The choice. BRCA1 testing in families with hereditary breast-ovarian cancer: a prospective study of patient decision making and outcomes
Purpose: Germline mutations in the BRCA1 and BRCA2 genes confer increased risks for breast cancers. However, the clinical presentation of breast cancer among women who are carriers of the BRCA1 or BRCA2 (BRCA1/2 carriers) mutations is heterogenous. We aimed to identify the effects of the reproductive histories of women with the BRCA1/2 mutations on the clinical presentation of breast cancer. Methods: We retrospectively analyzed clinical data on women with proven BRCA1 and BRCA2 mutations who were recruited to the Korean Hereditary Breast Cancer study, from 2007 to 2014. Results: Among the 736 women who were BRCA1/2 mutation carriers, a total of 483 women had breast cancers. Breast cancer diagnosis occurred at significantly younger ages in women who experienced menarche at ≤ 14 years of age, compared to those who experienced menarche at , 14 years of age (37.38±7.60 and 43.30±10.11, respectively, p, 0.001). Additionally, the number of full-term pregnancies was significantly associated with ...
Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95%
Rapid developments in cancer genetics have exposed a knowledge vacuum about genetic testing for susceptibility to cancer. Our experience in testing for BRCA1 or BRCA2 mutation in hereditary breast cancer (HBC) syndrome, with counseling about cancer surveillance and management, inclusive of the option of prophylactic surgery, provides some important information. We provided DNA-based (BRCA1, BRCA2 germ-line mutation) findings on 442 patients from 37 HBC families. The top two reasons for receiving genetic test results are for their children and for their own health surveillance. Of those women who have tested positive for BRCA1 and have been counseled, 40% had already developed breast cancer and 6% had already developed ovarian cancer, while in BRCA2 25% had developed breast cancer and 0% had developed ovarian cancer. Of the unaffected women, prior to counseling 59% from BRCA1 and 46% from BRCA2 said they would consider prophylactic mastectomy if their result was positive; 76% of BRCA1 and 50% of BRCA2
The 12 tumors with a hypermethylated BRCA1 promoter were also analyzed for the two BRCA1 founder mutations common in the Ashkenazi Jewish population, BRCA1 185delAG (exon 2) and BRCA1 5382 insC (exon 20), and found to be free of mutation (Table 1) ⇓ . These samples were also analyzed and found to be absent for the BRCA2 6174delT (exon 11) Jewish founder mutation. The lack of a Jewish founder mutation does not, however, rule out the possibility that other BRCA1 mutations are present. The absence of BRCA1 protein staining in 2 of 9 unmethylated OCs suggests that mechanisms other than promoter hypermethylation may also inhibit BRCA1 protein expression.. A relationship between the BRCA and p53 genes has long been suspected, based upon the higher incidence of p53 mutations in tumors with BRCA mutations than in sporadic carcinomas (31, 32, 33) In view of the critical role of p53 in cell cycle regulation, it has been postulated that BRCA1 mutant cells with wild-type p53 are less susceptible to ...
BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. METHODS: We genotyped rs3814113 in 10,029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. RESULTS: The minor allele of rs3814113 was
Mutations in BRCA1 and BRCA2 are responsible for a large proportion of breast-ovarian cancer families. Protein-truncating mutations have been effectively used in the clinical management of familial breast cancer due to their deleterious impact on protein function. However, the majority of missense variants identified throughout the genes continue to pose an obstacle for predictive informative testing due to low frequency and lack of information on how they affect BRCA1/2 function. Phosphorylation of BRCA1 and BRCA2 play an important role in their function as regulators of DNA repair, transcription and cell cycle in response to DNA damage but whether missense variants of uncertain significance (VUS) are able to disrupt this important process is not known. Here we employed a novel approach using NetworKIN which predicts in vivo kinasesubstrate relationship, and evolutionary conservation algorithms SIFT, PolyPhen and Align-GVGD. We evaluated whether 191 BRCA1 and 43 BRCA2 VUS from the Breast Cancer ...
Background: Germline BRCA mutations are associated with worse prostate cancer (PCa) outcomes; however, the most appropriate management for mutation carriers has not yet been investigated. Objective: To evaluate the response of BRCA carriers to conventional treatments for localised PCa by analysing metastasis-free survival (MFS) and cause-specific survival (CSS) following radical prostatectomy (RP) or external-beam radiation therapy (RT). Design, setting, and participants: Tumour features and outcomes of 1302 patients with local/locally advanced PCa (including 67 BRCA mutation carriers) were analysed. RP was undergone by 535 patients (35 BRCA); 767 received RT (32 BRCA). Median follow-up was 64 mo. Outcome measurements and statistical analysis: Median survival and 3-, 5-, and 10-yr survival rates were estimated using the Kaplan-Meier method. Generated survival curves were compared using the log-rank test. Cox regression analyses were used to assess the prognostic value of BRCA mutations. Results ...
Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC) and TP53 genes was performed in 54 unrelated patients |35 y; their tumors were investigated with respect to transcriptional and genomic profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22%) [7 in BRCA1 (13%), 4 in BRCA2 (7%) and one in TP53 (2%) gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes). Fifty
While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = ...
TY - JOUR. T1 - A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families. AU - Serova, Olga. AU - Montagna, Marco. AU - Torchard, Delphine. AU - Narod, Steven A.. AU - Tonin, Patricia. AU - Sylla, Bakary. AU - Lynch, Henry T.. AU - Feunteun, Jean. AU - Lenoir, Gilbert M.. PY - 1996. Y1 - 1996. N2 - We have analyzed 20 breast-ovarian cancer families, the majority of which show positive evidence of linkage to chromosome 17q12, for germ-line mutations in the BRCA1 gene. BRCA1 mutations cosegregating with breast and ovarian cancer susceptibility were identified in 16 families, including 1 family with a case of male breast cancer. Nine of these mutations have not been reported previously. The majority of mutations were found to generate a premature stop codon leading to the formation of a truncated BRCA1 protein of 2%-88% of the expected normal length. Two mutations altered the RING finger domain. Sequencing of genomic DNA led to the identification of a mutation in the coding region ...
ABSTRACT: INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12599 BRCA1 and 7132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele Hazard Ratio (HR)= 0.87, 95%CI:0.81-0.94, P-trend=3x10^-4). The association was restricted to mutations proven or predicted to
This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy at time of enrollment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrollment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically ...
A breast cancer (BRCA) gene test is a blood test to check for specific changes (mutations) in genes that help control normal cell growth. Finding changes in these genes, called BRCA1 and BRCA2, can help determine your chance of developing breast cancer and ovarian cancer. A BRCA gene test does not test for cancer itself. This test is only done for people with a strong family history of breast cancer, ovarian cancer and sometimes for those who already have one of these diseases. Genetic counseling before and after a BRCA test is very important to help you understand the benefits, risks, and possible outcomes of the test.. A womans risk of breast and ovarian cancer is higher if she has BRCA1 or BRCA2 gene changes. Breast cancer is extremely rare in men but BRCA2 gene changes have been linked to male breast cancer and possibly prostate, may also be higher. The gene changes can be inherited from either your mothers or fathers side of the family.. Certain people have a higher chance of inheriting ...
Our study reaffirms that specific BRCA1 and BRCA2 mutations found previously to recur in French Canadian breast cancer and breast-ovarian cancer families, also recur in women with ovarian cancer not selected for family history of cancer. This is especially evident with the number of BRCA1:C4446T mutation carriers (n = 15) identified in this study, which has been the most commonly reported mutation identified in this population and this has been attributed to shared ancestry as a consequence of common founders [24,25,27-29,32,33]. This mutation was also the most common mutation found in our previous study of 74 women with serous and endometrioid ovarian cancers screened for specific BRCA1/BRCA2 mutations [36].. Our study also highlights the significance of the BRCA2:E3002K mutation in the French Canadian population. We found five E3002K mutation-positive carriers in the cohort of 439 women with ovarian cancer, which is similar in frequency to the number of carriers of each of the other three ...
