JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.
Clin. Cancer Res.
PUBLISHED: 11-16-2014
Show Abstract
Hide Abstract
Purpose:To analyse the effect of germline mutations in BRCA1 and BRCA2 on mortality in ovarian cancer patients up to ten years after diagnosis. Experimental Design:We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival-time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analysed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analysed using Fine and Gray model. Results: The combined 10-year overall survival was 30% (95% CI, 28%-31%) for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The hazard ratio for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the hazard ratio was 0.42 at time zero and increased over time (predicted to become greater than one at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors, and to ovarian cancer specific mortality. Conclusions: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and, in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.
Related JoVE Video
Health professionals' evaluation of delivering treatment-focused genetic testing to women newly diagnosed with breast cancer.
Fam. Cancer
PUBLISHED: 11-14-2014
Show Abstract
Hide Abstract
Increasingly, women are offered genetic testing shortly after diagnosis of breast cancer to facilitate decision-making about treatment, often referred to as 'treatment-focused genetic testing' (TFGT). As understanding the attitudes of health professionals is likely to inform its integration into clinical care we surveyed professionals who participated in our TFGT randomized control study. Thirty-six completed surveys were received (response rate 59 %), 15 (42 %) health professionals classified as genetic and 21 (58 %) as non-genetic. Mainly positive experiences with participating in the TFGT trial were reported. The high cost of testing and who could best deliver information about TGFT to the patient were raised as key constraints to implementation of TFGT in usual care. More non-genetic than genetic health professionals (44 vs 8 %) preferred that the surgeon provide the information for decision-making about TFGT. While costs of TFGT itself and the time and effort of staff involved were perceived barriers, as testing costs become lower, it is expected that TFGT will become a routine part of standard clinical care for patients at high genetic risk in the near future.
Related JoVE Video
Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation.
J. Clin. Oncol.
PUBLISHED: 11-05-2014
Show Abstract
Hide Abstract
Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) -associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers.
Related JoVE Video
Patient-derived Xenografts Reveal that Intraductal Carcinoma of the Prostate Is a Prominent Pathology in BRCA2 Mutation Carriers with Prostate Cancer and Correlates with Poor Prognosis.
Eur. Urol.
PUBLISHED: 08-21-2014
Show Abstract
Hide Abstract
Intraductal carcinoma of the prostate (IDC-P) is a distinct clinicopathologic entity associated with aggressive prostate cancer (PCa). PCa patients carrying a breast cancer 2, early onset (BRCA2) germline mutation exhibit highly aggressive tumours with poor prognosis.
Related JoVE Video
Altered Significance of D'Amico Risk Classification in Prostate Cancer Patients linked to a Familial Breast Cancer (kConFab) cohort.
BJU Int.
PUBLISHED: 04-24-2014
Show Abstract
Hide Abstract
To ascertain whether D'Amico risk classification is an accurate discriminator of prostate cancer mortality risk in BRCA2 pathogenic mutation carriers and non-carriers from a familial breast cancer cohort.
Related JoVE Video
Li-Fraumeni syndrome: cancer risk assessment and clinical management.
Nat Rev Clin Oncol
PUBLISHED: 03-18-2014
Show Abstract
Hide Abstract
Carriers of germline mutations in the TP53 gene, encoding the cell-cycle regulator and tumour suppressor p53, have a markedly increased risk of cancer-related morbidity and mortality during both childhood and adulthood, and thus require appropriate and effective cancer risk management. However, the predisposition of such patients to multiorgan tumorigenesis presents a specific challenge for cancer risk management programmes. Herein, we review the clinical implications of germline mutations in TP53 and the evidence for cancer screening and prevention strategies in individuals carrying such mutations, as well as examining the potential psychosocial implications of lifelong management for a ubiquitous cancer risk. In addition, we propose an evidence-based framework for the clinical management of TP53 mutation carriers and provide a platform for addressing the management of other cancer predisposition syndromes that can affect multiple organs.
