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 ...
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 ...
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 ...
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
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 ...
This study confirms previous reports that BRCA2 mutation carriers have an increased risk of developing pancreatic cancer compared with the general population. It also supports previous evidence that BRCA1 mutation carriers have increased pancreatic cancer risk, but with a higher relative risk than that estimated by other studies. Furthermore, the availability of a large number of high-risk pancreatic cancer families negative for BRCA1 and BRCA2 mutations (∼5,200) has provided a unique opportunity to estimate pancreatic cancer risk in non-mutation carriers from families with breast and ovarian cancer.. The association between BRCA2 mutations and pancreatic cancer risk has been previously investigated; individuals from BRCA2 mutation carrier families have been reported to have a pancreatic cancer risk ranging from 2- to 7-fold higher than general population (14,16,17,24). In our study, we observed a relative risk of 5.79 (95% CI, 4.28-7.84), slightly higher than most previous estimates. Unlike ...
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).
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. ...
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. ...
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 ...
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 ...
There are a few genes that have been linked to high breast and ovarian cancer risk when theyre abnormal, or have a mutation.. Two of those genes are BRCA1 and BRCA2.. Most women have inherited BRCA genes without mutations. And even most women who develop breast cancer have "normal" BRCA genes. But, if you have inherited a BRCA gene with a mutation, it affects how the gene works. And youre at a much higher risk for developing breast, and ovarian, cancer than other women.. A genetic test can help you find out if you have BRCA mutations. But its recommended only if you have factors in your family that indicate an increased inherited risk for breast cancer. A genetic counselor can help you decide if getting tested for BRCA gene mutations is a good idea for you. ...
In families of patients with and without BRCA1 mutations, breast and ovarian cancer risks correlate with the patients cancer site. Moreover, in families of breast cancer patients without BRCA mutations, breast cancer risk depends on the patients age at diagnosis. These patterns support the presenc …
LOS ANGELES - Understanding the underlying genetic weakness of certain types of cancer may lead to targeted therapy and provide the key to effective treatment, a new study suggests. An international consortium of researchers has shown that an investigational drug, Olaparib, can reduce the size of tumors in women with advanced hereditary ovarian cancer with BRCA gene mutations. The Phase II ovarian cancer study results - as well as another Phase II trial in which Cedars-Sinai researchers also participated that evaluated the drugs effectiveness in the treatment of hereditary breast cancer - were published in a recent issue of Lancet. The two trials showed similar levels of response to the genetically-targeted drug in both breast and ovarian cancers with BRCA mutations. "These are significant new studies. Olaparib is the first single-agent, non-chemotherapy treatment to show benefit to patients with cancers that result from BRCA1 or BRCA2 gene mutations," said William Audeh, M.D., an oncologist ...
Hereditary Cancer Syndromes can be caused by faulty changes in genes called as "Hereditary Mutations." These can be passed down from parent to child and cause cancer to run in the family, making it a Hereditary Cancer. Women who carry a mutation in either of BRCA genes have a condition called Hereditary Breast Ovarian Cancers (HBOC) syndrome. Approximately 10-15 percent of Ovarian cancer cases and 10 percent of Breast cancer cases are caused by mutations in the BRCA1 or BRCA2 genes. Some more genes have also been found to be responsible for Hereditary Breast or Ovarian Cancer. In addition, mutation carriers who have already been diagnosed with cancer have a significantly increased risk of developing a second cancer in the future.. Lynch Syndrome is also called Hereditary Non Polyposis Colon Cancer (HNPCC). It caused by mutations in the MLH1, MSH2, MSH6 , PMS2 or EPCAM genes.. Out of 10 people with Lynch syndrome, between 7 to 9 people develop bowel cancer. People with Lynch syndrome are at ...
Germline BRCA mutation rates in the Latina population are yet to be well described. We aimed to quantitate the rates of referral for genetic testing in qualifyi...
The purpose of the study was to compare breast-conserving therapy (BCT) and mastectomy (M) in BRCA1/2 mutation carriers. Women with invasive breast cancer and a pathogenic mutation in BRCA1 or BRCA2 were included in the study (n = 162). Patients treated with BCT (n = 45) were compared with patients treated with M (n = 118). Endpoints were local recurrence as first recurrence (LR), overall survival (OS), breast cancer death, and distant recurrence. Cumulative incidence was calculated in the presence of competing risks. For calculation of hazard ratios and for multivariable analysis, cause-specific Cox proportional hazards regression was used. Compared to M, BCT was associated with an increased risk of LR in univariable analysis (HR 4.0; 95 % CI 1.6-9.8) and in multivariable analysis adjusting for tumor stage, age, and use of adjuvant chemotherapy (HR 2.9; CI 1.1-7.8). Following M, all local recurrences were seen in the first 5 years after breast cancer diagnosis. Following BCT, the rate of LR ...
