Publications by authors named "Amanda Brandt"

23 Publications

  • Page 1 of 1

Longitudinal follow-up after telephone disclosure in the randomized COGENT study.

Genet Med 2020 08 7;22(8):1401-1406. Epub 2020 May 7.

Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: To better understand the longitudinal risks and benefits of telephone disclosure of genetic test results in the era of multigene panel testing.

Methods: Adults who were proceeding with germline cancer genetic testing were randomized to telephone disclosure (TD) with a genetic counselor or in-person disclosure (IPD) (i.e., usual care) of test results. All participants who received TD were recommended to return to meet with a physician to discuss medical management recommendations.

Results: Four hundred seventy-three participants were randomized to TD and 497 to IPD. There were no differences between arms for any cognitive, affective, or behavioral outcomes at 6 and 12 months. Only 50% of participants in the TD arm returned for the medical follow-up appointment. Returning was associated with site (p < 0.0001), being female (p = 0.047), and not having a true negative result (p < 0.002). Mammography was lower at 12 months among those who had TD and did not return for medical follow-up (70%) compared with those who had TD and returned (86%) and those who had IPD (87%, adjusted p < 0.01).

Conclusion: Telephone disclosure of genetic test results is a reasonable alternative to in-person disclosure, but attention to medical follow-up may remain important for optimizing appropriate use of genetic results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-0808-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396300PMC
August 2020

Longitudinal outcomes with cancer multigene panel testing in previously tested BRCA1/2 negative patients.

Clin Genet 2020 04;97(4):601-609

Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Although multigene panel testing (MGPT) is increasingly utilized in clinical practice, there remain limited data on patient-reported outcomes. BRCA 1/2 negative patients were contacted and offered MGPT. Patients completed pre- and posttest counseling, and surveys assessing cognitive, affective and behavioral outcomes at baseline, postdisclosure and 6 and 12 months. Of 317 eligible BRCA1/2 negative patients who discussed the study with research staff, 249 (79%) enrolled. Decliners were more likely to be older, non-White, and recruited by mail or email. Ninety-five percent of enrolled patients proceeded with MGPT. There were no significant changes in anxiety, depression, cancer specific distress or uncertainty postdisclosure. There were significant but small increases in knowledge, cancer-specific distress and depression at 6-12 months. Uncertainty declined over time. Those with a VUS had significant decreases in uncertainty but also small increases in cancer specific distress at 6 and 12 months. Among those with a positive result, medical management recommendations changed in 26% of cases and 2.6% of all tested. Most BRCA1/2 negative patients have favorable psychosocial outcomes after receipt of MGPT results, although small increases in depression and cancer-specific worry may exist and may vary by result. Medical management changed in few patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13716DOI Listing
April 2020

Patients' Medical and Psychosocial Experiences After Detection of a Variant With Multigene Panel Testing.

JCO Precis Oncol 2019 28;3. Epub 2019 Mar 28.

University of Pennsylvania, Philadelphia, PA.

Purpose: Germline pathogenic variants (PV) are associated with hereditary diffuse gastric cancer and lobular breast cancer. Although prevalence of PV is low in the general population, detection of these variants is increasing with the growing use of multigene panel testing. Little is known about the experiences of individuals tested for variants in the multigene panel testing era.

Methods: Participants recruited from the Prospective Registry of Multiplex Testing completed a cross-sectional self-report survey regarding genetic testing experiences, medical management, and psychosocial adaptation.

Results: Discordance existed in interpretations of results; 13.3% of cases had disagreements in variant classifications among commercial laboratories, and 21.4% had disagreements between participant self-report and ClinVar classification. Survey data were available from 57 individuals reporting either PV (n = 16) or variants of uncertain significance (VUS; n = 41). Those with PV were more likely than those with VUS to report receiving a recommendation for prophylactic gastrectomy, although only 40.0% of those with PV received this recommendation. Participants with VUS were less satisfied with their health care providers' knowledge and reported less knowledge, distress, and worry about discrimination. Participants with PV perceived greater breast cancer risks, but similar gastric cancer risks, as those with VUS.

Conclusion: Few individuals with PV report receiving recommendations for prophylactic gastrectomy, and no differences in perceived gastric cancer risk were observed based on participants' results, suggesting serious unmet informational needs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.18.00300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738946PMC
March 2019

Preferences for in-person disclosure: Patients declining telephone disclosure characteristics and outcomes in the multicenter Communication Of GENetic Test Results by Telephone study.

Clin Genet 2019 02 7;95(2):293-301. Epub 2018 Dec 7.

Division of Hematology-Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois.