Related JoVE Video
Connecting patients, researchers and clinical genetics services: the experiences of participants in the Australian Ovarian Cancer Study (AOCS).
Eur. J. Hum. Genet.
PUBLISHED: 03-04-2014
Show Abstract
Hide Abstract
Population-based genetic research may produce information that has clinical implications for participants and their family. Researchers notify participants or their next of kin (NoK) about the availability of genetic information via a notification letter; however, many subsequently do not contact a family cancer centre (FCC) to clarify their genetic status. Therefore, the purpose of this study was to examine research participants' experience of receiving a notification letter and the factors that influenced contact with an FCC. Twenty-five semi-structured interviews were conducted with research participants (n=10) or their NoK (n=15) who had received a notification letter following participation in the Australian Ovarian Cancer Study. There were a number of factors which impacted participants' access to genetic counselling at an FCC. Some participants had unmet information and support needs, which were addressed by their participation in this psychosocial interview study. Recruitment and participation in this study therefore inadvertently increased a number of participants' intention to contact an FCC. For others, participation in this study facilitated access to an FCC. Recommendations are proposed regarding future notification as well as implications for clinical practice. An approach that also provides opportunity to address research participants' support and informational needs before contacting a clinical genetics service as well as practical guidance for accessing genetic services would facilitate timely and smooth access for research participants who are interested in following up clinically relevant genetic test results.European Journal of Human Genetics advance online publication, 14 May 2014; doi:10.1038/ejhg.2014.86.
Related JoVE Video
Molecular correlates of platinum response in human high-grade serous ovarian cancer patient-derived xenografts.
Mol Oncol
PUBLISHED: 01-14-2014
Show Abstract
Hide Abstract
Improvement in the ability to target underlying drivers and vulnerabilities of high-grade serous ovarian cancer (HG-SOC) requires the development of molecularly annotated pre-clinical models reflective of clinical responses.
Related JoVE Video
Targeted Prostate Cancer Screening in BRCA1 and BRCA2 Mutation Carriers: Results from the Initial Screening Round of the IMPACT Study.
Elizabeth K Bancroft, Elizabeth C Page, Elena Castro, Hans Lilja, Andrew Vickers, Daniel Sjoberg, Melissa Assel, Christopher S Foster, Gillian Mitchell, Kate Drew, Lovise Mæhle, Karol Axcrona, D Gareth Evans, Barbara Bulman, Diana Eccles, Donna McBride, Christi van Asperen, Hans Vasen, Lambertus A Kiemeney, Janneke Ringelberg, Cezary Cybulski, Dominika Wokolorczyk, Christina Selkirk, Peter J Hulick, Anders Bojesen, Anne-Bine Skytte, Jimmy Lam, Louise Taylor, Rogier Oldenburg, Ruben Cremers, Gerald Verhaegh, Wendy A van Zelst-Stams, Jan C Oosterwijk, Ignacio Blanco, Mónica Salinas, Jackie Cook, Derek J Rosario, Saundra Buys, Tom Conner, Margreet G Ausems, Kai-Ren Ong, Jonathan Hoffman, Susan Domchek, Jacquelyn Powers, Manuel R Teixeira, Sofia Maia, William D Foulkes, Nassim Taherian, Mariëlle Ruijs, Apollonia T Helderman-van den Enden, Louise Izatt, Rosemarie Davidson, Muriel A Adank, Lisa Walker, Rita Schmutzler, Kathy Tucker, Judy Kirk, Shirley Hodgson, Marion Harris, Fiona Douglas, Geoffrey J Lindeman, Janez Zgajnar, Marc Tischkowitz, Virginia E Clowes, Rachel Susman, Teresa Ramón Y Cajal, Nicholas Patcher, Neus Gadea, Allan Spigelman, Theo van Os, Annelie Liljegren, Lucy Side, Carole Brewer, Angela F Brady, Alan Donaldson, Vigdis Stefansdottir, Eitan Friedman, Rakefet Chen-Shtoyerman, David J Amor, Lucia Copáková, Julian Barwell, Veda N Giri, Vedang Murthy, Nicola Nicolai, Soo-Hwang Teo, Lynn Greenhalgh, Sara Strom, Alex Henderson, John McGrath, David Gallagher, Neil Aaronson, Audrey Ardern-Jones, Chris Bangma, David Dearnaley, Philandra Costello, Jorunn Eyfjord, Jeanette Rothwell, Alison Falconer, Henrik Grönberg, Freddie C Hamdy, Oskar Johannsson, Vincent Khoo, Zsofia Kote-Jarai, Jan Lubiński, Ulrika Axcrona, Jane Melia, Joanne McKinley, Anita V Mitra, Clare Moynihan, Gad Rennert, Mohnish Suri, Penny Wilson, Emma Killick, , Sue Moss, Rosalind A Eeles.