Ovarian cancer is a deadly disease that kills an estimated 15,000 women annually in the United States. It is estimated that approximately 10% of ovarian cancers are due to familial inheritance. The most commonly mutated genes in familial ovarian cancer are BRCA1 and BRCA2. It has been reported that cells carrying the BRCA1 185delAG mutation undergo an enhanced caspase-3 mediated apoptotic response. Here, we report on the transfection of cDNA coding for the putative truncated protein product of the BRCA1 185delAG mutant gene into BRCA1 wild-type human immortalized ovarian surface epithelial (IOSE) cells and ovarian cancer cells. Cells transfected with the BRCA1 185delAG truncation protein (BRAt) showed increased levels of active caspase 3, increased cleavage of caspase 3 substrates, PARP and DFF45, and decreased XIAP and cIAP1 following staurosporine (STS) treatment. BRAt also reduced Akt phosphorylation and over expression of activated Akt in BRAt cells restored caspase-3 activity to that seen in wild
PALB2 (Partner and Localizer of BRCA2) plays a key role in the repair of damaged DNA by localizing BRCA2 and initiating the repair process. The gene has been recognized as a third breast cancer (BC) predisposition gene, together with BRCA1 and BRCA2. The absolute risk for the development of BC for mutation carriers with a familial predisposition, represents 58% at 50 years of age, similar to that of BRCA2. Although germline loss-of-function PALB2 mutations is rare, the mutation spectrum internationally and in South African (SA) is still unknown. Eighty-six SA breast- and/or ovarian cancer (OVC) patients were selected. Patients had to be affected with either breast- and/or OVC, have a positive family history of BC (two or more affected family members, excluding the index), tested negative for pathogenic mutations in BRCA1/2, represent one of the four main SA ethnic groups and had sufficient amounts of good quality DNA stored to complete a comprehensive screen of the entire gene. The complete ...
In this study, we applied a TaqMan-based quantitative AI assay to compare the levels of AI in BRCA1 and BRCA2 genes between patients with familial ovarian cancer and cancer-free relative controls. The AI ratios of BRCA1 in familial ovarian cancer cases were significantly higher than those from cancer-free relative controls (P = 0.0007). In contrast, the AI ratios of BRCA2 were not significantly different between familial ovarian cancer cases and cancer-free controls (P = 0.328). The distribution of underexpressed alleles between cancer-free controls and familial cases was significantly different for BRCA1 gene expression but not for BRCA2 gene expression (P , 0.014 for BRCA1 and P = 0.66 for BRCA2). Using a cutoff point of BRCA1 AI (0.458) obtained from ROC analysis, higher levels of AI in BRCA1 were associated with a 4.22-fold increased risk of familial ovarian cancer. Furthermore, we have observed a significant trend of decreasing age at cancer diagnosis with increasing levels of AI in BRCA1 ...
Data from the National Cancer Institute, http://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet#q1.. ** Julia Carnevale and Alan Ashworth. Assessing the Significance of BRCA1and BRCA2 Mutations in Pancreatic Cancer. Published online before print May 18, 2015, doi:10.1200/JCO.2015.61.6961JCO May 18, 2015, http://jco.ascopubs.org/content/early/2015/05/18/JCO.2015.61.6961.full.. Couch FJ, Johnson MR, Rabe KG, et al. (2007) The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev 16:342-346.. Hahn SA, Greenhalf B, Ellis I, et al. (2003) BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst95:214-221.. Murphy KM, Brune KA, Griffin C, et al. (2002) Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: Deleterious BRCA2 mutations in 17%.Cancer Res 62:3789-3793.. Lucas, A.L., Shakya, R., Lipsyc, M.D., Mitchel, E.B., Kumar, S., Hwang, C., Deng, L., Devoe, C., Chabot, J.A., ...
Individuals with mutations in BRCA1 and BRCA2 genes have a significantly higher risk of developing breast and ovarian cancers. Families at risk have been seeking genetic testing and counseling based on their mutation carrier status, but the standard method of direct sequencing is labor-intensive, costly, and it only targets a part of the BRCA1 and BRCA2 genes. A group of Canadian scientists has developed a new sequencing approach to provide a more effective method of BRCA1/2 mutational analysis.
11 Feb 2016. Rates of genetic testing for BRCA1 and BRCA2 mutations have increased among women diagnosed with breast cancer at age 40 or younger, according to an article published online by JAMA Oncology.. Breast cancer is the most common cancer diagnosed in women younger than 40 in the United States.. The National Comprehensive Cancer Network guidelines recommend women diagnosed with breast cancer at 50 or younger undergo genetic testing because carriers of BRCA1 and BRCA2 mutations are at increased risk for developing early-onset breast cancer.. Assessing a young womens genetic risk after a breast cancer diagnosis can have implications for subsequent treatment decisions.. Ann H. Partridge, M.D., M.P.H., of the Dana-Farber Cancer Institute, Boston, and coauthors described the use of BRCA testing in a group of women diagnosed with breast cancer at 40 or younger and examined how concerns about genetic risk and genetic information affected treatment decisions.. The study included 897 women 40 and ...
Mutations in the BRCA1 and BRCA2 genes profoundly increase the risk of developing breast and/or ovarian cancer among women. To explore the contribution of BRCA1 and BRCA2 mutations in the development of hereditary breast cancer among Indian women, we carried out mutation analysis of the BRCA1 and BRCA2 genes in 61 breast or ovarian cancer patients from south India with a positive family history of breast and/or ovarian cancer. Mutation analysis was carried out using conformation-sensitive gel electrophoresis (CSGE) followed by sequencing. Mutations were identified in 17 patients (28.0%); 15 (24.6%) had BRCA1 mutations and two (3.28%) had BRCA2 mutations. While no specific association between BRCA1 or BRCA2 mutations with cancer type was seen, mutations were more often seen in families with ovarian cancer. While 40% (4/10) and 30.8% (4/12) of families with ovarian or breast and ovarian cancer had mutations, only 23.1% (9/39) of families with breast cancer carried mutations in the BRCA1 and BRCA2 ...
BRCA1 mutations were identified in 16 percent of women with a family history of breast cancer. Only 7 percent of women from families with a history of breast cancer but not ovarian cancer had BRCA1 mutations. The rates were higher among women from families with a history of both breast and ovarian cancer. Among family members, an average age of less than 55 years at the diagnosis of breast cancer, the presence of ovarian cancer, the presence of breast and ovarian cancer in the same woman, and Ashkenazi Jewish ancestry were all associated with an increased risk of detecting a BRCA1 mutation. No association was found between the presence of bilateral breast cancer or the number of breast cancers in a family and the detection of a BRCA1 mutation, or between the position of the mutation in the BRCA1 gene and the presence of ovarian cancer in a family. Conclusions: ...
It was proposed by Henderson and colleagues in 1985 that breast cancer incidence rates closely parallel the lifetime number of ovulatory cycles, in support of the hypothesis that endogenous estrogen and progesterone are important etiologic factors (2). We show here that among BRCA mutation carriers, the cumulative number of ovulatory cycles is not associated with risk. The mean number of ovulatory cycles for the controls was in fact greater (248) than it was for the cases (243), opposite to what we would expect if risk was positively associated with the number of cycles. The negative association between ovulatory cycles achieved and breast cancer risk is a reflection of the declining risk with age. Nevertheless, a number of reproductive factors are important in BRCA1 carriers including age at menarche, breastfeeding, and oophorectomy, whereas only oophorectomy was protective in BRCA2 carriers.. The diminution of risk associated with a delay of menarche by 1 year is approximately 9% and is ...
OBJECTIVE Women who are carriers of BRCA gene mutations have an elevated lifetime risk of developing breast or ovarian cancer. Although a number of risk-reducing options are currently available to mutation carriers, uncertainty exists in terms of their efficacy. A systematic review of the literature was conducted to describe the utilization of screening and preventive surgery among unaffected mutation carriers in the face of uncertainty. METHODS MEDLINE, PubMed, and CANCERLIT, English-only computerized literature searches were done to identify articles pertaining to decisions made by unaffected BRCA mutation carriers to reduce risk of breast and ovarian cancer. Studies were required to include information on choices taken by at-risk women following disclosure of a positive BRCA test. RESULTS Only seven studies (5 American and 2 Dutch studies) were identified. The proportion of mutation carriers who chose preventive surgery over screening varied widely across the studies, ranging from 0% to 54% for
TY - JOUR. T1 - Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. AU - Berry, Donald A.. AU - Parmigiani, Giovanni. AU - Sanchez, Juana. AU - Schildkraut, Joellen. AU - Winer, Eric. PY - 1997/2/5. Y1 - 1997/2/5. N2 - Background: Heritable mutations of the breast cancer gene BRCA1 are rare, occurring in fewer than 1% of women in the general population, and therefore account for a small proportion of cases of breast and ovarian cancers. Nevertheless, the presence of such mutations is highly predictive of the development of these cancers. Purpose: We developed and applied a mathematic model for calculating the probability that a woman with a family history of breast and/or ovarian cancer carries a mutation of BRCA1. Methods and Results: As a basis for the model, we use Mendelian genetics and apply Bayes theorem to information on the family history of these diseases. Of importance are the exact relationships of all family members, including both ...