Telephone disclosure of cancer genetic test results is noninferior to in-person disclosure. However, how patients who prefer in-person communication of results differ from those who agree to telephone disclosure is unclear but important when considering delivery models for genetic medicine. Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone to in-person disclosure of genetic test results. We evaluated preferences for in-person disclosure, factors associated with this preference and outcomes compared to those who agreed to randomization. Among 1178 enrolled patients, 208 (18%) declined randomization, largely given a preference for in-person disclosure. These patients were more likely to be older (P = 0.007) and to have had multigene panel testing (P < 0.001). General anxiety (P = 0.007), state anxiety (P = 0.008), depression (P = 0.011), cancer-specific distress (P = 0.021) and uncertainty (P = 0.03) were higher after pretest counseling. After disclosure of results, they also had higher general anxiety (P = 0.003), depression (P = 0.002) and cancer-specific distress (P = 0.043). While telephone disclosure is a reasonable alternative to in-person disclosure in most patients, some patients have a strong preference for in-person communication. Patient age, distress and complexity of testing are important factors to consider and requests for in-person disclosure should be honored when possible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453119PMC
February 2019

Correction to: Talking with Children about Adult-Onset Hereditary Cancer Risk: A Developmental Approach for Parents.

J Genet Couns 2018 12;27(6):1523

My Gene Counsel, North Haven, CT, USA.

The original article [1] was initially published with the following list of authors: Allison Werner-Lin, Shana L. Merrill, and Amanda C. Brandt. This author list is now corrected as follows: Allison Werner-Lin, Shana L. Merrill, Amanda C. Brandt, Rachel E. Barnett, & Ellen T. Matloff.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10897-018-0282-0DOI Listing
December 2018

Hepatocyte growth factor acts as a mitogen for equine satellite cells via protein kinase C δ-directed signaling.

J Anim Sci 2018 Sep;96(9):3645-3656

Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg VA.

Hepatocyte growth factor (HGF) signals mediate mouse skeletal muscle stem cell, or satellite cell (SC), reentry into the cell cycle and myoblast proliferation. Because the athletic horse experiences exercise-induced muscle damage, the objective of the experiment was to determine the effect of HGF on equine SC (eqSC) bioactivity. Fresh isolates of adult eqSC were incubated with increasing concentrations of HGF and the initial time to DNA synthesis was measured. Media supplementation with HGF did not shorten (P > 0.05) the duration of G0/G1 transition suggesting the growth factor does not affect activation. Treatment with 25 ng/mL HGF increased (P < 0.05) eqSC proliferation that was coincident with phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and AKT serine/threonine kinase 1 (AKT1). Chemical inhibition of the upstream effectors of ERK1/2 or AKT1 elicited no effect (P > 0.05) on HGF-mediated 5-ethynyl-2'-deoxyuridine (EdU) incorporation. By contrast, treatment of eqSC with 2 µm Gö6983, a pan-protein kinase C (PKC) inhibitor, blocked (P < 0.05) HGF-initiated mitotic activity. Gene-expression analysis revealed that eqSC express PKCα, PKCδ, and PKCε isoforms. Knockdown of PKCδ with a small interfering RNA (siRNA) prevented (P > 0.05) HGF-mediated EdU incorporation. The siPKCδ was specific to the kinase and did not affect (P > 0.05) expression of either PKCα or PKCε. Treatment of confluent eqSC with 25 ng/mL HGF suppressed (P < 0.05) nuclear myogenin expression during the early stages of differentiation. These results demonstrate that HGF may not affect activation but can act as a mitogen and modest suppressor of differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jas/sky234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127786PMC
September 2018

Randomized Noninferiority Trial of Telephone vs In-Person Disclosure of Germline Cancer Genetic Test Results.

J Natl Cancer Inst 2018 09;110(9):985-993

Division of Hematology-Oncology and Section of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and Center for Clinical Cancer Genetics and Global Health, The University of Chicago, Chicago, IL.

Background: Germline genetic testing is standard practice in oncology. Outcomes of telephone disclosure of a wide range of cancer genetic test results, including multigene panel testing (MGPT) are unknown.

Methods: Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone disclosure (TD) of genetic test results with usual care, in-person disclosure (IPD) after tiered-binned in-person pretest counseling. Primary noninferiority outcomes included change in knowledge, state anxiety, and general anxiety. Secondary outcomes included cancer-specific distress, depression, uncertainty, satisfaction, and screening and risk-reducing surgery intentions. To declare noninferiority, we calculated the 98.3% one-sided confidence interval of the standardized effect; t tests were used for secondary subgroup analyses. Only noninferiority tests were one-sided, others were two-sided.