Eur. Urol.
PUBLISHED: 01-02-2014
Show Abstract
Hide Abstract
Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations.
Related JoVE Video
Prophylactic bilateral salpingectomy as a prevention strategy in women at high-risk of ovarian cancer: a mini-review.
Front Oncol
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
Risk-reducing bilateral salpingo-oophorectomy is a proven strategy to reduce the risk of serous ovarian cancer associated with germline BRCA mutations. It is most effective when performed before natural menopause, but it will render a woman prematurely menopausal. The tubal hypothesis of serous ovarian cancer brings with it the possibility of the alternative surgical approach in younger women comprising of risk-reducing bilateral salpingectomy while conserving their ovaries until nearer the age of natural menopause, when a delayed bilateral oophorectomy can be performed. This article will review the evidence behind the tubal hypothesis of serous ovarian cancer and explore the opportunities for translating this into clinical cancer prevention practice.
Related JoVE Video
Synthetic lethality between CCNE1 amplification and loss of BRCA1.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 11-11-2013
Show Abstract
Hide Abstract
High-grade serous ovarian cancers (HGSCs) are characterized by a high frequency of TP53 mutations, BRCA1/2 inactivation, homologous recombination dysfunction, and widespread copy number changes. Cyclin E1 (CCNE1) gene amplification has been reported to occur independently of BRCA1/2 mutation, and it is associated with primary treatment failure and reduced patient survival. Insensitivity of CCNE1-amplified tumors to platinum cross-linking agents may be partly because of an intact BRCA1/2 pathway. Both BRCA1/2 dysfunction and CCNE1 amplification are known to promote genomic instability and tumor progression. These events may be mutually exclusive, because either change provides a path to tumor development, with no selective advantage to having both mutations. Using data from a genome-wide shRNA synthetic lethal screen, we show that BRCA1 and members of the ubiquitin pathway are selectively required in cancers that harbor CCNE1 amplification. Furthermore, we show specific sensitivity of CCNE1-amplified tumor cells to the proteasome inhibitor bortezomib. These findings provide an explanation for the observed mutual exclusivity of CCNE1 amplification and BRCA1/2 loss in HGSC and suggest a unique therapeutic approach for treatment-resistant CCNE1-amplified tumors.
Related JoVE Video
Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men.
Sci Rep
PUBLISHED: 06-03-2013
Show Abstract
Hide Abstract
Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0?ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals.
Related JoVE Video
The attitudes of people with sarcoma and their family towards genomics and incidental information arising from genetic research.
Clin Sarcoma Res
PUBLISHED: 05-09-2013
Show Abstract
Hide Abstract
The study aimed to examine attitudes of individuals diagnosed with sarcoma and their family members towards genetics, genomic research and incidental information arising as a result of participating in genetic research.
Related JoVE Video
Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations.
Clin. Cancer Res.
PUBLISHED: 04-30-2013
Show Abstract
Hide Abstract
High-grade serous carcinoma (HGSC) accounts for the majority of epithelial ovarian cancer deaths. Genomic and functional data suggest that approximately half of unselected HGSC have disruption of the BRCA pathway and defects in homologous recombination repair (HRR). Pathway disruption is regarded as imparting a BRCAness phenotype. We explored the molecular changes in HGSC arising in association with specific BRCA1/BRCA2 somatic or germline mutations and in those with BRCA1 DNA promoter methylation.