Screening for your G5193A BRCA1 and 999del5 BRCA2 mutations confirmed the 999del5 mutation from the 11 BRCA2 suggestive pairs in addition three pairs significantly less indicative of linkage, plus the G5193A BRCA1 mutation in a single pair. When regarded mutation carriers are faraway from the group, no indication of further more linkage to BRCA1 or BRCA2 is noticed. The effects of our research propose that a significant proportion of familial breast cancer in Iceland is the results of the 999del5 BRCA2 mutation, and it really is unlikely that BRCA1 and BRCA2 germline mutations aside from 999del5 and G5193A play a big position in hereditary breast most cancers in Iceland. Additionally it might be concluded that many family members with BRCA1 or BRCA2 linkage are easily recognized by finding out LOH across the site info faulty gene in as couple of as two impacted relatives. PMID: ...
Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 ...
1. Brody LC, Biesecker BB. Breast cancer susceptibility genes. BRCA1 and BRCA2. Medicine (Baltimore). 1998 ;77:208-26 2. Rebbeck TR, Lynch HT, Neuhausen SL. et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002 ;346:1616-22 3. Kauff ND, Satagopan JM, Robson ME. et al. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2002 ;346:1609-15 4. Metcalfe KA. Prophylactic bilateral mastectomy for breast cancer prevention. J Womens Health (Larchmt). 2004 ;13:822-9 5. Senkus-Konefka E, Konefka T, Jassem J. The effects of tamoxifen on the female genital tract. Cancer Treat Rev. 2004 ;30:291-301 6. Farmer H, McCabe N, Lord CJ. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005 ;434:917-21 7. Bryant HE, Schultz N, Thomas HD. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005 ;434:913-7 8. Hay T, Jenkins H, Sansom OJ. et ...
Key clinical point: Central nervous system involvement is common among patients with germline BRCA1/BRCA2 mutations who have newly recurrent breast cancer. Major finding: Prevalence of CNS disease was 25% in noncarriers, but 53% in BRCA1 mutation carriers (multivariate odds ratio, 2.11; P = .18) and 50% in BRCA2 mutation carriers (multivariate odds ratio, 3.33; P less than .006).
BRCA1 and BRCA2 are tumour suppressor genes that control the repair of genetic alterations throughout cellular division. Approximately 14% of patients with ovarian cancer carry a germline BRCA mutation; this proportion is higher for those with high-grade serous histology (22.6%). In addition, a minority of patients (7%) in whom no germline BRCA mutation is detected harbour a somatic BRCA mutation (21).. The aberrant expression of BRCA1 and BRCA2 is associated with an intrinsic sensitivity to poly(ADP ribose) polymerase (PARP) inhibitors which inhibit the repair of single-strand DNA breaks during normal DNA replication, leading to accumulation of DNA double-strand breaks at replication forks. Under normal circumstances, these are repaired via the efficient BRCA pathway-dependent homologous recombination mechanism. Tumors lacking BRCA function have to rely on double-strand repair through other means, such as non-homologous end joining; these are error prone and lead to cell death. Such carcinomas ...
BRCA mutation carriers with a known maternal transmission whose mother is deceased report higher perceived stress and anxiety, lower QOL, and a stress-associated biomarker profile that is potentially globally immune suppressive.
Mutations in the BRCA1 and BRCA2 genes are strongly associated with the development of breast or ovarian cancer: Carriers face a five- to 20-fold increased risk of developing these cancers and are usually subject to intensive screening and risk-reduction strategies. Female relatives who are tested and found not to carry the family-specific mutation have historically been advised that their cancer risks are the same as those of other relatives of breast cancer patients (that is, slightly higher than women in the general population).. The field was shaken up when a 2007 Journal of Medical Genetics paper showed that women who tested negative for a familial BRCA mutation had a two- to five-fold increased risk of developing breast cancer. Several other studies found a two-fold risk for non-carriers who had a relative with the mutation, prompting some to wonder whether ongoing breast cancer surveillance should be recommended for these relatives.. Our clinic received many calls about it - it was ...
Research overview. BRCA1/BRCA2 mutations in breast and ovarian cancer. Germline mutations of BRCA1/BRCA2 genes occur in up to 5% of breast cancer patients and 15% of ovarian cancers. These genes are major players in the repair of DNA double strand breaks. BRCA carriers have therefore increased sensitivity to DNA-damaging agents, such as platinum or PARP inhibitors. We recently showed a correlation between the BRCA2 genotype and response to platinum in ovarian cancer patients. Only BRCA2 carriers, harboring mutations located in the RAD51-binding domain (RAD51-BD), have prolonged treatment-free intervals and longer survival, whereas the other BRCA2 carriers did not show a survival benefit. We are currently investigating the impact of BRCA mutations on toxicity and response to chemotherapy in breast cancer patients.. Pathogenesis of high grade serous ovarian carcinoma. ...
TY - JOUR. T1 - AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers. T2 - A Consortium of Investigators of Modifiers of BRCA1/2 study. AU - Couch, Fergus J.. AU - Sinilnikova, Olga. AU - Vierkant, Robert A.. AU - Pankratz, V. Shane. AU - Fredericksen, Zachary S.. AU - Stoppa-Lyonnet, Dominique. AU - Coupier, Isabelle. AU - Hughes, David. AU - Hardouin, Agnès. AU - Berthet, Pascaline. AU - Peock, Susan. AU - Cook, Margaret. AU - Baynes, Caroline. AU - Hodgson, Shirley. AU - Morrison, Patrick J.. AU - Porteous, Mary E.. AU - Jakubowska, Anna. AU - Lubinski, Jan. AU - Gronwald, Jacek. AU - Spurdle, Amanda B.. AU - Chenevix-Trench, Georgia. AU - Spurdle, Amanda. AU - Schmutzler, Rita. AU - Versmold, Beatrix. AU - Engel, Christoph. AU - Meindl, Alfons. AU - Sutter, Christian. AU - Horst, Jurgen. AU - Schaefer, Dieter. AU - Offit, Kenneth. AU - Kirchhoff, Tomas. AU - Andrulis, Irene L.. AU - Ilyushik, Eduard. AU - Glendon, Gordon. AU - Devilee, Peter. AU - Vreeswijk, ...
Background: Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon. Methods: We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways. Results: Patients with an early AAO (73 women) had developed breast ...
Niraparib achieved its primary endpoint in a phase III ovarian cancer trial, demonstrating prolonged progression-free survival compared to placebo among patients who are germline BRCA mutation carriers; among patients who are not germline BRCA mutation carriers, but who have homologous recombination deficient tumors as determined by the Myriad myChoice HRD test; and overall in patients who are not germline BRCA mutation carriers.. The trial, NOVA, is a double-blind, international trial that enrolled more than 500 patients with recurrent ovarian cancer who were in a response to their most recent platinum-based chemotherapy. There is currently no therapy approved by FDA for maintenance treatment of patients with recurrent ovarian cancer following response to platinum, according to Tesaro Inc., niraparibs sponsor. Niraparib is an oral, once-daily PARP inhibitor. ...
This patients deletion of the entire BRCA1 gene and a larger region of chromosome 17q is rare, with only a few cases reported in the literature. Her exceptional response to multiple lines of platinum-based combination chemotherapy and subsequent ongoing complete response to PARP inhibition with olaparib are also unusual. Although prognosis after an OC diagnosis may be poor for some patients, others have experienced long-term survival.8 Long-term survivors display favorable clinical features, including optimal cytoreductive surgery at diagnosis and platinum-sensitive disease indicated by a recurrence-free interval of ,12 months after first-line chemotherapy.9 In addition, patients with germline BRCA mutations have clinical characteristics different from those of women with non-BRCA-related OCs, including younger age at presentation, high-grade histology, advanced stage at diagnosis, and better response to platinum-based chemotherapy.10 Large germline genomic rearrangements of BRCA1 or BRCA2 ...
