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Supplementary Figure 1 PDF file 108K, This document provides the raw data for V1736A genotyping used in LOH experiments

Supplementary Table 1 PDF file 38K, This table summarizes all additional V1736A pedigrees

Supplementary Methods PDF file 61K, This document describes the methods for all supplemental data

Supplementary Figure 2 PDF file 78K, This figure depicts the assay used to visualize repair proteins at DNA double-strand breaks

Supplementary Figure 3 PDF file 2065K, This figure provides functional data for BRCA1 V1736A and an example of tumor for LOH studies

Supplementary Figure 1 from The Relative Contribution of Point Mutations and Genomic Rearrangements in BRCA1 and BRCA2 in High-Risk Breast Cancer Families

Supplementary Figure 2 from The Relative Contribution of Point Mutations and Genomic Rearrangements in BRCA1 and BRCA2 in High-Risk Breast Cancer Families

Supplementary Figure 3 from The Relative Contribution of Point Mutations and Genomic Rearrangements in BRCA1 and BRCA2 in High-Risk Breast Cancer Families

Supplementary Tables 1-2 from The Relative Contribution of Point Mutations and Genomic Rearrangements in BRCA1 and BRCA2 in High-Risk Breast Cancer Families

Supplementary Figure Legends 1-3 from The Relative Contribution of Point Mutations and Genomic Rearrangements in BRCA1 and BRCA2 in High-Risk Breast Cancer Families

Osteosarcoma (OS) and Leiomyosarcoma (LMS) are sarcomas with complex genomes for which there has been limited progress in identifying new treatments and improving outcomes. Slow progress in OS and LMS is partially due to insufficient characterization of the genomic landscape. Generating large genomic datasets in OS and LMS is challenging because of the rarity of these sarcomas and recruitment barriers such as care fragmentation between institutions and specialties. The OS and LMS Project research studies aim to: 1) establish a network of engaged pediatric and adult participants with OS and LMS who will co-create a shared database of clinical, genomic, molecular, and patient reported data to enable research; 2) define the clinicogenomic landscape of OS and LMS; and 3) optimize the approach to direct patient engagement in cancer research. Count Me In, a research initiative with prior success in angiosarcoma, working with patients and advocates created websites (OSProject.org and LMSProject.org) where patients register and consent to participation. Within two months of launching, 233 patients age 6-79 from 149 Institutions have consented. Blood and saliva are collected from consented participants, tumor samples are obtained from pathology departments and medical records are requested from treating hospitals. WES and WGS of tumor and normal, and RNASeq of tumor is performed. ctDNA is obtained and sequenced. Results are shared with patient, advocacy, physician and research communities in several ways. Individual participants receive a shared learning report describing the somatic variants identified in their tumor from paired tumor-normal WES and are offered genetic counseling and clinical germline testing. Registered participants receive updates via email and Project websites. There are regular pre-publication data releases to the genomic data commons and to cBioPortal. A physician engagement committee meets regularly to discuss clinical insights and conundrums from shared learning reports and germline testing. Patient accrual over the next 3 years is anticipated to result in sequencing of 750 tumor-normal pairs and 500 ctDNA samples. Citation Format: Katherine A. Janeway, Suzanne George, Corrie Painter, Carrie Cibulskis, Taylor Cusher, Jordan Doucette, Elana Anastasio, Benjamin Zola, Ashley Mathews, Evelina Ceca, Maeve Smart, Beena Thomas, Jason Hornick, Alanna Church, Lorena Lazo De La Vega, Jill Stopfer, Sidney Benich, Ellen Sukharevsky, Sarah Winnicki, Brendan Reardon, Brian Crompton, Priscilla Merriam, Adrian Marino-Enriquez, Diane Diehl, Eliezer VanAllen, Judy Garber, Gad Getz, Stacey Gabriel, Timothy Rebbeck, Jennifer Mack, Nikhil Wagle. The Osteosarcoma and Leiomyosarcoma Count Me In Projects of the Cancer Moonshot funded PE-CGS Network directly engage patient participants in genomics research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6084.

PURPOSE: Although multigene panel testing (MGPT) is increasingly utilized in clinical practice, there remain limited data on patient-reported outcomes. METHODS: BRCA 1/2 negative patients were contacted and offered MGPT. Patients completed pre- and post-test counseling, and surveys assessing cognitive, affective and behavioral outcomes at baseline, post-disclosure and 6 and 12 months. RESULTS: 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 post-disclosure. 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. CONCLUSION: 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.

Background: The COVID-19 pandemic influenced patient health care decisions, but there is little information about the pandemic’s impact on decisions about cancer risk reduction. This includes women at elevated risk of breast or ovarian cancer considering risk-reducing salpingo-oophorectomy (RRSO), risk-reducing salpingectomy (RRS), or other preventive measures. During the pandemic patients needed to balance their concerns about cancer risk reduction with their risks associated with elective health procedures, a risk which changed as vaccines became available. Methods: To address the impact of the COVID-19 pandemic on cancer prevention decision making, we recruited N=396 pre-menopausal women with a personal history of breast cancer or familial history suggestive of increased breast and/or ovarian cancer risk between 4/2019 and 3/2022. We conducted a discrete choice experiment in which patients were asked to choose between two scenarios that specified type of surgery (RRSO, RRS vs. non-surgical surveillance), age of menopause (natural versus immediate), quality of menopausal symptoms (mild, moderate, severe), and risk of ovarian cancer, heart disease, or osteoporosis. Risk of ovarian cancer for the scenarios provided varied in discrete intervals from 0% to 40%. We examined temporal trends during the pandemic using interactions with time coinciding approximately with the beginning of pandemic, peak vaccination period, and the Omicron wave. Results: We identified significant temporal interactions on a woman’s prevention decisions. In 2019, women at higher risk of ovarian cancer were more likely to choose prevention scenarios that favored lower ovarian cancer risk (odds ratio [OR] = 0.48; 95% CI = 0.37, 0.69 per 10% increase in ovarian cancer risk difference). This association decreased through the pre-vaccine period of 2020 by OR=2.61/month (95% CI = 1.21, 5.65). By June 2020, the effect of a 10% increase in ovarian cancer risk on intervention choice had attenuated substantially (OR=0.84, 95% CI 0.67, 1.00). By January 2022, the effect strengthened (OR= 0.69, 95% CI .49, .88), but had not reached pre-pandemic levels. Before 3/2020, natural age of menopause (versus immediate) had a strong impact on the choice of a scenario (OR=3.56, 95% CI 1.65-7.65). At the beginning of the pandemic, the effect was reduced by 0.47/month (95% CI 0.22-0.99). The rate of attenuation slowed over time, such that the effect of having a natural age of menopause on choice was OR= 1.56 (95% CI 0.65, 2.46) by January 2022. Tests for temporal interactions were statistically significant for both ovarian cancer risk and age of menopause. Conclusions: Our results suggest that over the course of the pandemic, women seemed more accepting of higher risks of ovarian cancer and immediate (post treatment) menopause when considering preventive options. There was an inverse U shape curve of the effect of ovarian cancer risk on choices over time (Figure A), but the strength of the relationship had not reached pre-pandemic levels by January 2022. This may reflect patient tolerance for side effects as the pandemic evolved. These results suggest that factors such as ovarian cancer risk and delay of menopause influenced personal prevention choices, but that these choices were influenced by events related to events that hallmarked the COVID-19 pandemic. Citation Format: Brian Egleston, Mary Daly, Kaitlyn Lew, Lisa Bealin, Alexander Husband, Jill Stopfer, Pawel Przybysz, Olga Tchuvatkina, Yu-Ning Wong, Judy Garber, Timothy Rebbeck. Changes in preferences for ovarian cancer prevention strategies during the COVID-19 pandemic: Results of a discrete choice experiment. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-16.