Related JoVE Video
The incidence of PALB2 c.3113G>A in women with a strong family history of breast and ovarian cancer attending familial cancer centres in Australia.
Fam. Cancer
PUBLISHED: 03-09-2013
Show Abstract
Hide Abstract
The familial aggregation of breast cancer has been well-described with approximately 25% of breast cancers attributable to inherited mutations in currently known breast cancer susceptibility genes. PALB2 c.3113G>A (p.Trp1038*) is a protein-truncating mutation which has been associated with high estimated risk of breast cancer in Australian women (91%; 95% CI = 44-100) to age 70 years. This study screened for PALB2 c.3113G>A in germline DNA representing 871 unrelated individuals from "high-risk" breast and/or ovarian cancer families evaluated in the setting of a Familial Cancer Centre in Australia. The PALB2 c.3113G>A mutation was identified in eight of 871 probands (0.92%) from these families. Median age of diagnosis was 42 years. Five of these eight women had contra-lateral breast cancers. Available data suggests that PALB2 c.3113G>A is a rare mutation with estimated breast cancer risks similar in magnitude to that associated with BRCA2 mutations. Although the proportion of high-risk women carrying this PALB2 mutation is low, research efforts should continue in order to effect its translation into clinical genetic testing practice.
Related JoVE Video
The responses of research participants and their next of kin to receiving feedback of genetic test results following participation in the Australian Ovarian Cancer Study.
Genet. Med.
PUBLISHED: 02-28-2013
Show Abstract
Hide Abstract
The generation of clinically significant genetic data during research studies raises a number of ethical issues about the feedback of this information to research participants. Little is known about research participants experiences of this practice.
Related JoVE Video
Analysis of RAD51D in ovarian cancer patients and families with a history of ovarian or breast cancer.
PLoS ONE
PUBLISHED: 01-25-2013
Show Abstract
Hide Abstract
Mutations in RAD51D have been associated with an increased risk of hereditary ovarian cancer and although they have been observed in the context of breast and ovarian cancer families, the association with breast cancer is unclear. The aim of this current study was to validate the reported association of RAD51D with ovarian cancer and assess for an association with breast cancer. We screened for RAD51D mutations in BRCA1/2 mutation-negative index cases from 1,060 familial breast and/or ovarian cancer families (including 741 affected by breast cancer only) and in 245 unselected ovarian cancer cases. Exons containing novel non-synonymous variants were screened in 466 controls. Two overtly deleterious RAD51D mutations were identified among the unselected ovarian cancers cases (0.82%) but none were detected among the 1,060 families. Our data provide additional evidence that RAD51D mutations are enriched among ovarian cancer patients, but are extremely rare among familial breast cancer patients.
Related JoVE Video
High levels of genomic aberrations in serous ovarian cancers are associated with better survival.
PLoS ONE
PUBLISHED: 01-23-2013
Show Abstract
Hide Abstract
Genomic instability and copy number alterations in cancer are generally associated with poor prognosis; however, recent studies have suggested that extreme levels of genomic aberrations may be beneficial for the survival outcome for patients with specific tumour types. We investigated the extent of genomic instability in predominantly high-grade serous ovarian cancers (SOC) using two independent datasets, generated in Norway (n?=?74) and Australia (n?=?70), respectively. Genomic instability was quantified by the Total Aberration Index (TAI), a measure of the abundance and genomic size of copy number changes in a tumour. In the Norwegian cohort, patients with TAI above the median revealed significantly prolonged overall survival (p<0.001) and progression-free survival (p<0.05). In the Australian cohort, patients with above median TAI showed prolonged overall survival (p<0.05) and moderately, but not significantly, prolonged progression-free survival. Results were confirmed by univariate and multivariate Cox regression analyses with TAI as a continuous variable. Our results provide further evidence supporting an association between high level of genomic instability and prolonged survival of high-grade SOC patients, possibly as disturbed genome integrity may lead to increased sensitivity to chemotherapeutic agents.