4536 Germline mutations in the BRCA1 and BRCA2 tumor suppressor genes are highly penetrant for breast/ovarian cancer, and genetic testing is routinely recommended to patients with strong family histories. The contribution of hereditary breast cancers is generally 5-10% of all breast cancer cases, but the frequency and spectrum of BRCA1/2 germline mutations may vary in different ethnic populations. Breast cancer is less common in Africans and African Americans than other populations, yet its occurrence is associated with histopathological features similar to those in BRCA1 mutation carriers. To address whether this similarity results from a distinctive contribution of BRCA1/2-associated disease, we performed complete sequence analysis of the BRCA1 and BRCA2 exons and regions near intron/exon boundaries in a population of Nigerian breast cancer patients unselected for family history or age of disease onset. We identified 17/270 (6.3%, 95% confidence interval (CI) = 3.7%-9.9%) patients heterozygous ...
What should BRCA1 and BRCA2 carriers do with this information? Dr. Angela Bradbury shares her perspective related to the options for BRCA carriers.
Selected aspects of genetic counselling for BRCA1mutation carriers : This work consists of six parts based on seven manuscripts dealing with some aspects of genetic counselling for BRCA1 mutation carriers. It was demonstrated that the risk of breast and ovarian cancer in first-degree relatives of BRCA1 mutation carriers depends on the type of mutation and is higher in the younger generation. It was also shown that risk of breast cancer, but not of ovarian cancer,
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Risk for aggressive serous/serous-like endometrial cancer was increased in women with BRCA1 mutations, although the overall risk for uterine cancer after risk-reducing salpingo-oophorectomy (RRSO) to remove the fallopian tube and ovary was not increased, according to a new study published online by JAMA Oncology.. RRSO is part of the standard treatment for women with BRCA mutations but the role of accompanying hysterectomy remains controversial. Clarifying the issue is relevant because serous/serous-like subtypes account for only about 10% of uterine cancer cases but more than 40% of deaths due to the disease.. Noah D. Kauff, M.D., of the Duke University Health System, Durham, N.C., and coauthors looked at the risk of uterine cancer after RRSO in women with mutations in the BRAC1 and BRCA2 gene. The study included 1,083 women without a prior or associated hysterectomy. 67.1% had a history of breast cancer and 29.4% of 928 women with data available had used tamoxifen.. Researchers documented ...
In 2013, Hollywood star Angelina Jolie announced she had had both breasts surgically removed as a preventative measure after tests revealed she carried the mutation, despite not having been diagnosed with cancer. Lynparza has the broadest clinical development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to deliver Lynparza as quickly as possible to more patients across multiple settings, including breast, ovarian, prostate and pancreatic cancers.. According to the American Cancer Society, women with a mutation in the BRCA1 or BRCA2 genes have a seven-in-10 chance of getting breast cancer by the age of 80.. For the new study, Eccles and a team recruited 2,733 British women aged 18-40 who had been diagnosed with breast cancer between 2000 and 2008.. About 12 percent of the patients had a BRCA mutation, yet again confirming the association between this faulty gene and breast cancer. In the trial, olaparib significantly prolonged progression-free survival (PFS) ...
The BRCA gene test analyses DNA to look for harmful mutations in two breast cancer genes (BRCA1 or BRCA2). This test is performed as a routine blood test. The test should only be performed on patients who have specific types of breast cancers or have a family history suggesting the possibility of having an inherited mutation.
Recognition of early changes in the Fallopian tube cells of BRCA gene mutation carriers may be key to new strategies for preventing ovarian cancer that could also reduce the need for invasive surgery.
The clinical role of BRCA1 and BRCA2 mutation testing for younger women with breast cancer is in rapid transition because of advances in gene sequencing technologies and accumulating evidence for the contribution of BRCA mutation status to acute management of early breast cancer. Women diagnosed with breast cancer are offered genetic counseling and testing for germline mutations in BRCA1 and BRCA2 if they have a strong family history of the disease and/or they meet other criteria which point to a mutation detection rate that exceeds a predefined threshold for her local service. Genetic risk assessment has usually been offered on completion of surgery and adjuvant therapy for a new breast cancer, and routine genetic test results in Australia has to date taken between one and six months from blood draw. In contrast, genetic counseling and testing offered around the time of breast cancer diagnosis aims to provide the patient with genetic information that will assist in the choice of breast cancer ...
The stock of Martin Midstream Partners L.P. (NASDAQ: MMLP ) has Hold rating given on Thursday, September 14 by Stifel Nicolaus. Investors look at the Volatility 12m to determine if a company has a low volatility percentage or not over the course of a year. Having a faulty BRCA gene - either BRCA1 or BRCA2 - is known to increase a womans risk of breast cancer.. When those results were published last June, Mark Robson, an oncologist at Memorial Sloan Kettering Cancer Center who led the multisite trial, described the treatment as an early chapter in a womans journey dealing with breast cancer - one that can delay the start of chemotherapy and help preserve her quality of life.. Some women have previously chose to take preventative measures, such as pre-emptive mastectomies, when they discover they have faulty genes.. Clovis PARP inhibitor Rubraca (rucaparib) was approved in the U.S.in late 2016 for advanced ovarian cancer patients who have received at least two prior lines of chemo and whose ...
Mutations in BRCA1 or BRCA2 (BRCA) are common in patients with high-grade serous ovarian carcinomas, and, when the wild-type allele is lost, BRCA mutations can impair DNA-damage repair by homologous recombination, leading to deletion or duplication of chromosomal regions, which is termed genomic loss of heterozygosity (LOH). Homologous recombination-deficient tumors are sensitive to PARP inhibitors such as rucaparib, but although homologous recombination deficiencies can also occur in ovarian tumors without BRCA mutations, molecular predictors of rucaparib sensitivity in BRCA wild-type tumors have not been identified. Swisher, Lin, and colleagues hypothesized that genomic LOH might predict homologous recombination deficiency and rucaparib sensitivity and enrolled 206 patients in an open-label phase II trial of rucaparib in patients with relapsed, platinum-sensitive, high-grade ovarian carcinoma. In total, 192 patients could be classified into subgroups: 40 had BRCA mutations, 82 were BRCA ...
Breast Cancer is very common among Canadians. The Canadian Breast Cancer Foundation reported in 2014 1 in 9 women in Canada is expected to develop breast cancer during her lifetime. Today we are focusing on the genetic aspects of developing breast cancer in the body.. BRCA1 and BRCA2 genes - BRCA1 and BRCA 2 known, as a Breast Cancer Susceptibility Gene 1 and Breast Cancer Susceptibility Gene 2 are human genes and works as tumor suppressors.. How BRCA1 and BRCA2 connect to cancer? When any of those genes mutate, it causes DNA damage and it might not be able to repair properly, and as a results cell can develop additional genetic alterations. Inherited mutations in BRCA1 and BRCA2 then increase the risk of breast and ovarian cancer.. NOTE: BRCA1 and BRCA2 mutations can be inherited from a persons mother or father. Anyone who has inherited a BRCA1 or BRCA2 mutation could be an increase risk of developing breast and ovarian cancer.. Breast cancer statistics - Breast Cancer Society of Canada has ...
In recent years, numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of BRCA1-2 mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of BRCA1-2 germline mutations was also evaluated. Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for BRCA1-2 mutations by DHPLC analysis and DNA sequencing. Association of BRCA1 and BRCA2 mutational status with clinical and pathological parameters was evaluated by Pearsons Chi-Squared test. Overall, 8 BRCA1 and 5 BRCA2 deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in BRCA2 gene. The geographical distribution of BRCA1-2 mutations was related to
Germline mutations in the genes BRCA1 and BRCA2 have been demonstrated in the majority of hereditary breast and ovarian cancer families. The increased risk to develop both breast and ovarian cancer associated with inheriting a BRCA1 or BRCA2 mutation has been well established. It has also been suggested that is an overrepresentation of other cancers such as colon, prostate and pancreatic cancer present in BRCA1 or BRCA2 families. Population specific mutations in BRCA1 and BRCA2 have been identified. In the Ashkenazi Jewish population, 3 specific mutations have been seen in 2% of the population. This study will anonymously screen archived tissue samples of Ashkenazi Jewish individuals diagnosed with cancer between 1993 and 1996 at MSKCC for the three founder mutations seen in the Ashkenazi Jewish population. Results will be stratified by tumor type and compared with the population frequency to determine whether individuals inheriting mutations in BRCA1 or BRCA2 may have an increased risk to ...
