National Institutes of Health (Grant No. P30CA008748). SNP and JSR were funded in part by the Geoffrey Beene Cancer Centre. SP was funded in part by the Susan G Komen Postdoctoral Fellowship (PDF14298348). RWM is supported by P50 CA116201 from the Mayo Clinic Breast Cancer SPORE and the American Society of Radiation Oncology. Publisher Copyright: Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
AP - 2017/6
A1 - 2017/6
DNA repair deficient (HRD) homologous recombination (HR) breast cancers have been shown to be sensitive to targeted DNA repair therapies. Increasing evidence suggests that sporadic breast cancers without BRCA1/BRCA2 mutations may also be HRD. We developed the RAD51 ex vivo functional assay to identify HRD in primary breast cancer. An integrated approach of methylation, gene expression and whole exome sequencing was used to determine the etiology of HRD. HRD functional breast cancers showed genomic features of lacking a competent HR, including major state transitions and specific mutation signatures. Somatic and/or genetic germline changes resulting in biallelic loss of HR gene function supported functional HRD in 89% of cases and were observed in only one of the 15 HR competent strains tested. These findings indicate the importance of comprehensive genetic evaluation of biallelic changes in the HR pathway to provide a precision medicine approach to patient selection for targeted therapies for tumor-specific DNA repair defects.
AB - DNA repair-deficient breast cancer by homologous recombination (HR) has been shown to be sensitive to targeted DNA repair therapies. Increasing evidence suggests that sporadic breast cancers without BRCA1/BRCA2 mutations may also be HRD. We developed the RAD51 ex vivo functional assay to identify HRD in primary breast cancer. An integrated approach of methylation, gene expression and whole exome sequencing was used to determine the etiology of HRD. HRD functional breast cancers showed genomic features of lacking a competent HR, including major state transitions and specific mutation signatures. Somatic and/or genetic germline changes resulting in biallelic loss of HR gene function supported functional HRD in 89% of cases and were observed in only one of the 15 HR competent strains tested. These findings indicate the importance of comprehensive genetic evaluation of biallelic changes in the HR pathway to provide a precision medicine approach to patient selection for targeted therapies for tumor-specific DNA repair defects.
KW - BRCAness
KW - DNA repair
KW - no homologous recombination
KW - mutation
KW - RAD51
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U2 - 10.1002/put.4890
DO - 10.1002/put.4890
M3 - Article
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VL - 242 (view, expert).
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JO - Journal of Pathology
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Mutter RW, Riaz N, Ng CKY, Delsite R, Piscuoglio S, Edelweiss M i sur.Biallelic changes in DNA repair genes underlie homologous recombination DNA repair defects in breast cancer.Pathology Journal, 2017. June;242(2):165-177. doi:10.1002/ściżka.4890
FAQs
What are the DNA repair genes for breast cancer? ›
Many DNA repair genes such as MSH2, MLH1, PARP1, XRCC1, XRCC4, 53BP1, ERCC1, XPA have been found to be associated with the prognosis of breast cancer.
What does the BRCA gene do in homologous recombination? ›The function of BRCA2 in recombination is to control RAD51, a protein that catalyzes homologous pairing and DNA strand exchange. By physically interacting with both RAD51 and single-stranded DNA, BRCA2 mediates delivery of RAD51 preferentially to sites of ssDNA exposed as a result of DNA damage or replication problems.
Why are defects in DNA repair associated with cancer? ›Defects in DNA repair pathways enable cancer cells to accumulate genomic alterations that contribute to their aggressive phenotype.
What diseases are caused by homologous recombination repair? ›Homologous recombination repairs double-strand breaks in DNA caused by ionizing radiation or DNA-damaging chemicals. Left unrepaired, these double-strand breaks can cause large-scale rearrangement of chromosomes in somatic cells, which can in turn lead to cancer.
What are 2 common genes involved in breast cancer? ›The genes most commonly affected in hereditary breast and ovarian cancer are the breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) genes. About 3% of breast cancers (about 7,500 women per year) and 10% of ovarian cancers (about 2,000 women per year) result from inherited mutations in the BRCA1 and BRCA2 genes.
What causes DNA damage in breast cancer? ›In breast cancer management, radio- and chemotherapy exert their effects by causing DNA damage, and are usually used as first-line drugs in combination with hormone and target therapies.
What are the odds of having the BRCA gene? ›About 1 in every 500 women in the United States has a mutation in either her BRCA1 or BRCA2 gene. If either your mother or your father has a BRCA1 or BRCA2 gene mutation, you have a 50% chance of having the same gene mutation.
Are BRCA genes involved in DNA repair? ›Intensive research has shown that BRCA proteins are involved in a multitude of pivotal cellular processes. In particular, both genes contribute to DNA repair and transcriptional regulation in response to DNA damage.
What do you mean by homologous recombination? ›Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA.
Can DNA repair defects lead to cancer? ›But if the DNA damage occurs to a gene that makes a DNA repair protein, a cell has less ability to repair itself. So errors will build up in other genes over time and allow a cancer to form. Scientists have found damaged DNA repair genes in some cancers, including bowel cancer.