Related JoVE Video
No evidence for PALB2 methylation in high-grade serous ovarian cancer.
J Ovarian Res
PUBLISHED: 01-10-2013
Show Abstract
Hide Abstract
High-grade serous ovarian cancers are a distinct histological subtype of ovarian cancer often characterised by a dysfunctional BRCA/Fanconi anaemia (BRCA/FA) pathway, which is critical to the homologous recombination DNA repair machinery. An impaired BRCA/FA pathway sensitises tumours to the treatment with DNA cross-linking agents and to PARP inhibitors. The vast majority of inactivating mutations in the BRCA/FA pathway are in the BRCA1 and BRCA2 genes and occur predominantly in high-grade serous cancer. Another member of the BRCA/FA pathway, PALB2 (FANCN), was reported to have been inactivated by DNA methylation in some sporadic ovarian cancers. We therefore sought to investigate the role of PALB2 methylation in high-grade serous ovarian cancers.
Related JoVE Video
High frequency of germline TP53 mutations in a prospective adult-onset sarcoma cohort.
PLoS ONE
PUBLISHED: 01-01-2013
Show Abstract
Hide Abstract
Sarcomas are a key feature of Li-Fraumeni and related syndromes (LFS/LFL), associated with germline TP53 mutations. Current penetrance estimates for TP53 mutations are subject to significant ascertainment bias. The International Sarcoma Kindred Study is a clinic-based, prospective cohort of adult-onset sarcoma cases, without regard to family history. The entire cohort was screened for mutations in TP53 using high-resolution melting analysis and Sanger sequencing, and multiplex-ligation-dependent probe amplification and targeted massively parallel sequencing for copy number changes. Pathogenic TP53 mutations were detected in blood DNA of 20/559 sarcoma probands (3.6%); 17 were germline and 3 appeared to be somatically acquired. Of the germline carriers, one appeared to be mosaic, detectable in the tumor and blood, but not epithelial tissues. Germline mutation carriers were more likely to have multiple cancers (47% vs 15% for non-carriers, P?=?3.0×10(-3)), and earlier cancer onset (33 vs 48 years, P?=?1.19×10(-3)). The median survival of mutation carriers following first cancer diagnosis was not significantly different from non-carriers. Only 10/17 (59%) pedigrees met classical or Chompret criteria for LFS. In summary, germline TP53 mutations are not rare in adult patients with sarcoma, with implications for screening, surveillance, treatment and genetic counselling of carriers and family members.
Related JoVE Video
kConFab: a familial breast cancer consortium facilitating research and translational oncology.
J. Natl. Cancer Inst. Monographs
PUBLISHED: 11-02-2011
Show Abstract
Hide Abstract
In 2005, 100,514 Australians were diagnosed with cancer, and over 10,000 of these cancers will be due to heritable causes. The impact of familial cancer by definition extends beyond the individual, affecting tens of thousands of parents, siblings, and children. The study of familial cancer causes has arguably made the greatest single contribution to our understanding of cancer biology. This knowledge is used clinically to guide investment in screening and prevention, as well as being translated into new treatments.
Related JoVE Video
Practicalities of developing a breast magnetic resonance imaging screening service for women at high risk for breast cancer.
ANZ J Surg
PUBLISHED: 10-31-2011
Show Abstract
Hide Abstract
Demand for screening breast magnetic resonance imaging (MRI) for women with a hereditary predisposition to breast cancer has increased since the introduction of a medicare item number. To aid future service planning, we examined the practicalities of establishing and running a breast MRI screening programme for high risk women and to describe the early outcomes of our screening programme.
Related JoVE Video
The role of poly adenosine diphosphate ribose polymerase inhibitors in breast and ovarian cancer: current status and future directions.