Background: While BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 polymorphisms SNP309T>G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer.. G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer.. C in Norwegian patients with BRCA related ovarian cancer.. Methods: 221 BRCA related ovarian cancer cases (BRCA1; n = 161 and BRCA2; n = 60) were tested for the MDM2 polymorphisms. Results were compared to healthy controls (n = 2,465).. Results: The SNP309G allele was associated with elevated OR for ovarian cancer in BRCA1 mutation carriers (SNP309TG: OR 1.53; CI 1.07-2.19; p = 0.020; SNP309GG: OR 1.92; CI 1.19-3.10; p = 0.009; SNP309TG+GG combined: OR 1.61; CI 1.15-2.27; p = 0.005). In contrast, the SNP285C allele reduced risk of BRCA1 related ...
TY - JOUR. T1 - Inhibition of BRCT(BRCA1)-phosphoprotein interaction enhances the cytotoxic effect of olaparib in breast cancer cells. T2 - A proof of concept study for synthetic lethal therapeutic option. AU - Pessetto, Ziyan Yuan. AU - Yan, Ying. AU - Bessho, Tadayoshi. AU - Natarajan, Amarnath. PY - 2012/7. Y1 - 2012/7. N2 - Synthetic lethal therapeutic strategy using poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor olaparib in carriers of BRCA1 or BRCA2 mutation has shown promise in clinical settings. Since ≤5 % of patients are BRCA1 or BRCA2 mutation carriers, small molecules that functionally mimic BRCA1 or BRCA2 mutations will extend the synthetic lethal therapeutic option for non-mutation carriers. Here we provide proof of principle for this strategy using a BRCA1 inhibitor peptide 2 that targets the BRCT(BRCA1)-phosphoprotein interaction and mimics the M177R/K BRCA1 mutation. Reciprocal immunoprecipitation and immunoblotting of BRCA1 and Abraxas was used to ...
TY - JOUR. T1 - Hereditary breast cancer. T2 - Part II. Management of hereditary breast cancer: Implications of molecular genetics and pathology. AU - Silva, Edibaldo. AU - Gatalica, Zoran. AU - Snyder, Carrie. AU - Vranic, Semir. AU - Lynch, Jane F.. AU - Lynch, Henry T.. N1 - Copyright: Copyright 2008 Elsevier B.V., All rights reserved.. PY - 2008/1. Y1 - 2008/1. N2 - Management of patients at high risk for hereditary breast cancer (HBC) must critically assess its phenotypic and genotypic heterogeneity, particularly evidenced by the varying spectra of cancer sites that are integral to the respective HBC syndromes. Targeted management must consider their biology, pathology, and molecular genetics, all in concert with their respective carcinogenic pathways, as they may differ significantly from one breast cancer syndrome to the next. A striking example of management differences pertains to BRCA1 and BRCA2 mutation-positive breast cancers wherein those with BRCA1 mutations are frequently estrogen ...
About 5% to 10% of breast cancers are thought to be hereditary, caused by abnormal genes passed from parent to child.. Genes are particles in cells, contained in chromosomes, and made of DNA (deoxyribonucleic acid). DNA contains the instructions for building proteins. And proteins control the structure and function of all the cells that make up your body.. Most inherited cases of breast cancer are associated with two abnormal 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 cells growing normally. But when these genes contain abnormalities or mutations that are passed from generation to generation, the genes dont function normally and breast cancer risk increases. Abnormal BRCA1 and BRCA2 genes may account for up to 10% of all breast cancers, or 1 out of every 10 cases.. Having an abnormal BRCA1 or BRCA2 gene doesnt mean you will be diagnosed with breast cancer. ...
Given that breast cancers in germline BRCA1 carriers are predominantly estrogen-negative and triple-negative, it has been suggested that women diagnosed with triple-negative breast cancer (TNBC) younger than 50 years should be offered BRCA1 testing, regardless of family cancer characteristics. However, the predictive value of triple-negative breast cancer, when taken in the context of personal and family cancer characteristics, is unknown. The aim of this study was to determine whether TNBC is a predictor of germline BRCA1 mutations, in the context of multiple predictive factors. Germline mutations in BRCA1 and BRCA2 were analyzed by Sanger sequencing and multiple ligation-dependent probe amplification (MLPA) analysis in 431 women from the Malaysian Breast Cancer Genetic Study, including 110 women with TNBC. Logistic regression was used to identify and to estimate the predictive strength of major determinants. Estrogen receptor (ER) and phosphatase and tensin homologue (PTEN) status were assessed and
TY - JOUR. T1 - Benefits and costs of screening Ashkenazi Jewish women for BRCA1 and BRCA2. AU - Grann, Victor R.. AU - Whang, William. AU - Jacobson, Judith S.. AU - Heitjan, Daniel F.. AU - Antman, Karen H.. AU - Neugut, Alfred I.. PY - 1999/2. Y1 - 1999/2. N2 - Purpose: To determine the survival benefit and cost-effectiveness of screening Ashkenazi Jewish women for three specific BRCA 1/2 gene mutations. Methods: We used a Markov model and Monte Carlo analysis to estimate the survival benefit and cost-effectiveness of screening for three specific mutations in a population in which their prevalence is 2.5% and the associated cancer risks are 56% for breast cancer and 16% for ovarian cancer. We assumed that the sensitivity and specificity of the test were 98% and 99%, respectively, that bilateral prophylactic oophorectomy would reduce ovarian cancer risk by 45%, and that bilateral prophylactic mastectomy would reduce breast cancer risk by 90%. We used Medicare payment data far treatment costs ...
Given how BRCA2 is believed to function as a tumour suppressor, assays related to DNA repair are directly relevant to predicting the impact of BRCA2 variants on cancer risk and therapeutic response. Additionally, such assays have demonstrated high sensitivity and specificity for predicting known benign and pathogenic variants. For these reasons, DNA repair-related assays are considered here.21 Since DNA repair-related domains are distributed throughout BRCA2, as discussed earlier, such assays should be based on expression of full-length BRCA2. BRCA2 is even larger than BRCA1 (the protein is ~390 kDa and the cDNA is 10 254 bp). Thus, it has been difficult to express full-length BRCA2 in human cells using a cDNA.69 73 As such, some functional studies of BRCA2 VUS have been based on heterologous expression of full-length BRCA2 variants in mouse ESCs using BACs.71 72 These studies, in the laboratory of Shyam Sharan, focused on VUS in the N-terminal PALB2-binding domain and the C-terminal DBD, where ...
SNPedia currently contains 2606 BRCA1 SNPs and 3099 BRCA2 SNPs. Some of the variations in these genes are linked to Breast cancer and ovarian cancer, and other variations are benign. See also BRCA1 and BRCA2 for individual gene discussions and links. Microarray platforms used by DTC genomics testing companies such as FamilyTree DNA and 23andMe usually test a fraction of the known BRCA1 or BRCA2 SNPs, typically, the most common ones. While DTC genomics testing may lead to useful results, it is not a substitute for the full genetic panel testing or gene sequencing that may be warranted by a family history of breast cancer. The percent of known BRCA1 and BRCA2 syndrome disease-causing mutations that are tested by several companies is shown in the following table: ...
article{ac3c1e27-9238-408a-9002-fb95610acc6d, abstract = {Introduction - A small fraction of breast cancer is the result of germline mutations in the BRCA1 and BRCA2 cancer susceptibility genes. Mutation carriers frequently have a positive family history of breast and ovarian cancer, are often diagnosed at a young age, and may have a higher incidence of double or multiple primary breast tumours than breast cancer patients in general. Objectives - To estimate the prevalence and spectrum of BRCA1 and BRCA2 mutations in young Danish patients affected with bilateral or multifocal breast cancer and to determine the relationship of mutation status to family history of cancer. Subjects - From the files of the Danish Breast Cancer Cooperative Group (DBCG), we selected 119 breast cancer patients diagnosed before the age of 46 years with either bilateral (n=59) or multifocal (n=61) disease. Methods - DNA from the subjects was screened for BRCA1 and BRCA2 mutations using single strand conformation analysis ...