Results: A total of 1178 patients enrolled in the study. Two hundred eight (17.7%) participants declined random assignment due to a preference for in-person disclosure; 473 participants were randomly assigned to TD and 497 to IPD; 291 (30.0%) had MGPT. TD was noninferior to IPD for general and state anxiety and all secondary outcomes immediately postdisclosure. TD did not meet the noninferiority threshold for knowledge in the primary analysis, but it did meet the threshold in the multiple imputation analysis. In secondary analyses, there were no statistically significant differences between arms in screening and risk-reducing surgery intentions, and no statistically significant differences in outcomes by arm among those who had MGPT. In subgroup analyses, patients with a positive result had statistically significantly greater decreases in general anxiety with telephone disclosure (TD -0.37 vs IPD +0.87, P = .02).

Conclusions: Even in the era of multigene panel testing, these data suggest that telephone disclosure of cancer genetic test results is as an alternative to in-person disclosure for interested patients after in-person pretest counseling with a genetic counselor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djy015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136932PMC
September 2018

Talking with Children About Adult-Onset Hereditary Cancer Risk: A Developmental Approach for Parents.

J Genet Couns 2018 06 30;27(3):533-548. Epub 2018 Jan 30.

Smilow Cancer Genetics and Prevention, Yale New Haven Health, 330 Orchard Street, Suite 107 & 109, New Haven, CT, 06511, USA.

Families often express difficulty to their providers and request guidance regarding the task of communicating with children about potential adult-onset inherited cancer risks. This disclosure is often complicated by the parent's ongoing adjustment to their mutation status, guilt at potential transmission of the mutation to the child, concern over inciting distress in children, and the varied capacities of children in the home to understand genetic information. Providers often do not have adequate resources to support or facilitate disclosure of genetic test results to children. Optimally, communication about inherited cancer risk is an open, ongoing process within the family. We recommend that parents tailor conversations to the child's developmental, cognitive, emotional, and behavioral abilities to support comprehension. Based on well-established theories of child development, empirical research on family communication of hereditary cancer risk, and clinical counseling experience, we offer recommendations for parental disclosure of genetic risk to children, case examples with critical discussion of relevant topics, common child questions with sample scripted responses, and additional printed and online resources.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10897-017-0191-7DOI Listing
June 2018

Returning Individual Genetic Research Results to Research Participants: Uptake and Outcomes Among Patients With Breast Cancer.

JCO Precis Oncol 2018 16;2. Epub 2018 Apr 16.

Angela R. Bradbury, Kara N. Maxwell, Laura DiGiovanni, Jamie Brower, Dominique Fetzer, Jill Bennett Gaieski, Amanda Brandt, Danielle McKenna, Jessica Long, Jacquelyn Powers, Jill E. Stopfer, Katherine L. Nathanson, and Susan M. Domchek, Perelman School of Medicine at the University of Pennsylvania; Brian L. Egleston, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA; and Linda Patrick-Miller, The University of Chicago, Chicago, IL.

Purpose: Understanding the outcomes of returning individual genetic research results to participants is critical because some genetic variants are found to be associated with health outcomes and have become available for clinical testing.

Materials And Methods: -negative women with early-onset breast cancer, multiple primary cancers, or a family history of breast cancer who participated in a gene discovery cancer registry were offered the opportunity to learn their individual genetic research results of 24 breast cancer susceptibility genes with a genetic counselor after predisclosure genetic counseling. Outcomes included uptake of research results, knowledge, informed choice, psychosocial adjustment, uncertainty, satisfaction, and uptake of clinical confirmation testing.

Results: Four hundred two potential participants were contacted. One hundred ninety-four participants (48%) did not respond despite multiple attempts, and 85 participants (21%) actively or passively declined. One hundred seven participants (27%) elected for predisclosure counseling and were more likely to be younger, married, and white. Ninety percent of participants who had predisclosure counseling elected to receive their genetic research results, and 89% made an informed choice. Knowledge increased significantly after predisclosure counseling, and anxiety, intrusive cancer-specific distress, uncertainty, and depression declined significantly after receipt of results. General anxiety and intrusive cancer-specific distress declined significantly for both participants with a positive result and those with a negative result. Sixty-four percent of participants had clinical confirmation testing when recommended, including all participants with a mutation in a high-penetrance gene.

Conclusion: Uptake of genetic research results may be lower than anticipated by hypothetical reports and small select studies. Participants who elected to receive research results with genetic providers did not experience increases in distress or uncertainty, but not all patients return for confirmation testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/po.17.00250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039346PMC
April 2018

Use and Patient-Reported Outcomes of Clinical Multigene Panel Testing for Cancer Susceptibility in the Multicenter Communication of Genetic Test Results by Telephone Study.

JCO Precis Oncol 2018 18;2. Epub 2018 Dec 18.