Asia Pac J Clin Oncol
PUBLISHED: 09-03-2011
Show Abstract
Hide Abstract
Poly adenosine diphosphate ribose polymerase (PARP) inhibitors have demonstrated single agent activity in the treatment of patients with recurrent BRCA1-mutated and BRCA2-mutated breast and ovarian cancers. They also appear to have a potential role as maintenance therapy following chemotherapy in patients with platinum sensitive recurrent sporadic and BRCA1/2 related high-grade serous ovarian cancers. The concept of BRCAness raises the possibility that PARP inhibitors may be active in selected patients with homologous recombination (HR) DNA repair-deficient tumors, even if they do not harbor a BRCA1/2 germline mutation. Further research will be required to identify the subset of patients with sporadic cancers who may benefit from PARP inhibitor therapy. Precise details on the mechanisms of action, relative potency and anti-cancer effects of different PARP inhibitors remain to be clarified and are being investigated. PARP inhibitors are known to inhibit the base excision repair (BER) pathway but in addition, recent reports indicate that aberrant activation of the error-prone non-homologous end-joining (NHEJ) pathway occurs in HR-deficient cells and that cell death provoked by PARP inhibition is dependent on NHEJ-induced genomic instability. Characterization of the precise molecular mechanisms responsible for PARP inhibitor activity should lead to the identification of predictive biomarkers of response and help identify which patients should be treated with PARP inhibitors. This is a very active field of research and the current status and future directions are reviewed.
Related JoVE Video
Decreased prostate cancer-specific survival of men with BRCA2 mutations from multiple breast cancer families.
Cancer Prev Res (Phila)
PUBLISHED: 07-08-2011
Show Abstract
Hide Abstract
The role of a germ-line BRCA2 mutation in the development of prostate cancer is established, but the clinical presentation linked to outcome for this group of men has not been well described. A total of 148 men from 1,423 families were ascertained from the kConFab consortium. Each participant met the following criteria: (i) a verified case of prostate cancer; (ii) confirmed as either a carrier or noncarrier of a family-specific BRCA pathogenic mutation; (iii) comprehensive clinical and treatment data were available. Clinical data were linked to treatment received and overall survival was analyzed by Kaplan-Meier. Prostate cancer in men from breast cancer-prone families has a high risk of disease progression, irrespective of mutation status. BRCA2 mutation carriers have an increased risk of death and prostate cancer-related death [HR (95% CI) 4.5 (2.12-9.52), P = 8.9 × 10(-5)] by comparison with noncarriers. Serum PSA readings taken prior to diagnosis in 90% of all men, age adjusted, were above clinical significance. Following DAmico risk stratification, 77.5% of BRCA2 mutation carriers and 58.7% of noncarriers had high-risk disease. BRCA2 mutation status was also an independent prognostic indicator of overall survival. Furthermore, there was a poor overall survival outcome for both the BRCA2 mutation carriers and noncarriers given curative-intent treatment. All men in breast cancer-prone families are at risk of developing aggressive prostate cancer. This information is significant and should be included in discussions with genetic counselors and medical professionals when discussing prostate cancer treatment options for men in these families, irrespective of mutation status.
Related JoVE Video
Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients.
Hum. Mutat.
PUBLISHED: 07-06-2011
Show Abstract
Hide Abstract
There is strong evidence that overtly inactivating mutations in RAD51C predispose to hereditary breast and ovarian cancer but the prevalence of such mutations, and whether they are associated with a particular clinical phenotype, remains unclear. Resolving these questions has important implications for the implementation of RAD51C into routine clinical genetic testing. Consequently, we have performed a large RAD51C mutation screen of hereditary breast and ovarian cancer families, and the first study of unselected patients diagnosed with ovarian cancer. Our data confirm a consistent but low frequency (2/335 families) of inactivating RAD51C mutations among families with a history of both breast and ovarian cancer and an absence of mutations among breast cancer only families (0/1,053 families). Our data also provide support for the designation of the missense variant p.Gly264Ser as a moderate penetrance allele.
Related JoVE Video
A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes.