TY - JOUR. T1 - BRCA1 wild-type allele modifies risk of ovarian cancer in carriers of BRCA1 germ-line mutations. AU - Ginolhac, Sophie M.. AU - Gad, Sophie. AU - Corbex, Marilys. AU - Bressac-de-Paillerets, Brigitte. AU - Chompret, Agnès. AU - Bignon, Yves Jean. AU - Peyrat, Jean Philippe. AU - Fournier, Joelle. AU - Lasset, Christine. AU - Giraud, Sophie. AU - Muller, Danièle. AU - Fricker, Jean Pierre. AU - Hardouin, Agnès. AU - Berthet, Pascaline. AU - Maugard, Christine. AU - Nogues, Catherine. AU - Lidereau, Rosette. AU - Longy, Michel. AU - Olschwang, Sylviane. AU - Toulas, Christine. AU - Guimbaud, Rosine. AU - Yannoukakos, Drakoulis. AU - Szabo, Csilla. AU - Durocher, Francine. AU - Moisan, Anne Marie. AU - Simard, Jacques. AU - Mazoyer, Sylvie. AU - Lynch, Henry T.. AU - Goldgar, David. AU - Stoppa-Lyonnet, Dominique. AU - Lenoir, Gilbert M.. AU - Sinilnikova, Olga M.. PY - 2003/2/1. Y1 - 2003/2/1. N2 - Strong inter- and intrafamilial variation of penetrance of breast and ovarian ...
ContextWomen with BRCA1 or BRCA2 mutation are often advised to undergo preventive oophorectomy. The effectiveness of this intervention has not been prospectivel
In a study reported in The New England Journal of Medicine, Antonis C. Antoniou, PhD, Reader in Cancer Risk Prediction and Cancer Research UK Senior Cancer Research Fellow at the University of Cambridge, and colleagues identified lifetime risk of breast cancer in families with germline loss-of-function mutations in PALB2.1 Estimated cumulative risk among female mutation carriers was 14% by 50 years of age and 35% by 70 years of age. Compared with risk in the general UK population, risk was increased eight- to ninefold in mutation carriers aged , 40 years, six- to eightfold in those aged 40 to 60 years, and fivefold in those aged , 60 years.. PALB2 (partner and localizer of BRCA2) was first identified as a protein integral to BRCA2 genome caretaker functions and was also found to interact with BRCA1. Monoallelic loss-of-function mutations have been associated with increased risks of breast and pancreatic cancers. These loss-of-function mutations have been identified in persons from many countries ...
article{a9258659-ef2d-45d5-8a04-0d3549499900, abstract = {Previous studies have reported variation in BRCA1 breast and ovarian cancer risks with mutation position, suggesting that mutations toward the 3 end of the gene are associated with lower ovarian cancer risks. We evaluated the evidence for genotype-phenotype correlations in 356 families with protein-truncating BRCA1 mutations. In contrast to previous reports, the ovarian:breast cancer ratio associated with mutations in a central region of the gene (nucleotides 2401-4190) was significantly higher than for other mutations [odds ratio, 1.70 (P = 0.017) compared with nucleotides 1-2400; odds ratio, 1.89 (P = 0.02) compared with nucleotides 4191-end]. The risks of breast and ovarian cancer conferred by mutations in different regions of the gene were estimated separately by conditional maximum likelihood. According to the best fitting model, the breast cancer risk associated with mutations in the central region was found to be significantly ...
Women with a germline BRCA1/2 gene mutation have high risks of developing breast cancer (BC), estimated to range from 45 to 88% for a first BC up to
The breast cancer associated genes BRCA1 and BRCA2 were discovered in 1994 and 1995 respectively. Since then in addition to our understanding how these proteins function in particular reference to DNA repair, enormous amount of knowledge has been gained regarding genetic epidemiology of inherited breast and ovarian cancer, mutation prevalence among different ethnic groups, presence of founder mutations, varying penetrance, genetic testing and potential management options of mutation carriers. This review will focus on the status of understanding of the role of BRCA1 and BRAC2 mutations among Indian women, structure and biology of these two genes, different methods used for mutation detection and different management options available for BRCA1 and BRCA2 mutation carriers ...
The first patient was enrolled on July 8, 2008 and efficacy and safety data were collected up to the data cut-off of March 26, 2010. Patients were enrolled at 6 centres in Canada. Of the 112 patients who gave informed consent 21 patients failed eligibility criteria or withdrew their consent and were not allocated to treatment ...