University of Pennsylvania.

Purpose: Multigene panels (MGPs) are increasingly being used despite questions regarding their clinical utility and no standard approach to genetic counseling. How frequently genetic providers use MGP testing and how patient-reported outcomes (PROs) differ from targeted testing (eg, only) are unknown.

Methods: We evaluated use of MGP testing and PROs in participants undergoing cancer genetic testing in the multicenter Communication of Genetic Test Results by Telephone study (ClinicalTrials.gov identifier: ), a randomized study of telephone versus in-person disclosure of genetic test results. PROs included genetic knowledge, general and state anxiety, depression, cancer-specific distress, uncertainty, and satisfaction. Genetic providers offered targeted or MGP testing based on clinical assessment.

Results: Since the inclusion of MGP testing in 2014, 395 patients (66%) were offered MGP testing. MGP testing increased over time from 57% in 2014 to 66% in 2015 ( = .02) and varied by site (46% to 78%; < .01). Being offered MGP testing was significantly associated with not having Ashkenazi Jewish ancestry, having a history of cancer, not having a mutation in the family, not having made a treatment decision, and study site. After demographic adjustment, patients offered MGP testing had lower general anxiety ( = .04), state anxiety ( = .03), depression ( = .04), and uncertainty ( = .05) pre-disclosure compared with patients offered targeted testing. State anxiety ( = .05) and cancer-specific distress ( = .05) were lower at disclosure in the MGP group. There was a greater increase in change in uncertainty ( = .04) among patients who underwent MGP testing.

Conclusion: MGP testing was more frequently offered to patients with lower anxiety, depression, and uncertainty and was associated with favorable outcomes, with the exception of a greater increase in uncertainty compared with patients who had targeted testing. Addressing uncertainty may be important as MGP testing is increasingly adopted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.18.00199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901130PMC
December 2018

Utilizing Remote Real-Time Videoconferencing to Expand Access to Cancer Genetic Services in Community Practices: A Multicenter Feasibility Study.

J Med Internet Res 2016 Feb 1;18(2):e23. Epub 2016 Feb 1.

Division of Hematology-Oncology, Department of Medicine, The University of Pennsylvania, Philadelphia, PA, United States.

Background: Videoconferencing has been used to expand medical services to low-access populations and could increase access to genetic services at community sites where in-person visits with genetic providers are not available.

Objective: To evaluate the feasibility of, patient feedback of, and cognitive and affective responses to remote two-way videoconferencing (RVC) telegenetic services at multiple sociodemographically diverse community practices without access to genetic providers.

Methods: Patients at 3 community sites in 2 US states outside the host center completed RVC pretest (visit 1, V1) and post-test (visit 2, V2) genetic counseling for cancer susceptibility. Surveys evaluated patient experiences, knowledge, satisfaction with telegenetic and cancer genetics services, anxiety, depression, and cancer worry.

Results: A total of 82 out of 100 (82.0%) approached patients consented to RVC services. A total of 61 out of 82 patients (74%) completed pretest counseling and 41 out of 61 (67%) proceeded with testing and post-test counseling. A total of 4 out of 41 (10%) mutation carriers were identified: BRCA2, MSH2, and PMS2. Patients reported many advantages (eg, lower travel burden and convenience) and few disadvantages to RVC telegenetic services. Most patients reported feeling comfortable with the video camera--post-V1: 52/57 (91%); post-V2: 39/41 (95%)--and that their privacy was respected--post-V1: 56/57 (98%); post-V2: 40/41 (98%); however, some reported concerns that RVC might increase the risk of a confidentiality breach of their health information--post-V1: 14/57 (25%); post-V2: 12/41 (29%). While the majority of patients reported having no trouble seeing or hearing the genetic counselor--post-V1: 47/57 (82%); post-V2: 39/41 (95%)--51 out of 98 (52%) patients reported technical difficulties. Nonetheless, all patients reported being satisfied with genetic services. Compared to baseline, knowledge increased significantly after pretest counseling (+1.11 mean score, P=.005); satisfaction with telegenetic (+1.74 mean score, P=.02) and genetic services (+2.22 mean score, P=.001) increased after post-test counseling. General anxiety and depression decreased after pretest (-0.97 mean anxiety score, P=.003; -0.37 mean depression score, P=.046) and post-test counseling (-1.13 mean anxiety score, P=.003; -0.75 mean depression score, P=.01); state anxiety and cancer-specific worry did not significantly increase.