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, BRCA1/2 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: NCT01736345), 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 ( P = .02) and varied by site (46% to 78%; P < .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 ( P = .04), state anxiety ( P = .03), depression ( P = .04), and uncertainty ( P = .05) pre-disclosure compared with patients offered targeted testing. State anxiety ( P = .05) and cancer-specific distress ( P = .05) were lower at disclosure in the MGP group. There was a greater increase in change in uncertainty ( P = .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.

Purpose To better understand the longitudinal risks and benefits of telephone disclosure of genetic test results in the era of multi-gene panel testing. Patients and 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) of test results (i.e., usual care). All participants who received TD were recommended to return to meet with a physician to discuss medical management recommendations. Results 473 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

Background While there is increasing interest in sharing genetic research results with participants, how best to communicate the risks, benefits and limitations of research results remains unclear. Methods Participants who received genetic research results answered open and closed‐ended questions about their experiences receiving results and interest in and advantages and disadvantages of a web‐based alternative to genetic counseling. Results 107 BRCA1/2 negative women with a personal or family history of breast cancer consented to receive genetic research results and 82% completed survey items about their experience. Most participants reported there was nothing they disliked (74%) or would change (85%) about their predisclosure or disclosure session (78% and 89%). They most frequently reported liking the genetic counselor and learning new information. Only 24% and 26% would not be willing to complete predisclosure counseling or disclosure of results by a web‐based alternative, respectively. The most frequently reported advantages included convenience and reduced time. Disadvantages included not being able to ask questions, the risk of misunderstanding and the impersonal nature of the encounter. Conclusion Most participants receiving genetic research results report high satisfaction with telephone genetic counseling, but some may be willing to consider self‐directed web alternatives for both predisclosure genetic education and return of results.

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.BRCA1/2-negative and untested patients completed pre- and posttest counseling and surveys evaluating testing experiences and cognitive and affective responses to multiplex testing.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%; P0.01). 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.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.

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.

This study examines the analytic validity of a software tool designed to provide individuals with risk assessments for colorectal cancer based on personal health and family history information. The software is compatible with the US Surgeon General's My Family Health Portrait (MFHP).An algorithm for risk assessment was created using accepted colorectal risk assessment guidelines and programmed into a software tool (MFHP). Risk assessments derived from 150 pedigrees using the MFHP tool were compared with "gold standard" risk assessments developed by three expert cancer genetic counselors.Genetic counselor risk assessments showed substantial, but not perfect, agreement. MFHP risk assessments for colorectal cancer yielded a sensitivity for colorectal cancer risk of 81% (95% confidence interval: 54-96%) and specificity of 90% (95% confidence interval: 83-94%), as compared with genetic counselor pedigree review. The positive predictive value for risk for MFHP was 48% (95% confidence interval: 29-68%), whereas the negative predictive value was 98% (95% confidence interval: 93-99%). Agreement between MFHP and genetic counselor pedigree review was moderate (κ = 0.54).The analytic validity of the MFHP colorectal cancer risk assessment software is similar to those of other types of screening tools used in primary care. Future investigations should explore the clinical validity and utility of the software in diverse population groups.Genet Med 17 9, 753-756.

Clinical testing for germ-line variation in multiple cancer susceptibility genes is available using massively parallel sequencing. Limited information is available for pretest genetic counseling regarding the spectrum of mutations and variants of uncertain significance in defined patient populations.We performed massively parallel sequencing using targeted capture of 22 cancer susceptibility genes in 278 BRCA1/2-negative patients with early-onset breast cancer (diagnosed at younger than 40 years of age).Thirty-one patients (11%) were found to have at least one deleterious or likely deleterious variant. Seven patients (2.5% overall) were found to have deleterious or likely deleterious variants in genes for which clinical guidelines exist for management, namely TP53 (4), CDKN2A (1), MSH2 (1), and MUTYH (double heterozygote). Twenty-four patients (8.6%) had deleterious or likely deleterious variants in a cancer susceptibility gene for which clinical guidelines are lacking, such as CHEK2 and ATM. Fifty-four patients (19%) had at least one variant of uncertain significance, and six patients were heterozygous for a variant in MUTYH.These data demonstrate that massively parallel sequencing identifies reportable variants in known cancer susceptibility genes in more than 30% of patients with early-onset breast cancer. However, only few patients (2.5%) have definitively actionable mutations given current clinical management guidelines.Genet Med 17 8, 630-638.

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.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.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.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.