Men with prostate cancer who are carriers of the BRCA2 gene mutation have significantly increased mortality rates.. The study identified 938 families with the BRCA2 mutation, of which 277 (29.5%) contained one or more cases of prostate cancer, with a total of 434 cases. Of these, 67 men were found to carry the familial BRCA2 mutation and 116 were probable mutation carriers. A comparison group of men with the BRCA1 mutation was also identified. Of 1,735 families, 316 contained one or more cases of prostate cancer (18.2%), with a total of 457 cases. Of these, 37 carried the BRCA1 mutation and 82 men were probable carriers. The average age at diagnosis was similar for the two groups.. Survival analysis was performed to establish the overall survival of BRCA2 carriers with prostate cancer and relative survival compared with BRCA1 carriers. The median survival time was 4.0 years for the BRCA2 group compared with 8.0 years for the BRCA1 group, and the risk of mortality was found to be 70% greater in ...
Women harboring heterozygous germline mutations of BRCA2 have a 50-80% risk of developing breast cancer, yet the early pathogenesis of these cancers is poorly understood. To reveal early steps in BRCA2-associated carcinogenesis we analyzed sorted cell populations from freshly-isolated, non-cancerous breast tissues of BRCA2 mutation carriers and matched controls. Single-cell whole-genome sequencing demonstrates that ,25% of BRCA2 carrier (BRCA2mut/+) luminal progenitor (LP) cells exhibit sub-chromosomal copy number variations (CNVs), which are rarely observed in non-carriers. Correspondingly, primary BRCA2mut/+ breast epithelia exhibit spontaneous DNA damage together with attenuated replication checkpoint and apoptotic responses, associated with an age-associated expansion of the LP compartment. We provide evidence that these phenotypes do not require loss of the wild-type BRCA2 allele. Collectively, our findings suggest that BRCA2 haploinsufficiency and associated DNA damage precede histologic ...
TY - JOUR. T1 - p53 mediates repression of the BRCA2 promoter and down-regulation of BRCA2 mRNA and protein levels in response to DNA damage. AU - Wu, Kangjian. AU - Jiang, Shi Wen. AU - Couch, Fergus J.. PY - 2003/5/2. Y1 - 2003/5/2. N2 - Adriamycin and other DNA-damaging agents have been shown to reduce BRCA2 mRNA levels in breast cancer cell lines, but the mechanism by which this occurs is unknown. In this study, we show that adriamycin and mitomycin C, but not other DNA-damaging agents, repress BRCA2 promoter activity in a dose- and time-dependent manner. We demonstrate that the effect is dependent on wild type p53 and that adriamycin and p53 mediate repression of the BRCA2 promoter by inhibiting binding of an upstream stimulatory factor protein complex to the promoter. In addition, we present evidence indicating that adriamycin and other DNA-damaging agents reduce BRCA2 mRNA and protein levels by altering both BRCA2 mRNA stability and protein stability. Thus, BRCA2 levels in the cell are ...
Ataxia-telangiectasia mutation (ATM) has previously been shown to be necessary for the phosphorylation of BRCA1 to occur in response to gamma-irradiation, and capable of directly phosphorylating BRCA1 in vitro (see additional information). This paper indicates that ATM can also cause the phosphorylation of BRCA1 by activating the hCds1/CHK2 kinase, for which BRCA1 is a substrate. Phosphorylation of BRCA1 in response to other genotoxins appears to be independent of ATM (Scully et al, Cell 1997, 90: 425-435 [Abstract]). ATM-independent activation of hCds1/CHK2 may explain how some of these other genotoxins cause BRCA1 phosphorylation.. The ATM-hCds1/CHK2-BRCA1 DNA damage response pathway is clearly important for tumour suppression since heterozygous carriers of mutant BRCA1, ATM and hCds1/hCHK2 genes (see additional information) have all been reported to be predisposed to breast cancer. ...
Consistent with previous reports, we observed somatic or germline mutations in the BRCA1 and BRCA2 genes associated with a large proportion of HGSC tumors, and these were almost completely mutually exclusive. Mutual exclusivity may reflect a functional equivalence of the mutations, in which there is no selective advantage to a tumor cell by possessing more than one defect in the BRCA pathway. Sensitivity to platinum-based therapy in the primary (28) and relapse setting (8), as well as significant responses to PARP inhibitors (29) are all consistent with the notion of a shared BRCAness phenotype of tumors arising in BRCA1/2 carriers (30). However, recent evidence points to important clinical and pathologic differences in the behavior of tumors arising in women with BRCA1 compared with BRCA2 mutations.. Although both genes encode proteins that participate in the HRR pathway, BRCA1 has both an earlier and wider role in DNA damage response (31-33) and additional cellular functions, including ...
TY - JOUR. T1 - Strategies for recruitment of relatives of BRCA mutation carriers to a genetic testing program in the Bahamas. AU - Trottier, M.. AU - Lunn, J.. AU - Butler, R.. AU - Curling, D.. AU - Turnquest, T.. AU - Royer, R.. AU - Akbari, M. R.. AU - Donenberg, T.. AU - Hurley, Judith. AU - Narod, S. A.. PY - 2015/8/1. Y1 - 2015/8/1. N2 - The prevalence of BRCA1 and BRCA2 mutations among unselected breast cancer patients in the Bahamas is 23%. It is beneficial to advise relatives of mutation carriers that they are candidates for genetic testing. Women who test positive are then eligible for preventive interventions, such as oophorectomy. It is not clear how often relatives of women with a mutation in the Bahamas wish to undergo genetic testing for the family mutation. Furthermore, it is not clear how best to communicate this sensitive information to relatives in order to maximize patient compliance. We offered genetic testing to 202 first-degree relatives of 58 mutation carriers. Of 159 ...
Introduction: While it has been reported that the risk of contralateral breast cancer in patients from BRCA1 or BRCA2 positive families is elevated, little is known about contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations. Methods: A retrospective, multicenter cohort study was performed from 1996 to 2011 and comprised 6,235 women with unilateral breast cancer from 6,230 high risk families that had tested positive for BRCA1 (n = 1,154) or BRCA2 (n = 575) mutations or tested negative (n = 4,501). Cumulative contralateral breast cancer risks were calculated using the Kaplan-Meier product-limit method and were compared between groups using the log-rank test. Cox regression analysis was applied to assess the impact of the age at first breast cancer and the familial history stratified by mutation status. Results: The cumulative risk of contralateral breast cancer 25 years after first breast cancer was 44.1% (95% CI, 37.6% to 50.6%) for ...
The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific
TY - JOUR. T1 - Routine germline BRCA1 and BRCA2 testing in ovarian carcinoma patients. T2 - analysis of the Scottish real life experience. AU - Rust, Kelly. AU - Spiliopoulou, Pavlina. AU - Tang, Chee Yuan. AU - Bell, Christine. AU - Stirling, Diane. AU - Phang, Tze Hui Fifi. AU - Davidson, Rosemarie. AU - Mackean, Melanie. AU - Nussey, Fiona. AU - Glasspool, Ros. AU - Reed, Nick. AU - Sadozye, Azmat. AU - Porteous, Mary. AU - McGoldrick, Trevor. AU - Ferguson, Michelle. AU - Miedzybrodzka, Zofia. AU - McNeish, Iain A. AU - Gourley, Charlie. N1 - Funding Information Edinburgh Ovarian Cancer Database Cancer Research UK. PY - 2018/10. Y1 - 2018/10. N2 - OBJECTIVE: To determine the rate of germline BRCA1 and BRCA2 mutations in Scottish ovarian cancer patients before and after a change in testing policy.DESIGN: Retrospective cohort study.SETTING: Four cancer/genetics centres in Scotland.POPULATION: Ovarian cancer patients undergoing germline BRCA1 and BRCA2 (gBRCA1/2) gene sequencing before 2013 ...