Conclusions: Remote videoconferencing telegenetic services are feasible, identify genetic carriers in community practices, and are associated with high patient satisfaction and favorable cognitive and affective outcomes, suggesting an innovative delivery model for further study to improve access to genetic providers and services. Potential barriers to dissemination include technology costs, unclear billing and reimbursement, and state requirements for provider licensure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/jmir.4564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754531PMC
February 2016

Patient feedback and early outcome data with a novel tiered-binned model for multiplex breast cancer susceptibility testing.

Genet Med 2016 Jan 2;18(1):25-33. Epub 2015 Apr 2.

Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Purpose: The risks, benefits, and utilities of multiplex panels for breast cancer susceptibility are unknown, and new counseling and informed consent models are needed. We sought to obtain patient feedback and early outcome data with a novel tiered-binned model for multiplex testing.

Methods: BRCA1/2-negative and untested patients completed pre- and posttest counseling and surveys evaluating testing experiences and cognitive and affective responses to multiplex testing.

Results: Of 73 patients, 49 (67%) completed pretest counseling. BRCA1/2-negative patients were more likely to proceed with multiplex testing (86%) than those untested for BRCA1/2 (43%; P < 0.01). Many patients declining testing reported concern for uncertainty and distress. Most patients would not change anything about their pre- (76%) or posttest (89%) counseling sessions. Thirty-three patients (72%) were classified as making an informed choice, including 81% of those who proceeded with multiplex testing. Knowledge increased significantly. Anxiety, depression, uncertainty, and cancer worry did not significantly increase with multiplex testing.

Conclusion: Some patients, particularly those without prior BRCA1/2 testing, decline multiplex testing. Most patients who proceeded with testing did not experience negative psychological responses, but larger studies are needed. The tiered-binned approach is an innovative genetic counseling and informed consent model for further study in the era of multiplex testing.Genet Med 18 1, 25-33.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2015.19DOI Listing
January 2016

Genotype-Phenotype Correlations by Ethnicity and Mutation Location in BRCA Mutation Carriers.

Breast J 2015 May-Jun;21(3):260-7. Epub 2015 Mar 19.

Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

The genotype-phenotype correlations of the specific BRCA1 and BRCA2 mutations in multi-ethnic populations in USA have not yet been fully investigated. This study was designed to evaluate the effects of ethnicity at specific mutation locations and breast/ovarian cancer phenotypes. Our cohort included 445 women with different ethnic backgrounds who underwent BRCA genetic testing between 1997 and 2010. Known clinical and pathologic characteristics were compared with Chi-Square Analysis or Fisher's Exact test as appropriate. The three most common mutation locations in BRCA1 (exons 2, 11, and 20) and BRCA2 (exons 10, 11, and 25) genes were chosen. Prevalence of BRCA1 exon 2 mutations were significantly higher in Ashkenazi Jewish (AJ) women compared to Caucasians (41% versus 15%; p = 0.001). Similarly, AJ women with breast cancer were more likely to have BRCA1 exon 2 mutation (47% positivity in AJ women versus 0-12.5% positivity in other ethnicities; p = 0.004). Women carrying the exon 20 BRCA1 mutation had the highest probability of having combined breast and ovarian cancers compared to women carrying other exon mutations (p = 0.05). The median age at initial cancer diagnosis, phenotypic features of breast cancer tumors, and overall survival did not vary significantly by ethnicity or mutation location. Our data suggest that ethnicity does not affect age of onset, overall survival or confer different risks of breast and ovarian cancer development in BRCA carriers. These results also suggest that women carrying the exon 20 BRCA1 mutation may warrant mutation-specific counseling and be more aggressively managed for risk reduction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tbj.12392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411012PMC
May 2016

Development of a tiered and binned genetic counseling model for informed consent in the era of multiplex testing for cancer susceptibility.

Genet Med 2015 Jun 9;17(6):485-92. Epub 2014 Oct 9.

1] Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA [2] Department of Translational Medicine and Human Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Purpose: Multiplex genetic testing, including both moderate- and high-penetrance genes for cancer susceptibility, is associated with greater uncertainty than traditional testing, presenting challenges to informed consent and genetic counseling. We sought to develop a new model for informed consent and genetic counseling for four ongoing studies.

Methods: Drawing from professional guidelines, literature, conceptual frameworks, and clinical experience, a multidisciplinary group developed a tiered-binned genetic counseling approach proposed to facilitate informed consent and improve outcomes of cancer susceptibility multiplex testing.

Results: In this model, tier 1 "indispensable" information is presented to all patients. More specific tier 2 information is provided to support variable informational needs among diverse patient populations. Clinically relevant information is "binned" into groups to minimize information overload, support informed decision making, and facilitate adaptive responses to testing. Seven essential elements of informed consent are provided to address the unique limitations, risks, and uncertainties of multiplex testing.