Background: Given the increasing demand for genetic services and limited genetic workforce, many patients do not receive recommended pre- and post-test genetic counseling. Telemedicine has been used to expand specialized medical services to low access populations. The feasibility and outcomes of telemedicine in clinical genetics are not well described. Methods: Patients at 3 community sites without genetic counseling services received real-time pre-test (V1) and post-test (V2) counseling for cancer susceptibility with a genetic counselor (GC) at a center of expertise via community sites’ and host institution’s computers equipped with web cameras and videoconferencing software. Mixed-methods surveys assessed patient knowledge, satisfaction, psychosocial responses and experiences at baseline (BL), post-V1 and post-V2. We used paired T-tests to assess change between time points and linear regressions. Results: Of 100 patients approached, 83% consented to telegenetic services. To date, 57 have completed BL and V1, and 70% proceeded with genetic testing, 31 patients have received results, including 3 carriers (BRCA2, MSH2, PMS2). Patient characteristics did not differ between those who agreed to and declined telegenetics. 4% of sessions were aborted due to technology failures. 30% experienced disconnections but were completed. Nearly all (94%) were satisfied with their telegenetic experience. Knowledge and satisfaction with telegenetic services significantly increased and general anxiety and depression significantly decreased. Event related (state) anxiety did not change significantly. Table 1.OutcomeBL Mean (sd)Post-V1 Mean(sd)Post-V2 Mean(sd)pKnowledge (6-28)20.9(2.8)22.0 (3.0) 0.007 20.8 (3.3)21.8(3.2)21.5(3.1)NSSGeneral Anxiety (0-21)7.4(4.1)6.6(4.1) 0,02 6.6 ((4.0)5.7 (3.8)5.7 (3.5)0.06Genarla Depression(0-21)3.9 (3.9)3.5 (3.4) 0,05 3.6 (3.7)3.4(3.5)2.9 (3.5)0.07State Anxiety(20-80)36.0(15.2)35.7(13.7) NSS 34.6(15.0)34.5(13.1)32.1(12.5)NSSSatisfaction with Genetic Services 39.5(3.( 39.8(4.0)42.2(3.6)0.002Satisfaction with Telemedicine 51.3(5.6) 51.5(5.7)53.0(5.3)0.008 Patients reported several advantages to telegenetics (e.g. decreased travel burden) and few disadvantages (e.g. audio challenges and technical glitches).Conclusions: Telemedicine delivery of cancer genetic services is feasible, identifies genetic mutation carriers, increases knowledge, decreases anxiety and depression and is associated with high satisfaction, suggesting an innovative model for delivery of genetic services for patients and community practices without access to local genetic providers. Citation Format: Linda Patrick-Miller, Diana Harris, Evelyn Stevens, Brian Egleston, Linda Fleisher, Rebbeca Mueller, Amanda Brandt, Jill Stopfer, Susan Domchek, Angela Bradbury. Telemedicine: Expanding access to cancer genetic services to underserved populations [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-11-02.

Background: New counseling models for multiplex genetic testing for breast cancer susceptibility are needed. Further, the risks, benefits and utilities of multiplex genetic panels are unknown. Purpose: To obtain stakeholder feedback on an innovative tiered-binned model for pretest counseling and informed consent for multiplex testing and to evaluate the uptake of, cognitive and affective responses to and perceived utility of panel testing. Methods: Patients previously BRCA1/2- or BRCA1/2 untested completed in-person pre-test (V1) and post-test counseling (V2) and surveys regarding the novel counseling model and evaluating cognitive and affective responses to, and perceived utility of the 26 gene Myriad MyRisk panel for cancer susceptibility. Results: 49 patients (62% of eligible) enrolled and completed V1. 38% of decliners were not interested in panel testing. BRCA1/2- were more likely to proceed with MyRisk (89%) than BRCA1/2 untested (48%, p Table 1 BaselinePost V1Post V2 Mean (SD)Mean (SD)Mean (SD)General Anxiety6.8 (3.9)*6.1 (4.0)* 7.2 (3.5)*6.1 (3.6)*5.8 (4.2)*General Depression2.6 (3.0)2.3 (2.6) 2.6 (2.9)2.3 (2.6)2.9 (3.6)Event Anxiety37.1 (9.6)37.7 (9.5) 37.0 (8.9)37.3 (8.5)37.3 (9.4)Cancer Worry18.3 (15.7)16.9 (14.1) 18.4 (15.4)15.7 (14.1)6.6 (14.7)Knowledge (K) Total61.8 (6.1)**63.9 (6.4)** 62.1 (6.7)**64.1 (6.8)**66.3 (6.9)**K-Inheritance29.5 (3.2)30.0 (3.2) 29.7 (3.5)29.8 (3.3)30.3 (3.7)K-Benefits12.0 (1.4)12.3 (1.8) 12.0 (1.4)12.4 (1.7)12.4 (1.9)K-Limitations20.3 (3.2)**21.6 (2.8)** 20.4 (3.4)**21.9 (3.0)**23.6 (2.6)**Satisfaction 42.8 (3.8) 42.9 (3.6)*41.4 (2.6)*Uncertainty7.5 (4.3)6.9 (4.6) 7.7 (4.0)6.5 (4.5)6.7 (4.6)Perceived Utility 37.2 (7.9) 37.7 (7.0)*33.8 (8.6)**p,0.05, **p Conclusion: With a tiered-binned counseling model, patients experience increased knowledge. Uptake of panel testing varies by prior testing and potentially by patient affective factors. Most patients do not experience negative psychological responses, although this may vary by test result. Declines in satisfaction and perceived utility may also vary by test result and may reflect the current unclear utility and uncertainty of multiplex testing. Citation Format: Angela R Bradbury, Linda Patrick-Miller, Brian L Egleston, Amanda Brandt, Jessica Long, Jacquelyn Powers, Jill Stopfer, Laura DiGiovanni, Jamie Brower, Susan M Domchek. Uptake and outcomes of multiplex testing for breast cancer susceptibility [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-10.

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.