TY - JOUR. T1 - The prevalence and spectrum of BRCA1 and BRCA2 mutations in Korean population. T2 - recent update of the Korean Hereditary Breast Cancer (KOHBRA) study. AU - Kang, Eunyoung. AU - Seong, Moon Woo. AU - Park, Sue K.. AU - Lee, Jong Won. AU - Lee, Jihyoun. AU - Kim, Lee Su. AU - Lee, Jeong Eon. AU - Kim, Sung Yong. AU - Jeong, Joon. AU - Han, Sang Ah. AU - Kim, Sung Won. AU - Korean Hereditary Breast Cancer Study Group, Hereditary Breast Cancer Study Group. AU - Kwak, Beom Seok. AU - Park, Byeong Woo. AU - Son, Byung Ho. AU - Moon, Byung In. AU - Yom, Cha Kyong. AU - Park, Chan Heun. AU - Yoon, Chan Seok. AU - Lee, Chang Hyun. AU - Yoon, Dae Sung. AU - Noh, Dong Young. AU - Choi, Doo Ho. AU - Chang, Eundeok. AU - Kim, Eun Kyu. AU - Kang, Eunyoung. AU - Lee, Hae Kyung. AU - Park, Hai Lin. AU - Lee, Hyde. AU - Moon, Hyeong Gon. AU - Kim, Hyun Ah. AU - Lee, Il Kyun. AU - Lee, Jeong Eon. AU - Lee, Jihyoun. AU - Lee, Jong Won. AU - Yu, Jong Han. AU - Jeong, Joon. AU - Yoon, Jung ...
Abnormalities caused by targeted disruption of the Brca2 gene include increased sensitivity to DNA damage induced by ionizing irradiation, UV light, and other genotoxic agents (27, 33, 34). The accumulation of double-strand DNA breaks and chromosomal abnormalities combined with the lack of obvious checkpoint or apoptotic response abnormalities in Brca2 mutant cells have implied a role of BRCA2 in DNA repair (33, 34). Recent findings that BRCA2 and RAD51 interact in vitro have suggested further that BRCA2 may be involved in RAD51-mediated repair pathways (27, 35, 36). In this study, we identified the BRCA2 gene product as a 460-kDa nuclear phosphoprotein that forms a complex with RAD51 in vivo. While this manuscript was in preparation, Chen et al. (44) reported detection of BRCA2 as a nuclear protein, consistent with our findings. They also reported detection of immunocomplexes containing BRCA2 and RAD51 (44). Our findings established that a major fraction of endogenous RAD51 is associated with ...
article{81b520fa-fde6-40e1-9977-b09909f3e717, abstract = {Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose carriers to breast and ovarian cancer. The authors have identified a mutation in BRCA2, 7845+1G > A (c.7617+1G > A), not previously regarded as deleterious because of incorrect mapping of the splice junction in the originally published genomic reference sequence. This reference sequence is generally used in many laboratories and it maps the mutation 16 base pairs inside intron 15. However, according to the recent reference sequences the mutation is located in the consensus donor splice sequence. By reverse transcriptase analysis, loss of exon 15 in the final transcript interrupting the open reading frame was demonstrated. Furthermore, the mutation segregates with a cancer phenotype in 18 Danish families. By genetic analysis of more than 3,500 Danish breast/ovarian cancer risk families, the mutation was identified as the most common BRCA2 mutation in West ...
Mutation of BRCA1 and BRCA2 is the most common cause of inherited breast and ovarian cancer. Genetic screens to detect carriers of variants can aid in cancer prevention by identifying individuals with a greater cancer risk and can potentially be used to predict the responsiveness of tumours to therapy. Frequently, classification cannot be performed based on traditional approaches such as segregation analyses, including for many missense variants, which are therefore referred to as variants of uncertain significance (VUS). Functional assays provide an important alternative for classification of BRCA1 and BRCA2 VUS. As reviewed here, both of these tumour suppressors promote the maintenance of genome stability via homologous recombination. Thus, related assays may be particularly relevant to cancer risk. Progress in implementing functional assays to assess missense variants of BRCA1 and BRCA2 is considered here, along with current limitations and the path to more impactful assay systems. While ...
The BRCA2 and MRE11 proteins participate in the repair of double-strand DNA breaks by homologous recombination. Germline BRCA2 mutations predispose to ovarian, breast and pancreatic cancer, while a germline MRE11 mutation is associated with an ataxia telangiectasia-like disorder. Somatic mutations of BRCA2 are rare in typical sporadic cancers. In tumors having microsatellite instability (MSI), somatic truncating mutations in a poly [A] tract of BRCA2 are reported on occasion. We analyzed gastrointestinal MSI cancers by whole gene BRCA2 sequencing, finding heterozygous truncating mutations in seven (47%) of 15 patients. There was no cellular functional defect in RAD51 focus-formation in three heterozygously mutated lines studied, although other potential functions of the BRCA2 protein could still be affected. A prior report of mutations in primary MSI tumors affecting the IVS5-(5-15) poly [T] tract of the MRE11 gene was confirmed and extended by analysis of the genomic sequence and protein expression in
A womans lifetime chance of developing breast and/or ovarian cancer is greatly increased if she inherits an altered BRCA1 or BRCA2 gene. Women with an inherited alteration in one of these genes have an increased risk of developing these cancers at a young age (before menopause), and often have multiple close family members with the disease. These women may also have an increased chance of developing colon cancer. Men with an altered BRCA1 or BRCA2 gene also have an increased risk of breast cancer (primarily if the alteration is in BRCA2), and possibly prostate cancer. Alterations in the BRCA2 gene have also been associated with an increased risk of lymphoma, melanoma, and cancers of the pancreas, gallbladder, bile duct, and stomach in some men and women.. According to estimates of lifetime risk, about 13.2 percent (132 out of 1,000 individuals) of women in the general population will develop breast cancer, compared with estimates of 36 to 85 percent (360-850 out of 1,000) of women with an ...
To explore the relation of BRCA1 to these foci, we assayed, for IRIF (17), HCC1937 cells that express a COOH-terminally truncated BRCA1 protein (19). BRCA1 foci were diminished in these cells, and the nuclear staining of BRCA1 was homogenous, albeit much dimmer, in HCC1937 cells regardless of treatment (Fig. 3B). Interestingly, hRad50, hMre11, and p95 IRIF were dramatically reduced in HCC1937 cells. Most of the irradiated cells displayed a diffuse nuclear pattern of hRad50, hMre11, or p95 immunostaining similar to that seen in untreated HCC1937 cells. In contrast, IRIF that were positive for hRad51 antibodies were readily and efficiently detected in both T24 and HCC1937 cells (Fig. 3B).. In addition to BRCA1 mutation, HCC1937 also harbors many other genetic changes (19). To determine whether the BRCA1 deficiency was responsible for the defect in IRIF formation, we transiently transfected hemagglutinin (HA)-tagged wild-type BRCA1 into HCC1937 cells and irradiated cells 40 hours later. Of the ...
TY - JOUR. T1 - Efficacy versus effectiveness of clinical genetic testing criteria for BRCA1 and BRCA2 hereditary mutations in incident breast cancer. AU - Nilsson, Martin P.. AU - Winter, Christof. AU - Kristoffersson, Ulf. AU - Rehn, Martin. AU - Larsson, Christer. AU - Saal, Lao H.. AU - Loman, Niklas. PY - 2017/4. Y1 - 2017/4. N2 - Increasing evidence supports the benefit of identifying BRCA1 and BRCA2 germline mutations in early breast cancer. Selection of patients for genetic testing is based on defined criteria taking individual and family history related factors into account. It is important to make a distinction between efficacy and effectiveness of BRCA testing criteria. Efficacy can be defined as the performance under ideal circumstances, whereas effectiveness refers to its real life performance. To allow for an unbiased and detailed evaluation of efficacy and effectiveness of the Swedish BRCA testing criteria, we retrospectively analyzed a prospectively collected cohort of 273 breast ...