Can DNA repair genes cause cancer? ›
If one of your DNA repair genes has a mutation, mistakes in DNA do not get corrected. This means mutations can develop, and eventually lead to cancer. This is especially true if the mutation is in a tumor suppressor gene or an oncogene.
What type of DNA damage causes cancer? ›Cancers are caused by damage to the DNA in your cells. These changes are called “gene mutations.” Gene mutations can build up in cells in your body over time. Cells with too many mutations may stop working normally, grow out of control and become cancerous.
What cancers have homologous recombination deficiency? ›A deficiency in the HRR pathway has been associated with several tumor types including breast, ovarian, prostate, and pancreatic cancers (Fig. 1) and has been termed homologous recombination deficiency (HRD), whereas tumors that are not HRD are termed homologous recombination proficient (HRP).
What is an example of homologous repair? ›The most common form of HDR is homologous recombination. The HDR mechanism can only be used by the cell when there is a homologous piece of DNA present in the nucleus, mostly in G2 and S phase of the cell cycle. Other examples of homology-directed repair include single-strand annealing and breakage-induced replication.
What type of DNA damage does homologous recombination? ›Homologous recombination (HR) is a DNA metabolic process found in all forms of life that provides high-fidelity, template-dependent repair or tolerance of complex DNA damages including DNA gaps, DNA double-stranded breaks (DSBs), and DNA interstrand crosslinks (ICLs).
How do you know if you have the gene for breast cancer? ›Genetic testing for hereditary breast and ovarian cancer looks for mutations in the BRCA1 and BRCA2 genes. Your doctor might suggest testing using a multigene panel, which looks for mutations in several genes at the same time, including BRCA1 and BRCA2.
What gene makes breast cancer more likely? ›Most hereditary breast cancers are caused by abnormal BRCA1 and BRCA2 genes. However, even if a BRCA1 or BRCA2 gene mutation does not run in the family, a strong family health history of breast cancer makes it more likely that a person will get breast cancer, possibly due to mutations in other genes.
What percentage of breast cancer is genetic? ›Researchers estimate that inherited genetic mutations account for between 5 and 10 percent to as many as 27 percent of all breast cancers.
Should you get a mastectomy if you have the BRCA gene? ›Breast cancer patients with BRCA1 or BRCA2 mutations are also more likely to later develop a second cancer, either in the same or the opposite breast. Because of this, they may opt for a double mastectomy instead of a single or partial mastectomy (also known as lumpectomy).
How do you know if you have BRCA gene mutation? ›A BRCA gene test uses a sample of your blood, saliva (spit), or cells from inside of your cheek to look for changes in your BRCA1 and BRCA2 genes that may increase your risk of cancer. Changes in your genes are called gene variants or mutations. Not all gene variants are harmful.
Can faulty DNA repair lead to BRCA linked cancers? ›
Error-prone DNA replication and repair may lead to mutations and cancer in individuals who inherit a mutant copy of the BRCA1 gene, according to a new study by Weill Cornell Medicine investigators.
Who should be tested for BRCA gene mutations? ›- A personal history of breast cancer diagnosed before age 45.
- A personal history of breast cancer diagnosed before age 50 and a second primary breast cancer, one or more relatives with breast cancer, or an unknown or limited family medical history.
BRCA1 and BRCA2 play a crucial role in maintaining genome integrity by repairing double-strand DNA breaks via the homologous recombination repair (HRR) pathway. Any mutations that cause functional disruption of these proteins may prove to be highly deleterious, leading to the development of cancer.
What are the consequences of homologous recombination? ›Homologous recombination (HR) is critical both for repairing DNA lesions in mitosis and for chromosomal pairing and exchange during meiosis. However, some forms of HR can also lead to undesirable DNA rearrangements.
What are the disadvantages of homologous recombination? ›Disadvantages of Homologous Recombination
During gamete formation, chromosomes can align incorrectly and result in too many or too few chromosomes in the sperm and ovum. Down's syndrome, an abnormality in chromosome 21 is a result of the failure of homologous recombination.
Homologous recombination (HR) is a high-fidelity DSB repair pathway used to repair both endogenous and exogenous sources of DNA damage (1). Mutations in HR genes are associated with many cancers but are especially prevalent in breast, ovarian, and prostate cancers (2–4).
What are the 3 types of cancer genes? ›The genes ATM, PALB2, and CHEK2 may increase the risk for several types of cancer, including breast, ovarian, colon, prostate, and pancreatic.
What is the most serious type of DNA damage? ›DSB Repair Double-strand breaks (DSBs) are perhaps the most serious form of DNA damage because they pose problems for transcription, replication, and chromosome segregation.
What happens to your DNA when you have cancer? ›As cancer cells divide, they acquire more DNA changes over time. Two cancer cells in the same tumor can have different DNA changes. In addition, every person with cancer has a unique combination of DNA changes in their cancer.
What is an example of a DNA repair deficient disorder? ›Today, a limited number of rare hereditary diseases characterized by genetic defects of DNA repair mechanisms is known, comprising ataxia telangiectasia, Nijmegen breakage syndrome, Werner syndrome, Bloom Syndrome, Fanconi anemia, xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy.