A1 Introduction to the 8th Annual Conference on the Science of Dissemination and Implementation: Optimizing Personal and Population Health David Chambers1, Lisa Simpson2 1Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Rockville, MD, 20850, USA; 2AcademyHealth, Washington, DC, 20036, USA For the second year in a row, we are pleased to be able to share the proceedings of the Annual Conference on the Science of Dissemination and Implementation in Health, a large meeting reflecting the expanding and evolving research field that seeks to optimize the use of evidence, interventions, and tools from health research within the myriad of settings where people receive health care, make health-related decisions, and increase knowledge of influences on the health of the population. We once again benefitted from a strong partnership, co-led by AcademyHealth and the National Institutes of Health (NIH), with co-sponsorship from the Agency for Healthcare Research and Quality (AHRQ), the Patient Centered Outcomes Research Institute (PCORI), the Robert Wood Johnson Foundation (RWJF), the US Department of Veterans Affairs (VA), and the WT Grant Foundation. In addition, we benefitted from the collaboration of staff from the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). NIH and AcademyHealth again co-led the program planning committee, which focused on the development of the plenary sessions, and convened a scientific advisory panel to suggest speakers and advise on the overall conference development. The planning committee identified four key areas around which to focus the plenary panels and keynote address. Dr. America Bracho, M.D., M.P.H., Executive Director of Latino Health Access in Orange County, California, spoke about the opportunities for implementation science to inform efforts to improve community health and engage underserved populations. The three plenary panels each focused on a significant future direction for dissemination and implementation (D & I) research: the interface between D&I science and population health, emerging opportunities for global implementation science, and the challenges around implementation of precision medicine. The plenary sessions were complemented by facilitated lunchtime discussions on the same three topics, which offered participants an opportunity to identify key research questions for each and brainstorm next steps. Synopses of the lunchtime discussions are included in this supplement. Given the overwhelming success of the 2014 conference and the large number of abstracts received in 2014 (660), the program planning committee identified eight program tracks for abstract submitters to respond to, and through which the concurrent sessions of the conference would be organized. These tracks—Behavioral Health, Big Data and Technology for Dissemination and Implementation Research, Clinical Care Settings, Global Dissemination and Implementation, Promoting Health Equity and Eliminating Disparities, Health Policy Dissemination and Implementation, Prevention and Public Health, and Models, Measures and Methods— were designed to enable conference participants to follow a consistent theme across the multiple sessions of the conference and form the structure of this supplement. The call for abstracts, including individual paper presentations, individual posters and panel presentations, resulted in 515 submissions, spread across the eight thematic tracks. Over one hundred reviewers devoted their time to ensuring a comprehensive and expert review, and reviews were conducted within each track and coordinated by the track leads. For the final program, 64 oral presentations, 12 panels, and 263 posters were presented over the two-day meeting. Slides for the oral presentations and panels (with the agreement of the authors) were posted on the conference website (http://diconference.academyhealth.org/archives/2015archives) and all abstracts were included on the conference webapp (https://academyhealth.confex.com/academyhealth/2015di/meetingapp.cgi). This supplement has compiled the abstracts for presented papers, panel sessions, and lunchtime discussions from the 8th Annual Meeting on the Science of Dissemination and Implementation in Health: Optimizing Personal and Population Health. We are pleased to have the abstracts from the conference together in one volume once again, and look forward to the 9th Annual meeting, scheduled for December in Washington, D.C.

Experimental and clinical data support a role for estrogens in the development and growth of breast cancer, and lowered estrogen exposure reduces breast cancer recurrence and new diagnoses in high-risk women. There is varied evidence that increased physical activity is associated with breast cancer risk reduction in both pre- and postmenopausal women, perhaps via lowered estrogen levels. The purpose of this study was to assess whether exercise intervention in premenopausal women at increased breast cancer risk reduces estrogen or progesterone levels. Seven healthy premenopausal women at high risk for breast cancer completed a seven-menstrual-cycle study. The study began with two preintervention cycles of baseline measurement of hormone levels via daily first-morning urine collection, allowing calculation of average area under the curve (AUC) hormone exposure across the menstrual cycle. Participants then began five cycles of exercise training to a maintenance level of 300 min per week at 80–85% of maximal aerobic capacity. During the last two exercise cycles, urinary estradiol and progesterone levels were again measured daily. Total estrogen exposure declined by 18.9% and total progesterone exposure by 23.7%. The declines were mostly due to decreased luteal phase levels, although menstrual cycle and luteal phase lengths were unchanged. The study demonstrated the feasibility of daily urine samples and AUC measurement to assess hormone exposure in experimental studies of the impact of interventions on ovarian hormones. The results suggest value in exercise interventions to reduce hormone levels in high-risk women with few side effects and the potential for incremental benefits to surgical or pharmacologic interventions.

Purpose Short-term reactions to BRCA1 and BRCA2 (BRCA1/2) genetic test results have been described in several reports, but the long-terms effects of testing have not been examined extensively. Methods We conducted an observational study to characterize the long-term impact of genetic testing for BRCA1/2 mutations in 167 women who had received genetic test results at least 4 years ago. We also evaluated the relationship between genetic testing–specific reactions and breast and ovarian cancer screening to determine the behavioral significance of adverse reactions. Results Seventy-four percent of women were not experiencing any distress regarding their test result, 41% were not experiencing any uncertainty, and 51% had a score for positive experiences that was suggestive of low levels of adverse reactions in terms of family support and communication. Mutation carriers (odds ratio, 3.96; 95% CI, 1.44 to 10.89; P = .01) were most likely to experience distress. Only less time since disclosure was related significantly to experiencing uncertainty (odds ratio, 0.62; 95% CI, 0.44 to 0.88; P = .008). In terms of cancer screening, 81% of women had a mammogram during the year before study enrollment, 25% had magnetic resonance imaging (MRI), 20% had a transvaginal ultrasound, and 20% had a CA-125. Experiencing distress was associated significantly with having a CA-125 (χ2 = 3.89, P = .05), and uncertainty was associated with having an MRI (χ2 = 8.90, P = .003). Conclusion Our findings show that women are not likely to experience genetic testing concerns several years after receiving BRCA1/2 test results; distress and uncertainty are not likely to have adverse effects on screening among women at risk for hereditary disease.