Loss of heterozygosity data from familial tumors suggest that BRCA1, a gene that confers susceptibility to ovarian and early-onset breast cancer, encodes a tumor suppressor. The BRCA1 region is also subject to allelic loss in sporadic breast and ovarian cancers, an indication that BRCA1 mutations may occur somatically in these tumors. The BRCA1 coding region was examined for mutations in primary breast and ovarian tumors that show allele loss at the BRCA1 locus. Mutations were detected in 3 of 32 breast and 1 of 12 ovarian carcinomas; all four mutations were germline alterations and occurred in early-onset cancers. These results suggest that mutation of BRCA1 may not be critical in the development of the majority of breast and ovarian cancers that arise in the absence of a mutant germline allele ...
The breast cancer susceptibility gene 1 (BRCA1) has been well established as a tumor suppressor and functions primarily by maintaining genome integrity. Genome stability is compromised when cells are exposed to oxidative stress. Increasing evidence suggests that BRCA1 regulates oxidative stress and this may be another mechanism in preventing carcinogenesis in normal cells. Oxidative stress caused by reactive oxygen species (ROS) is implicated in carcinogenesis and is used strategically to treat human cancer. Thus, it is essential to understand the function of BRCA1 in oxidative stress regulation. In this review, we briefly summarize BRCA1s many binding partners and mechanisms, and discuss data supporting the function of BRCA1 in oxidative stress regulation. Finally, we consider its significance in prevention and/or treatment of BRCA1-related cancers.
The breast cancer susceptibility gene 1 (BRCA1) has been well established as a tumor suppressor and functions primarily by maintaining genome integrity. Genome stability is compromised when cells are exposed to oxidative stress. Increasing evidence suggests that BRCA1 regulates oxidative stress and this may be another mechanism in preventing carcinogenesis in normal cells. Oxidative stress caused by reactive oxygen species (ROS) is implicated in carcinogenesis and is used strategically to treat human cancer. Thus, it is essential to understand the function of BRCA1 in oxidative stress regulation. In this review, we briefly summarize BRCA1s many binding partners and mechanisms, and discuss data supporting the function of BRCA1 in oxidative stress regulation. Finally, we consider its significance in prevention and/or treatment of BRCA1-related cancers.
our genes, which can prevent tumors from forming. When they are functioning properly, they are considered to be tumor suppressors. When mutations occur in the BRCA genes, their function is disrupted. They cannot effectively repair DNA damage, and defects accumulate, making cells more prone to cancer.. Mutations in BRCA are often inherited and people who have them are at increased risk for breast cancer - called inherited breast cancer. But BRCA mutations can also occur sporadically (not inherited). 15-25% of inherited breast cancers are a result of BRCA mutations; however, not all people with the BRCA mutation will get breast cancer.. ...
article{8622899, abstract = {BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in ...
Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04
Cancer is in essence a genetic disease, brought about by an accumulation of alterations in genes that encode proteins responsible for the control of cell growth, cell death and the maintenance of genomic integrity. Recent years have seen the unravelling of numerous genes that are targeted in carcinogenesis. Although several genes implicated in breast cancer have been identified, a substantial proportion of breast cancer cases is not linked to any definite gene, implying that more gene targets remain to be discovered. Based on clinicopathological differences observed between early and late onset breast cancers, it has been proposed that they may be biologically different with separate genetic origins and/or development. The work included in this thesis was initiated with the intent to identify some of the genetic aberrations that characterise early onset breast cancer.. The p53 protein is central in cell cycle control and alterations in its gene sequence are among the most commonly observed ...
Title:BRCA1 as Target for Breast Cancer Prevention and Therapy. VOLUME: 15 ISSUE: 1. Author(s):Alberto P.G. Romagnolo, Donato F. Romagnolo and Ornella I. Selmin. Affiliation:University of Arizona Cancer Center, 1515 N. Campbell, Room 3999A, Tucson, AZ 85724, USA.. Keywords:Breast Cancer, BRCA1, diet, gene regulation, prevention, therapy.. Abstract:The Breast Cancer 1 protein (BRCA1) is a tumor suppressor involved in basic cellular functions necessary for cell replication and DNA synthesis, but reduced expression of BRCA1, due to mutations or epigenetic inactivation, leads to impaired mammary gland differentiation and increased risk of breast cancer development. Although BRCA1 acts as a tumor suppressor and is present in all cells, where it is essential for the maintenance of the genome integrity, it is still not clear why mutations in the BRCA1 gene predispose to breast and ovarian, but not to other types of cancer. In the first part of this review, we briefly discuss the function and regulation ...
The underlying mechanism behind age-induced wastage of the human ovarian follicle reserve is unknown. We identify impaired ATM (ataxia-telangiectasia mutated)-mediated DNA double-strand break (DSB) repair as a cause of aging in mouse and human oocytes. We show that DSBs accumulate in primordial follicles with age. In parallel, expression of key DNA DSB repair genes BRCA1, MRE11, Rad51, and ATM, but not BRCA2, declines in single mouse and human oocytes. In Brca1-deficient mice, reproductive capacity was impaired, primordial follicle counts were lower, and DSBs were increased in remaining follicles with age relative to wild-type mice. Furthermore, oocyte-specific knockdown of Brca1, MRE11, Rad51, and ATM expression increased DSBs and reduced survival, whereas Brca1 overexpression enhanced both parameters. Likewise, ovarian reserve was impaired in young women with germline BRCA1 mutations compared to controls as determined by serum concentrations of anti-Müllerian hormone. These data implicate DNA ...
BRCA1 and BRCA2 are important breast and ovarian cancer susceptibility genes, and mutations in these two genes confer lifetime risks of breast cancer of up to 80% and ovarian cancer risks of up to 40%. Clinico-pathological studies have identified features that are specific to BRCA1-related breast ca …
Recent gene expression profiling of breast cancer has identified specific subtypes with clinical, biologic, and therapeutic implications. The basal-like group of tumors is associated with aggressive behavior and poor prognosis, and typically do not express hormone receptors or HER-2 (triple-negative phenotype). Therefore, patients with basal-like cancers do not benefit from currently available targeted systemic therapy.. There is a lot of evidence about a link between basal-like breast cancer and BRCA1 deficiency. Many clinical characteristics and molecular features are shared by basal-like breast cancers and tumors that arise in carriers of BRCA1 germline mutations.. Some studies have indicated that BRCA1 mRNA expression was lower in basal-like sporadic cancers than in controls matched for age and grade. BRCA1 is rarely mutated in sporadic breast cancers and, therefore, it is believed that this may be a result of epigenetic mechanisms such as acquired methylation of the BRCA1 gene promoter or ...
Breast cancer 1, early onset (BRCA1) expression is often reduced in sporadic breast tumors, even in the absence of BRCA1 genetic modifications, but the molecular basis for this is unknown. In this study, we identified homeobox A9 (HOXA9) as a gene frequently downregulated in human breast cancers and tumor cell lines and noted that reduced HOXA9 transcript levels associated with tumor aggression, metastasis, and patient mortality. Experiments revealed that loss of HOXA9 promoted mammary epithelial cell growth and survival and perturbed tissue morphogenesis. Restoring HOXA9 expression repressed growth and survival and inhibited the malignant phenotype of breast cancer cells in culture and in a xenograft mouse model. Molecular studies showed that HOXA9 restricted breast tumor behavior by directly modulating the expression of BRCA1. Indeed, ectopic expression of wild-type BRCA1 phenocopied the tumor suppressor function of HOXA9, and reducing BRCA1 levels or function inhibited the antitumor activity ...
Breast cancer 1, early onset (BRCA1) expression is often reduced in sporadic breast tumors, even in the absence of BRCA1 genetic modifications, but the molecular basis for this is unknown. In this study, we identified homeobox A9 (HOXA9) as a gene frequently downregulated in human breast cancers and tumor cell lines and noted that reduced HOXA9 transcript levels associated with tumor aggression, metastasis, and patient mortality. Experiments revealed that loss of HOXA9 promoted mammary epithelial cell growth and survival and perturbed tissue morphogenesis. Restoring HOXA9 expression repressed growth and survival and inhibited the malignant phenotype of breast cancer cells in culture and in a xenograft mouse model. Molecular studies showed that HOXA9 restricted breast tumor behavior by directly modulating the expression of BRCA1. Indeed, ectopic expression of wild-type BRCA1 phenocopied the tumor suppressor function of HOXA9, and reducing BRCA1 levels or function inhibited the antitumor activity ...