Conclusion: A tiered-binned model for informed consent and genetic counseling has the potential to address the challenges of multiplex testing for cancer susceptibility and to support informed decision making and adaptive responses to testing. Future prospective studies including patient-reported outcomes are needed to inform how to best incorporate multiplex testing for cancer susceptibility into clinical practice.Genet Med 17 6, 485-492.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2014.134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983405PMC
June 2015

Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study.

J Clin Oncol 2014 Apr 17;32(12):1249-55. Epub 2014 Mar 17.

Molly S. Daniels, Diana L. Urbauer, Brittany A.L. Batte, Amanda C. Brandt, Christopher I. Amos, and Karen H. Lu, The University of Texas MD Anderson Cancer Center, Houston, TX; Sheri A. Babb and David G. Mutch, Washington University School of Medicine, St Louis, MO; Robin H. King and Adam H. Buchanan, Duke University, Durham, NC.

Purpose: Identification of the 10% to 15% of patients with ovarian cancer who have germline BRCA1 or BRCA2 mutations is important for management of both patients and relatives. The BRCAPRO model, which estimates mutation likelihood based on personal and family cancer history, can inform genetic testing decisions. This study's purpose was to assess the accuracy of BRCAPRO in women with ovarian cancer.

Methods: BRCAPRO scores were calculated for 589 patients with ovarian cancer referred for genetic counseling at three institutions. Observed mutations were compared with those predicted by BRCAPRO. Analysis of variance was used to assess factors impacting BRCAPRO accuracy.

Results: One hundred eighty (31%) of 589 patients with ovarian cancer tested positive. At BRCAPRO scores less than 40%, more mutations were observed than expected (93 mutations observed v 34.1 mutations expected; P < .001). If patients with BRCAPRO scores less than 10% had not been tested, 51 (28%) of 180 mutations would have been missed. BRCAPRO underestimated the risk for high-grade serous ovarian cancers but overestimated the risk for other histologies (P < .001), underestimation increased as age at diagnosis decreased (P = .02), and model performance varied by institution (P = .02).

Conclusion: Patients with ovarian cancer classified as low risk by BRCAPRO are more likely to test positive than predicted. The risk of a mutation in patients with low BRCAPRO scores is high enough to warrant genetic testing. This study demonstrates that assessment of family history by a validated model cannot effectively target testing to a high-risk ovarian cancer patient population, which strongly supports the recommendation to offer BRCA1/BRCA2 genetic testing to all patients with high-grade serous ovarian cancer regardless of family history.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2013.50.6055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876344PMC
April 2014

Virus-induced gene silencing in hexaploid wheat using barley stripe mosaic virus vectors.

Methods Mol Biol 2012 ;894:93-112

Department of Agronomy, Purdue University, West Lafayette, IN, USA.

Virus-induced gene silencing (VIGS) is a useful functional genomics tool for rapidly creating plant gene knockout phenotypes that can be used to infer gene function. Until recently, VIGS has only been possible in dicotyledonous plants. However, the development of cloning vectors based on Barley stripe mosaic virus (BSMV) has now made VIGS possible in barley and wheat. VIGS has particular advantages for functional genomics in wheat, where the organism's hexaploidy and recalcitrance to transformation have greatly hindered strategies for the functional identification of genes. In this chapter, methods are presented for using the Barley stripe mosaic virus VIGS system (BSMV-VIGS) to silence genes in hexaploid wheat.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-61779-882-5_7DOI Listing
November 2012

A clinical perspective on genetic counseling and testing during end of life care for women with recurrent progressive ovarian cancer: opportunities and challenges.

Fam Cancer 2011 Jun;10(2):193-7

U.T.M.D. Anderson Cancer Center, Department of Gynecologic Oncology, Unit 1362, PO Box 301439, Houston, TX 77230-1439, USA.

10-15% of invasive epithelial ovarian cancer is attributable to hereditary breast and ovarian cancer. The identification of BRCA1/BRCA2 mutations in women with ovarian cancer allows for accurate predictive genetic testing of their at-risk relatives, who can then avail themselves of early detection and risk reduction strategies. In the case of women with recurrent progressive ovarian cancer, the window of opportunity for genetic testing can be particularly limited. Here we describe our perspective on providing genetic counseling during these patients' end of life care, incorporating two illustrative examples from our clinical practice. While these situations pose unique challenges, they also present a significant opportunity to benefit the patient and her family. Further attention and research should be directed towards provision of genetic counseling and testing during end of life care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10689-011-9418-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286250PMC
June 2011

Knowledge, attitudes, and clinical experience of physicians regarding preimplantation genetic diagnosis for hereditary cancer predisposition syndromes.