Annual MRI screening is recommended as an adjunct to mammography for BRCA1 and BRCA2 mutation carriers. Prophylactic oophorectomy has been shown to decrease breast cancer risk in BRCA1/2 mutation carriers. Here, we aimed to examine the combined effects of MRI and oophorectomy. For this purpose, 93 BRCA1/2 mutation carriers were screened with yearly mammograms and yearly MRI scans. Study endpoints were defined as date of breast cancer diagnosis, date of prophylactic mastectomy, or date of most recent contact. Of 93 women, with a median age of 47, 80 (86%) had prophylactic oophorectomy. Fifty-one women (55%) had BRCA1 mutations. A total of 283 MRI scans were performed. Eleven breast cancers (9 invasive, 2 ductal carcinoma in situ) were detected in 93 women (12%) with a median follow-up of 3.2 years (incidence 40 per 1,000 person-years). Six cancers were first detected on MRI, three were first detected by mammogram, and two were “interval cancers.” All breast cancers occurred in BRCA1 mutation carriers (incidence 67 per 1,000 person-years). Apart from BRCA1 vs. BRCA2 mutation status, there were no other significant predictors of breast cancer incidence. Most invasive breast cancers were estrogen receptor negative (7 of 9) and lymph node negative (7 of 9). There have been no systemic recurrences with a median follow-up of 19 months after cancer diagnosis. Finally, it was concluded that all breast cancers occurred in BRCA1 mutation carriers, in most cases despite oophorectomy. These data suggest that surveillance and prevention strategies may have different outcomes in BRCA1 and BRCA2 mutation carriers.

This observational study evaluated utilization of religious coping strategies among 95 African American women who were at increased risk for having a BRCA1/BRCA2 (BRCA1/2) mutation. Overall, women reported high levels of collaborative coping; however, women with fewer than 2 affected relatives (beta = -1.97, P = 0.04) and those who had a lower perceived risk of having a BRCA1/2 mutation (beta = -2.72, P = 0.01) reported significantly greater collaborative coping. These results suggest that African American women may be likely to use collaborative strategies to cope with cancer-related stressors. It may be important to discuss utilization of religious coping efforts during genetic counseling with African American women.

The demand for BRCA1 and BRCA2 mutation screening is increasing as their identification will affect medical management. However, both the contribution of different mutation types in BRCA1 and BRCA2 and whom should be offered testing for large genomic rearrangements have not been well established in the U.S. high-risk population. We define the prevalence and spectrum of point mutations and genomic rearrangements in BRCA genes in a large U.S. high-risk clinic population of both non-Ashkenazi and Ashkenazi Jewish descent, using a sample set representative of the U.S. genetic testing population. Two hundred fifty-one probands ascertained through the University of Pennsylvania high-risk clinic, all with commercial testing for BRCA1 and BRCA2, with an estimated prevalence of BRCA mutation ≥10% using the Myriad II model and a DNA sample available, were studied. Individuals without deleterious point mutations were screened for genomic rearrangements in BRCA1 and BRCA2. In the 136 non-Ashkenazi Jewish probands, 36 (26%) BRCA point mutations and 8 (6%) genomic rearrangements (7 in BRCA1 and 1 in BRCA2) were identified. Forty-seven of the 115 (40%) Ashkenazi Jewish probands had point mutations; no genomic rearrangements were identified in the group without mutations. In the non-Ashkenazi Jewish probands, genomic rearrangements constituted 18% of all identified BRCA mutations; estimated mutation prevalence (Myriad II model) was not predictive of their presence. Whereas these findings should be confirmed in larger sample sets, our data suggest that genomic rearrangement testing be considered in all non-Ashkenazi Jewish women with an estimated mutation prevalence ≥10%. [Cancer Res 2008;68(17):7006–14]

Uptake of genetic testing remains low, even in families with known BRCA1 and BRCA2 (BRCA1/2) mutations, despite effective interventions to reduce risk. We report disclosure and uptake patterns by BRCA1/2-positive individuals to at-risk relatives, in the setting of no-cost genetic counseling and testing.Relatives of BRCA1/2-positive individuals were offered cost-free and confidential genetic counseling and testing. If positive for a BRCA1/2 mutation, participants were eligible to complete a survey about their disclosure of mutation status and the subsequent uptake of genetic testing by at-risk family members.One hundred and fifteen of 142 eligible individuals responded to the survey (81%). Eighty-eight (77%) of those surveyed disclosed results to all at-risk relatives. Disclosure to first-degree relatives (FDRs) was higher than to second-degree relatives (SDRs) and third-degree relatives (TDR) (95% vs. 78%; p0.01). Disclosure rates to male versus female relatives were similar, but reported completion of genetic testing was higher among female versus male FDRs (73% vs. 49%; p0.01) and SDRs (68% vs. 43%; p0.01), and among members of maternal versus paternal lineages (63% vs. 0%; p0.01). Men were more likely than women to express general difficulty discussing positive BCRA1/2 results with at-risk family members (90% vs. 70%; p = 0.03), while women reported more emotional distress associated with disclosure than men (48% vs. 13%; p0.01).We report a very high rate of disclosure of genetic testing information to at-risk relatives. However, uptake of genetic testing among at-risk individuals was low despite cost-free testing services, particularly in men, SDRs, and members of paternal lineages. The complete lack of testing among paternally related at-risk individuals and the lower testing uptake among men signify a significant barrier to testing and a challenge for genetic counselors and physicians working with high-risk groups. Further research is necessary to ensure that family members understand their risk and the potential benefits of genetic counseling.

Although African American breast cancer survivors are at increased risk for developing breast cancer again, empirical data are not available on breast cancer risk perceptions in these women. This study characterized perceived risk of developing breast cancer in African American breast cancer survivors at risk for having a BRCA1 or BRCA1 (BRCA1/2) mutation and identified factors having significant independent associations with risk perceptions. Participants were 95 African American breast cancer survivors at an increased risk for having a BRCA1/2 mutation. Risk perceptions and sociodemographic, clinical, treatment, and sociocultural factors were collected during a structured telephone interview. Most women reported that they had the same or lower risk of developing breast cancer again compared with other women (53%); however, a substantial minority of women (47%) reported that they had a higher or much higher risk. Factors having significant independent associations with heightened risk perceptions included having a ≥10% prior probability of having a BRCA1/2 mutation [odds ratio (OR), 2.91; 95% confidence interval (95% CI), 1.09-7.72; P = 0.03] and more years of formal education (OR, 2.74; 95% CI, 1.02-7.36; P = 0.05). In addition, women who thought about the past a lot were three times more likely to report heightened risk perceptions compared with those who did not think about the past a lot (OR, 3.72; 95% CI, 1.45-9.57; P = 0.01). These results suggest that it may be important to ensure adequate risk comprehension among African American women as part of genetic counseling for inherited breast-ovarian cancer risk. Discussion of risk perceptions within the context of existing beliefs and values may facilitate this process. (Cancer Epidemiol Biomarkers Prev 2007;16(2):244–8)