BMC Cancer
PUBLISHED: 01-25-2011
Show Abstract
Hide Abstract
Detection of mutations by DNA sequencing can be facilitated by scanning methods to identify amplicons which may have mutations. Current scanning methods used for the detection of germline sequence variants are laborious as they require post-PCR manipulation. High resolution melting (HRM) is a cost-effective rapid screening strategy, which readily detects heterozygous variants by melting curve analysis of PCR products. It is well suited to screening genes such as BRCA1 and BRCA2 as germline pathogenic mutations in these genes are always heterozygous.
Related JoVE Video
Moving toward personalized medicine: treatment-focused genetic testing of women newly diagnosed with ovarian cancer.
Int. J. Gynecol. Cancer
PUBLISHED: 10-27-2010
Show Abstract
Hide Abstract
The presence of a germline BRCA mutation defines a genotype-specific group of women whose invasive ovarian cancer is associated with an increasingly well-defined prognostic and chemosensitivity biological profile. To determine the criteria that may be used to select patients for BRCA treatment-focused genetic testing, we performed a systemic literature search of studies that assessed BRCA1 and BRCA2 mutation frequency in women with ovarian cancer unselected for family history. The results are discussed with regard to the added clinical value gained by identifying a germline BRCA mutation at the time of the ovarian cancer diagnosis.
Related JoVE Video
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.
Lancet
PUBLISHED: 07-06-2010
Show Abstract
Hide Abstract
Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer.
Related JoVE Video
The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine.
PLoS ONE
PUBLISHED: 06-30-2010
Show Abstract
Hide Abstract
Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk.
Related JoVE Video
Gene methylation in breast ductal fluid from BRCA1 and BRCA2 mutation carriers.
Cancer Epidemiol. Biomarkers Prev.
PUBLISHED: 01-09-2010
Show Abstract
Hide Abstract
Genomic alterations (including gene hypermethylation) are likely to precede the phenotypic changes associated with breast tumorigenesis. From a prospective collection of ductal lavage (DL) samples from women with a known mutation in BRCA1 or BRCA2, we have assessed promoter methylation with a comparison of results with several variables, including breast cancer (BC) outcome.
Related JoVE Video
A role for common genomic variants in the assessment of familial breast cancer.
J. Clin. Oncol.
Show Abstract
Hide Abstract
Genome-wide association studies have identified common genomic variants associated with increased susceptibility to breast cancer. In the general population, the risk associated with these known variants seems insufficient to inform clinical management. Their contribution to the development of familial breast cancer is less clear.
Related JoVE Video
Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles.
PLoS Genet.
Show Abstract
Hide Abstract
Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.
Related JoVE Video
Profiles of genomic instability in high-grade serous ovarian cancer predict treatment outcome.
Clin. Cancer Res.
Show Abstract
Hide Abstract
High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR causes uniparental deletions and loss of heterozygosity (LOH). Our purpose is to profile LOH in HGSC and correlate our findings to clinical outcome, and compare HGSC and high-grade breast cancers.
Related JoVE Video
How should we discuss genetic testing with women newly diagnosed with breast cancer? Design and implementation of a randomized controlled trial of two models of delivering education about treatment-focused genetic testing to younger women newly diagnosed
BMC Cancer
Show Abstract
Hide Abstract
Germline BRCA1 and BRCA2 mutation testing offered shortly after a breast cancer diagnosis to inform womens treatment choices - treatment-focused genetic testing TFGT - has entered clinical practice in specialist centers and is likely to be soon commonplace in acute breast cancer management, especially for younger women. Yet the optimal way to deliver information about TFGT to younger women newly diagnosed with breast cancer is not known, particularly for those who were not suspected of having a hereditary breast cancer syndrome prior to their cancer diagnosis. Also, little is known about the behavioral and psychosocial impact or cost effectiveness of educating patients about TFGT. This trial aims to examine the impact and efficiency of two models of educating younger women newly diagnosed with breast cancer about genetic testing in order to provide evidence for a safe and effective future clinical pathway for this service.