Fam Cancer 2010 Sep;9(3):479-87

Department of Gynecologic Oncology, University of Texas M. D. Anderson Cancer Center, Unit 1362, P.O. Box 301439, Houston, TX 77230-1439, USA.

Approximately 5-10% of cancers are caused by an inherited predisposition. Individuals affected by hereditary cancer are often concerned about transmitting a predisposition to cancer to their children. Preimplantation genetic diagnosis (PGD) is a technology that allows embryos without a deleterious mutation associated with a hereditary cancer syndrome to be identified and implanted. The aim of this study is to assess the knowledge, attitudes, and clinical experience of physicians regarding PGD for hereditary cancer predisposition syndromes. Hereditary Breast and Ovarian Cancer (HBOC) and Familial Adenomatous Polyposis (FAP) are two hereditary cancer syndromes highlighted in this present study. A survey assessing physicians' attitudes, knowledge, and clinical practice was completed by a total of 373 gynecologic oncologists (GYN ONCs) and obstetrics and gynecologists (OB/GYNs). Physicians had a limited knowledge of PGD for hereditary cancer; however, physicians reported PGD was an appropriate option for patients with either HBOC or FAP. Although GYN ONCs were more likely to care for patients with hereditary cancer (P < 0.001), they were less likely than OB/GYNs to refer their patients to a PGD specialist (P = 0.004). While 80% of GYN ONCs and 91% of OB/GYNs would refer patients to a PGD specialist, clinical experience indicates that only 29% actually referred their patients. Since 68% of physicians had incorrect or limited knowledge of PGD for hereditary cancer, there is a need for additional education.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10689-010-9343-8DOI Listing
September 2010

Endometrial cancer in an adolescent: a possible manifestation of Cowden syndrome.

Obstet Gynecol 2009 Aug;114(2 Pt 2):477-479

From the Departments of Gynecologic Oncology and Clinical Cancer Genetics, the University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Background: Cowden syndrome is an autosomal dominant disorder characterized by the development of multiple intestinal hamartomas, distinctive mucocutaneous lesions, and an increased risk of endometrial, breast, and thyroid cancer.

Case: An adolescent girl whose mother had a known germline PTEN mutation presented with abnormal vaginal bleeding and was diagnosed with a grade 2 endometrial adenocarcinoma. She underwent a robotic hysterectomy and was found to have no myometrial invasion or distant disease. Genetic testing revealed the patient to have the familial germline PTEN mutation.

Conclusion: The strikingly young age of onset of this patient's endometrial cancer highlights the need for additional study to better understand Cowden syndrome and to determine what endometrial cancer screening and preventive strategies are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AOG.0b013e31819dade8DOI Listing
August 2009

Small-interfering RNAs from natural antisense transcripts derived from a cellulose synthase gene modulate cell wall biosynthesis in barley.

Proc Natl Acad Sci U S A 2008 Dec 15;105(51):20534-9. Epub 2008 Dec 15.

Department of Botany and Plant Pathology, Purdue University, West Lafayette, IN 47907-2054, USA.

Small-interfering RNAs (siRNAs) from natural cis-antisense pairs derived from the 3'-coding region of the barley (Hordeum vulgare) CesA6 cellulose synthase gene substantially increase in abundance during leaf elongation. Strand-specific RT-PCR confirmed the presence of an antisense transcript of HvCesA6 that extends > or = 1230 bp from the 3' end of the CesA-coding sequence. The increases in abundance of the CesA6 antisense transcript and the 21-nt and 24-nt siRNAs derived from the transcript are coincident with the down-regulation of primary wall CesAs, several Csl genes, and GT8 glycosyl transferase genes, and are correlated with the reduction in rates of cellulose and (1 --> 3),(1 --> 4)-beta-D-glucan synthesis. Virus induced gene silencing using unique target sequences derived from HvCesA genes attenuated expression not only of the HvCesA6 gene, but also of numerous nontarget Csls and the distantly related GT8 genes and reduced the incorporation of D-(14)C-Glc into cellulose and into mixed-linkage (1 --> 3),(1 --> 4)-beta-D-glucans of the developing leaves. Unique target sequences for CslF and CslH conversely silenced the same genes and lowered rates of cellulose and (1 --> 3),(1 --> 4)-beta-D-glucan synthesis. Our results indicate that the expression of individual members of the CesA/Csl superfamily and glycosyl transferases share common regulatory control points, and siRNAs from natural cis-antisense pairs derived from the CesA/Csl superfamily could function in this global regulation of cell-wall synthesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0809408105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603254PMC
December 2008

A guardian of grasses: specific origin and conservation of a unique disease-resistance gene in the grass lineage.

Proc Natl Acad Sci U S A 2008 Feb 29;105(5):1762-7. Epub 2008 Jan 29.