Background: Dysregulation of adipokines, such as adiponectin and leptin, is associated with a variety of chronic diseases, including cancer. Physical activity protects against breast cancer and one of the mechanisms which may underlie this association is exercise-induced changes in adipokine levels. The WISER Sister Trial was a three-armed randomized controlled trial in premenopausal women (n = 137) with an elevated risk for breast cancer. Methods: A 5-menstrual-cycle-long dosed aerobic exercise intervention compared low-dose exercise (150 min/wk; n = 44) or high-dose exercise (300 min/wk; n = 48) with a control group asked to maintain usual activity levels (n = 45). Exercise intensity progressed to and was maintained at 70% to 80% of age predicted heart rate max. Body composition and adipokine levels were measured at baseline and follow-up. Results: We observed significant linear trends for increased fitness capacity (Δ%: −2.0% control, 10.1% low dose, 13.1% high dose), decreased fat tissue-to-total tissue mass (Δ%: 0.7% control, −2.9% low dose, −3.7% high dose), increased body fat adjusted adiponectin (Δ%: −0.6% control, 0.6% low dose, 0.9% high dose), and decreased body fat adjusted leptin (Δ%: 0.7% control, −8.2% low dose, −10.2% high dose). Conclusions: In this randomized clinical trial of premenopausal women at risk for breast cancer, we demonstrate a dose–response effect of exercise on adiponectin and leptin and that dose response is dependent on changes in body fat. Impact: Improved adipokine levels, achieved by aerobic exercise training-induced decreases in body fat, may decrease breast cancer risk for high-risk premenopausal women. Cancer Epidemiol Biomarkers Prev; 25(8); 1195–200. ©2016 AACR.

Medical and surgical interventions for elevated breast cancer risk (e.g., BRCA1/2 mutation, family history) focus on reducing estrogen exposure. Women at elevated risk may be interested in less aggressive approaches to risk reduction. For example, exercise might reduce estrogen, yet has fewer serious side effects and less negative impact than surgery or hormonal medications. Randomized controlled trial. Increased risk defined by risk prediction models or BRCA mutation status. Eligibility: Age 18–50, eumenorrheic, non-smokers, and body mass index (BMI) between 21 and 50 kg/m2. 139 were randomized. Treadmill exercise: 150 or 300 min/week, five menstrual cycles. Control group maintained exercise

Purpose: This study evaluated rates of BRCA1 and BRCA2 (BRCA1/2) test result acceptance among African American women and identified determinants of test result acceptance. Methods: Acceptance of BRCA1/2 test results was evaluated among 157 African American women at high and moderate risk for having a BRCA1/2 mutation who were offered genetic testing as part of a clinical genetic counseling research program. Results: Twenty-two percent of women received BRCA1/2 test results. Test result acceptance differed between women with ≥10% prior probability of having a BRCA1/2 mutation (34%) and those who had a 5% prior probability (8%). Among women with ≥10% prior probability, test result acceptors were most likely to be married (OR = 5.29, 95% CI = 1.82, 15.38, P = 0.002) and be less certain about their risk of developing cancer (OR = 3.18, 95% CI = 1.04, 9.80, P = 0.04). Conclusion: These results demonstrate that acceptance of BRCA1/2 test results may be limited among African American women. Being married and having less certainty about one's cancer risk may motivate acceptance of BRCA1/2 test results among African American women. It may be important to emphasize the possibility that BRCA1/2 test results may not clarify cancer risks during pre-test counseling with African American women to ensure informed decision-making about testing.

These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in this document is derived from extensive review of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provide information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Key components include the intake (medical and family histories), psychosocial assessment (assessment of risk perception), cancer risk assessment (determination and communication of risk), molecular testing for hereditary cancer syndromes (regulations, informed consent, and counseling process), and follow-up considerations. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of a client.

Background: Increasing numbers of BRCA1 mutation carriers are being identified in cancer risk evaluation programs. However, no estimates of cancer risk specific to a clinic-based population of mutation carriers are available. These data are clinically relevant, because estimates based on families ascertained for linkage studies may overestimate cancer risk in mutation carriers, and population-based series may underestimate it. Wide variation in risk estimates from these disparate ascertainment groups makes counseling in risk evaluation programs difficult. The purpose of this study was to estimate BRCA1-related cancer risks for individuals ascertained in a breast cancer risk evaluation clinic. Methods: Cumulative observed and age-adjusted cancer risk estimates were determined by analyzing 483 BRCA1 mutation carriers in 147 families identified in two academic breast and ovarian cancer risk evaluation clinics. Cancer risks were computed from the proportion of individuals diagnosed with cancer during a 10-year age interval from among the total number of individuals alive and cancer-free at the beginning of that interval. Age-of-diagnosis comparisons were made using two-sided Student's t tests. Results: By age 70, female breast cancer risk was 72.8% (95% confidence interval [CI] = 67.9% to 77.7%) and ovarian cancer risk was 40.7% (95% CI = 35.7% to 45.6%). The risk for a second primary breast cancer by age 70 was 40.5% (95% CI = 34.1% to 47.0%). We also identified an increased risk of cancer of the colon (twofold), pancreas (threefold), stomach (fourfold), and fallopian tube (120-fold) in BRCA1 mutation carriers as compared with Surveillance, Epidemiology, and End Results (SEER) Program population-based estimates. Conclusion: The estimates for breast and ovarian cancer risk in BRCA1 mutation carriers is higher than population-based estimates but lower than estimates based on families ascertained for linkage studies. These cancer risk estimates may most closely approximate those faced by BRCA1 mutation carriers identified in risk evaluation clinics.