Related JoVE Video
BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group.
J. Clin. Oncol.
Show Abstract
Hide Abstract
The frequency of BRCA1 and BRCA2 germ-line mutations in women with ovarian cancer is unclear; reports vary from 3% to 27%. The impact of germ-line mutation on response requires further investigation to understand its impact on treatment planning and clinical trial design.
Related JoVE Video
Analysis of KLLN as a high-penetrance breast cancer predisposition gene.
Breast Cancer Res. Treat.
Show Abstract
Hide Abstract
KLLN is a p53 target gene with DNA binding function and represents a highly plausible candidate breast cancer predisposition gene. We screened for predisposing variants in 860 high-risk breast cancer families using high resolution melt analysis. A germline c.339_340delAG variant predicted to cause premature termination of the protein after 57 alternative amino acid residues was identified in 3/860 families who tested negative for BRCA1 and BRCA2 mutations and in 1/84 sporadic breast cancer cases. However, the variant was also detected in 2/182 families with known BRCA1 or BRCA2 mutations and in 2/464 non-cancer controls. Furthermore, loss of the mutant allele was detected in 2/2 breast tumors. Our data suggest that pathogenic mutations in KLLN are rare in breast cancer families and the c.339_340delAG variant does not represent a high-penetrance breast cancer risk allele.
Related JoVE Video
Triple-negative breast cancer: making the most of a misnomer.
Asia Pac J Clin Oncol
Show Abstract
Hide Abstract
Triple-negative breast cancer (TNBC) is defined by its lack of (or minimal) estrogen receptor and progesterone receptor expression, together with the absence of human epidermal growth factor receptor 2 overexpression or gene amplification. It can be a particularly aggressive form of breast cancer, often characterized by early systemic relapse. This subtype, absent from traditional pathology classifications, has quietly crept into the oncologists lexicon over the last decade and aroused considerable research interest. Based on tumor pathology, immunohistochemistry and gene profiling studies, TNBC is likely to represent a heterogeneous mix of breast cancer subtypes. This observation will have important implications for the selection of optimal therapies, which are yet to be defined. This article reviews recent insights in the classification and ontogeny of TNBC, current approaches to its management and promising therapeutic targets that are forming the basis for innovative early and late phase clinical trials.
Related JoVE Video
The consequences of risk reducing salpingo-oophorectomy: the case for a coordinated approach to long-term follow up post surgical menopause.
Fam. Cancer
Show Abstract
Hide Abstract
Women with germline mutations in BRCA1 and BRCA2 genes have significantly increased lifetime risks of breast and ovarian cancer. To manage both the ovarian and breast cancer risks the current recommendation is undergo a risk reducing salpingo-oophorectomy (RRSO) prior to natural menopause. To date, studies have focussed on quality of life and sexual dysfunction in women who undergo RRSO, but few have reported on the wider physical consequences. We performed a questionnaire study in women with BRCA 1 or 2 gene mutations known to the Peter MacCallum Familial Cancer Centre. We gathered information about ovarian surgery, ongoing follow-up, management of risk factors including osteoporosis, and current severity of menopausal symptoms. Two hundred and nineteen women were surveyed. One hundred and forty-three of 157 responding participants (91 %) reported having RRSO. Sixty one were pre-menopausal at RRSO. Post surgical follow-up rates were generally low, and a minority of women reported recent bone density imaging or pharmaceutical prevention or treatment of osteoporosis. Menopausal symptoms appeared generally mild. No significant differences in symptom severity were observed in women who underwent a pre-menopausal RRSO compared to RRSO after natural menopause. These data indicate that a formalised follow-up protocol is necessary to optimally manage the consequences of a RRSO.
Related JoVE Video
Getting to the point: what women newly diagnosed with breast cancer want to know about treatment-focused genetic testing.
Oncol Nurs Forum
Show Abstract
Hide Abstract
To identify young womens information preferences regarding treatment-focused genetic testing (TFGT) and to develop and evaluate a novel educational resource.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.