Department of Botany and Plant Pathology, Purdue University, 915 West State Street, West Lafayette, IN 47907, USA.

The maize Hm1 gene provides protection against a lethal leaf blight and ear mold disease caused by Cochliobolus carbonum race 1 (CCR1). Although it was the first disease-resistance (DR) gene to be cloned, it remains a novelty because, instead of participating in the plant recognition and response system as most DR genes do, Hm1 disarms the pathogen directly. It does so by encoding an NADPH-dependent reductase, whose function is to inactivate Helminthosporium carbonum (HC) toxin, an epoxide-containing cyclic tetrapeptide, which the pathogen produces as a key virulence factor to colonize maize. Although CCR1 is strictly a pathogen of maize, orthologs of Hm1 and the HC-toxin reductase activity are present in the grass family, suggesting an ancient and evolutionarily conserved role of this DR trait in plants. Here, we provide proof for such a role by demonstrating its involvement in nonhost resistance of barley to CCR1. Barley leaves in which expression of the Hm1 homologue was silenced became susceptible to infection by CCR1, but only if the pathogen was able to produce HC toxin. Phylogenetic analysis indicated that Hm1 evolved exclusively and early in the grass lineage. Given the devastating ability of CCR1 to kill maize, these findings imply that the evolution and/or geographical distribution of grasses may have been constrained if Hm1 did not emerge.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0711406105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2234218PMC
February 2008

Development of a virus-induced gene-silencing system for hexaploid wheat and its use in functional analysis of the Lr21-mediated leaf rust resistance pathway.

Plant Physiol 2005 Aug 15;138(4):2165-73. Epub 2005 Jul 15.

United States Department of Agriculture, Agricultural Research Service, Crop Production and Pest Control Research Unit, West Lafayette, Indiana 47907, USA.

Virus-induced gene silencing (VIGS) is an important tool for the analysis of gene function in plants. In VIGS, viruses engineered to carry sequences derived from plant gene transcripts activate the host's sequence-specific RNA degradation system. This mechanism targets the RNAs of the viral genome for degradation, and as the virus contains transcribed plant sequence, homologous host mRNAs are also targeted for destruction. While routinely used in some dicots, no VIGS system was known for monocot plants until the recent report of silencing in barley (Hordeum vulgare) by barley stripe mosaic virus (BSMV). Here, we report development of protocols for use of BSMV to efficiently silence genes in hexaploid wheat (Triticum aestivum). The VIGS system was first optimized in studies silencing phytoene desaturase expression. Next, we used it to assay genes functioning in leaf rust resistance mediated by Lr21, which encodes a nucleotide binding site-leucine-rich repeat class resistance gene product. We demonstrated that infection with BSMV constructs carrying a 150-bp fragment of Lr21 caused conversion of incompatible interactions to compatible, whereas infection with a control construct or one that silences phytoene desaturase had no effect on resistance or susceptibility. Additionally, silencing the RAR1, SGT1, and HSP90 genes, known to be required in many but not all nucleotide binding site-leucine-rich repeat resistance pathways in diverse plant species, resulted in conversion to compatibility, indicating that these genes are essential in Lr21-mediated resistance. These studies indicate that BSMV-VIGS is a powerful tool for dissecting the genetic pathways of disease resistance in hexaploid wheat.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1104/pp.105.061861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1183404PMC
August 2005

Transcriptome identification of putative genes involved in protein catabolism and innate immune response in human body louse (Pediculicidae: Pediculus humanus).

Insect Biochem Mol Biol 2003 Nov;33(11):1135-43

Indiana Center for Insect Genomics, University of Notre Dame, Notre Dame, IN 46556-0369, USA.

Genomics information relating to human body lice is surprisingly scarce, and this has constrained studies of their physiology, immunology and vector biology. To identify novel body louse genes, we used engorged adult lice to generate a cDNA library. Initially, 1152 clones were screened for inserts, edited for removal of vector sequences and base pairs of poor quality, and viewed for splicing variations, gene families and polymorphism. Computational methods identified 506 inferred open reading frames including the first predicted louse defensin. The inferred defensin aligns well with other insect defensins and has highly conserved cysteine residues, as are known for other defensin sequences. Two cysteine and five serine proteinases were categorized according to their inferred catalytic sites. We also discovered seven putative ubiquitin-pathway genes and four iron metabolizing deduced enzymes. Finally, glutathione-S-transferases and cytochrome P450 genes were among the detoxification enzymes found. Results from this first systematic effort to discover human body louse genes should promote further studies in Phthiraptera and lice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/s0965-1748(03)00133-4DOI Listing
November 2003
-->