What cancers have mismatch repair genes? ›
Mismatch repair (MMR) deficient cells usually have many DNA mutations, which may lead to cancer. MMR deficiency is most common in colorectal cancer, other types of gastrointestinal cancer, and endometrial cancer, but it may also be found in cancers of the breast, prostate, bladder, and thyroid.
What cancers are BRCA defective? ›If you have an inherited faulty gene it increases your risk of developing certain types of cancer. Some faulty genes increase the risk of more than one cancer type. Faulty BRCA1 and BRCA2 genes increase the risk of developing breast, ovarian, pancreatic and prostate cancer.
What cancers are associated with BRCA1 mutation? ›Women who have a BRCA1 or BRCA2 genetic mutation are at an increased risk of breast, ovarian, and pancreatic cancers. Men who have a BRCA1 or BRCA2 genetic mutation are at an increased risk of prostate, pancreatic, and breast cancers.
What are 3 examples of homologous? ›An example of homologous structures are the limbs of humans, cats, whales, and bats. Regardless of whether it is an arm, leg, flipper or wing, these structures are built upon the same bone structure.
What are 5 examples of homologous? ›- Flipper - whale.
- Wing - bat.
- Fore limb -horse.
- Paw - cat.
- Hand - human.
- Thorn - bougainvillaea.
- Tendril - cucurbita.
Orthologs and paralogs are two fundamentally different types of homologous genes that evolved, respectively, by vertical descent from a single ancestral gene and by duplication. Orthology and paralogy are key concepts of evolutionary genomics.
What are the two types of homologous recombination? ›| Recombination type | Frequency | Requirements |
|---|---|---|
| 1. Illegitimate | extremely low | Micro- or no homology |
| 2. Transposition | very low (regulated) | Ends of the jumping element |
| 3. Homologous | low (when DNA damage is low) | Extensive homology |
| 4. Site-specifichigh | A pair of short sites | |
In bacteria, the major function of homologous genetic recombination is recombinational DNA repair. This is not a process reserved only for rare double-strand breaks caused by ionizing radiation, nor is it limited to situations in which the SOS response has been induced.
Can recombination cause mutations? ›Errors in meiotic recombination are often a source of harmful mutations, aberrant chromosomes and defective gametes, with important clinical consequences.
Are BRCA1 and BRCA2 DNA repair genes? ›BRCA1 (BReast CAncer gene 1) and BRCA2 (BReast CAncer gene 2) are genes that produce proteins that help repair damaged DNA. Everyone has two copies of each of these genes—one copy inherited from each parent.
What are the list of genes involved in BReast CAncer? ›
There are a number of other genes, including ATM, BARD1, BRIP1, CASP8, CTLA4, CYP19A1, FGFR2, H19, LSP1, MAP3K1, MRE11A, NBN, RAD51, and TERT, that are thought to also increase the risk of developing breast cancer when they carry a mutation.
Are BRCA1 and BRCA2 involved in DNA repair? ›BRCA1 is a pleiotropic DDR protein that functions in both checkpoint activation and DNA repair, whereas BRCA2 is a mediator of the core mechanism of homologous recombination.
What are the most important genes in BReast CAncer? ›Most inherited cases of breast cancer are associated with mutations in two genes: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two). Everyone has BRCA1 and BRCA2 genes. The function of the BRCA genes is to repair cell damage and keep breast, ovarian, and other cells growing normally.
Can you be BRCA positive with no family history? ›The rate of germline BRCA1 or 2 mutations in ovarian cancer patients without a family history or breast or ovarian cancer is low. However, in women with additional family members affected, the prevalence is considerably higher than previously reported.
What are highly mutated genes in breast cancer? ›BRCA1 and BRCA2
The BRCA1 (breast cancer gene one) and BRCA2 (breast cancer gene two) inherited gene mutations are the most common cause of hereditary breast cancer.
About BRCA1 and BRCA2
If you have a fault (mutation) in one of the BRCA genes, your risk of developing breast cancer and ovarian cancer is greatly increased. Women with the faulty BRCA1 gene, for example, have a 65 to 79% lifetime risk of breast cancer and a 36 to 53% risk of ovarian cancer before the age of 80.
Women who have a BRCA1 or BRCA2 genetic mutation are at an increased risk of breast, ovarian, and pancreatic cancers. Men who have a BRCA1 or BRCA2 genetic mutation are at an increased risk of prostate, pancreatic, and breast cancers.
What type of DNA repair is BRCA? ›BRCA1 and BRCA2 occupy a central role in the repair of a specific type of damage to the DNA through a DNA repair pathway called homologous recombination repair (HRR).
What is the difference between BRCA1 and 2? ›Differences Between BRCA1 and BRCA2
Both mutations increase the risk of ovarian cancer, as well as pancreatic cancer. A BRCA1 mutation can also increase the risk of cervical, uterine, and colon cancer, while BRCA2 can increase the likelihood of stomach, gallbladder, and bile duct cancer, plus melanoma.
Breast cancer is diagnosed by breast biopsy or excision and is subsequently staged. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) biomarker testing is performed to establish hormone receptor status, which provides both prognostic and predictive value.