BRCA1 and BRCA2 are the most important breast and ovarian cancer susceptibility genes. Biallelic mutations in BRCA2 can lead to Fanconi anemia and predisposition to cancers, whereas biallelic BRCA1 mutations have not been confirmed, presumably because one wild-type BRCA1 allele is required during embryogenesis. This study describes an individual who was diagnosed with ovarian carcinoma at age 28 and found to have one allele with a deleterious mutation in BRCA1, c.2457delC (p.Asp821Ilefs*25), and a second allele with a variant of unknown significance in BRCA1, c.5207T>C (p.Val1736Ala). Medical records revealed short stature, microcephaly, developmental delay, and significant toxicity from chemotherapy. BRCA1 p.Val1736Ala cosegregated with cancer in multiple families, associated tumors showed loss of wild-type BRCA1, and BRCA1 p.Val1736Ala showed reduced DNA damage localization. These findings represent the first validated example of biallelic deleterious human BRCA1 mutations and have implications for the interpretation of genetic test results. Significance: Accurate assessment of genetic testing data for BRCA1 mutations is essential for clinical monitoring and treatment strategies. Here, we report the first validated example of an individual with biallelic BRCA1 mutations, early-onset ovarian cancer, and clinically significant hypersensitivity to chemotherapy. Cancer Discov; 3(4); 399–405. ©2012 AACR. See related commentary by D'Andrea, p. 376 This article is highlighted in the In This Issue feature, p. 363

Low rates of genetic counseling among African American women have generated concerns about disparities; however, to the extent that women's decisions to accept or decline counseling are consistent with their values, then lower participation may reflect preferences and not disparities. We evaluated the extent to which women were satisfied with their decision about participating in genetic counseling for BRCA1/2 mutations and identified variables that were associated significantly with satisfaction. Prospective study of decision satisfaction with 135 African American women who had a minimum 5% prior probability of having a BRCA1/2 mutation. Decision satisfaction was evaluated one month after women were offered participation in genetic counseling using a structured questionnaire. Women were satisfied with their participation decision; more than 80% reported that their decision was consistent with their family values. However, women who declined pre-test counseling had significantly lower satisfaction scores. Our findings highlight the importance ensuring that racial differences that are due to preferences and values are not misclassified as disparities in order to identify and address the root causes of disparate treatment.

BACKGROUND: This study sought to estimate the risk of breast cancer (BC) after a diagnosis of ovarian cancer (OC) associated with mutation of the BRCA1/2 (breast cancer, early onset) genes (BRCA-OC). METHODS: The Memorial Sloan-Kettering Cancer Center and the University of Pennsylvania, clinical genetics databases were searched to identify women with BRCA-OC who participated in genetic testing and follow-up studies from 1995 to 2009. The primary objective was to determine the risk of developing BC after BRCA-OC. Overall survival (OS) and BC-free survival (BCFS) were determined by the Kaplan-Meier method; patients were censored at the time of last follow-up. RESULTS: A total of 164 patients had BRCA-OC (115 with BRCA1; 49 with BRCA2). Of these 164 patients, 152 developed OC prior to BRCA testing (median time to testing, 2.4 years [0.01-55 years]). Median follow-up from OC for those not developing BC was 5.8 years (0.25-55.6 years). There were 46 deaths, but none were due to BC. The 5- and 10-year OS were 85% (95% confidence interval [CI] = 0.78, 0.90) and 68% (95% CI = 0.59, 0.76), respectively. There were 18 metachronous BC diagnoses. The 5- and 10-year BCFS were 97% (95% CI = 0.92, 0.99) and 91% (95% CI = 0.82, 0.95), respectively. A subset of 64 women were tested either before or within 12 months of BRCA-OC. In this pseudo-incident subset, 5- and 10- year OS was 71% (95% CI = 0.53, 0.83) and 62% (95% CI = 0.44, 0.75), respectively, and 5- and 10-year BCFS were 100% and 87% (95% CI = 0.56, 0.96), respectively. CONCLUSIONS: OS was dominated by OC deaths. Metachronous BC risk was lower than reported for unaffected BRCA mutation carriers. These results support nonsurgical management of BC risk in women with BRCA-OC. Cancer 2013. © 2012 American Cancer Society.

Background In developed countries, the lifetime risk of developing colorectal cancer (CRC) is 5%, and it is the second leading cause of death from cancer. The presence of family history is a well established risk factor with 25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer syndromes account for approximately 5%, leaving greater than 20% without clear genetic definition. Familial colorectal cancer has been linked to chromosome 7q31 by multiple affected relative pair studies. The MET proto-oncogene which resides in this chromosomal region is considered a candidate for genetic susceptibility. Methods MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a LightScanner (Idaho Technologies). Samples demonstrating alternative melt curves were sequenced. A TaqMan assay for the specific c.2975C >T change was used to confirm this mutation in a cohort of 299 colorectal cancer cases and to look for allelic amplification in tumors. Results Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position T992I (also reported as MET p.T1010I) in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of colon cancers, and in Conclusions Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different at-risk populations will be an important extension of this work to define the clinical significance.

The occurrence of multiple primary (MP) cancers in a patient suggests a genetic predisposition to tumor formation. Multiplex panel testing may be an efficient way of evaluating MP patients for the presence of germline mutations in cancer susceptibility genes. However the spectrum of mutations in many cancer susceptibility genes in the MP patient population is largely unknown. We performed massively parallel sequencing using targeted capture of 15 genes with well-established risks of breast and/or other cancers, specifically TP53, CDH1, PTEN, STK11, ATM, CHEK2, MRE11A, NBN, RAD50, PALB2, MLH1, MSH2, MSH6, PMS2, and MUTYH. Our patient cohort consisted of 221 BRCA1/2 negative patients diagnosed with breast cancer and at least one other primary cancer, excluding non-melanoma skin cancer. Patients diagnosed with contralateral breast cancer were included. Thirty patients (14%) were found to have at least one deleterious variant in these 15 genes. Deleterious variants were found in CHEK2 (16 patients, 7.2%), TP53 (4, 1.8%), MSH6 (3, 1.4%), ATM (2, 0.9%) and one patient each had deleterious variants in CDKN2A, PTEN, PMS2, PALB2, BRIP1 and NBN. In addition, six patients (2.7%) were found to be heterozygous carriers of a MUTYH mutation. In comparison, deleterious variants were identified in 9% of 341 patients with breast cancer only, indicating a small but nonsignificant increase in the rate of deleterious variants in MP patients. The rate of MUTYH heterozygous mutations was also non-significantly different in patients with breast cancer only (1.2%). There was a significant increase in the rate of CHEK2 and MSH6 mutations in the MP versus breast-only patients (7.2% vs 3.5%, p = 0.04 for CHEK2 and 1.4% vs 0%, p = 0.05 for MSH6). As a corollary study, a subset of MP patients (n = 165) were assayed on a panel including TET2. Deleterious TET2 mutations were identified in 2 of 165 patients (1.2%) at allele frequencies of 0.17 and 0.36. These patients blood samples were ascertained at ages 77 and 72, respectively. These preliminary data show that in our cohort of patients with multiple primary cancers, over 16% of patients were found to have deleterious variants in 15 cancer susceptibility genes. In addition, approximately 1% of MP patients have deleterious variants in TET2 that may be due to age-related clonal hematopoiesis, although it is unknown if these mutations are related to the development of the tumors in these individuals. Further analysis of variants in less well-characterized cancer susceptibility genes and unclassified variants is ongoing. Discovery of clinically relevant mutations can potentially guide future treatment practices for those with similar diagnoses to our patients. Citation Format: Brandon Wenz, Kara N. Maxwell, Bradley Wubbenhorst, Kurt D'Andrea, Bradley Garman, Jessica M. Long, Jacquelyn Powers, Jill E. Stopfer, Angela R. Bradbury, Angela DeMichele, Susan M. Domchek, Katherine L. Nathanson. Identification of germline variants in cancer susceptibility genes in patients with multiple primary cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4663. doi:10.1158/1538-7445.AM2015-4663

Germline mutations in the BRCA1 and BRCA2 genes are associated with breast cancer, ovarian cancer and other malignancies. Biallelic mutations of BRCA2 are a cause of Fanconi anemia and characteristic childhood cancers. We undertook this study to evaluate the contribution of familial BRCA mutations to childhood cancer in hereditary breast cancer families.We compared the prevalence of childhood cancers in 379 families with BRCA1 or BRCA2 mutations and 426 families without mutations. All families were ascertained at a high-risk breast cancer clinic. Our study included first- through fourth-degree relatives of BRCA mutation carriers and cancer-affected individuals with negative testing for BRCA mutations. The primary endpoint was any case of childhood cancer (diagnosedage 21).20 cases of childhood cancer occurred in 379 families with BRCA1 or BRCA2 mutations and 35 cases of childhood cancer occurred in 426 families with negative mutation testing (p = 0.12). Nine childhood cancers occurred in 240 families with BRCA1 mutations, and 11 childhood cancers occurred in 141 families with BRCA2 mutations (p = 0.1). 13 of 18 families with childhood cancer and BRCA1 or BRCA2 mutations (72%) and 13 of 31 families with childhood cancer and negative mutation testing (42%) met the Birch criteria for Li-Fraumeni like syndrome (LFL).In this retrospective analysis, heterozygous BRCA1 and BRCA2 mutations were not a risk factor for childhood cancer in hereditary breast cancer families. These data support the current practice of delaying BRCA mutation testing until adulthood.

The function of BRCA1 is complex and includes roles in DNA damage repair, cell cycle control, regulation of transcription, and X chromosome inactivation.1,2 TSIX is thought to control X chromosome inactivation by blocking the accumulation of XIST on the active X chromosome.3 BRCA1 co-localises with XIST inactive X chromosomes (Xi) and stabilises Xi. Because of this interaction, the loss of BRCA1 is associated with altered Xi chromatin structure and increased expression of silenced Xi genes.1,2 Mouse models have suggested a link between aberrant X chromosome inactivation and sex ratio skewing, with a bias towards male births when TSIX activity is abolished.3 In addition, non-random X chromosome inactivation has been seen in BRCA1 mutation carriers with ovarian cancer.4 With these data as background, a skewed sex ratio in offspring of BRCA1 mutation carriers was reported,5 with a bias towards females, compared with offspring of women with BRCA2 mutations and those without mutations in either gene. Others have not found a difference in the sex ratios of offspring of BRCA1 and BRCA2 mutation carriers.6–8 Here, we analysed the sex ratio of offspring in a large cohort of BRCA1 and BRCA2 mutation carriers, as well as in HBOC families who tested negative for BRCA1 and BRCA2 mutations or were not tested. ### Database We included data from 1276 families evaluated between 1992 and 1994 (University of Michigan) and between 1994 and 2003 (University of Pennsylvania) in breast cancer risk evaluation clinics and considered to be at increased risk for having a breast cancer susceptibility gene mutation. Individuals were either self referred or physician referred for assessment of inherited susceptibility to breast or ovarian cancer. All individuals providing data signed their informed consent before genetic testing and entry into our database, which includes detailed pedigree information. …

Risk information from health care providers is relevant to and used in nearly all medical decisions. Patients often misunderstand their risks, yet little is known about the risk perception that patients derive from risk communications with health care providers. This study examines patients' risk perceptions following communication with health care providers during genetic counseling about the risks of breast cancer and BRCA1/2 mutations.A prospective, longitudinal study was conducted from October 2002 to February 2004 of women who received genetic counseling. The women completed a survey before their counseling and a telephone interview in the week after the counseling. Main outcome measures included change from precounseling in risk perception and accuracy of postcounseling risk perception (relative to actual risk information communicated).A total of 108 women agreed to participate in the study. The women's postcounseling risk perceptions were significantly lower than their precounseling risk perceptions (breast cancer: 17%, P.001; mutation: 13%, P.001) but were significantly higher than the actual risk information communicated (breast cancer: 19%, P.001; mutation: 24%, P.001). Accuracy of breast cancer risk perception but not mutation risk perception was associated with precounseling worry (P = .04), even after adjusting for trait anxiety (P = .01).This research demonstrates patients' resistance to risk information. Inappropriately high risk perception derived from a risk communication with a health care provider can lead patients to make different, and potentially worse, medical decisions than they would with an accurate risk perception and to be unnecessarily distressed about their risk.

Approximately 5-10% of breast cancers are likely attributable to single gene mutations. Multiple breast cancer susceptibility genes have been identified; however, there is insufficient information on the clinical benefit of testing for variants in many of these genes outside of BRCA1, BRCA2, TP53 and PTEN. To obtain further information on the spectrum of variants in breast cancer susceptibility genes, we performed massively parallel sequencing using targeted capture of 28 known or proposed breast cancer susceptibility genes in over 250 patients with breast cancer diagnosed under age 40, negative clinical BRCA1 and BRCA2 testing and no personal or family history of ovarian cancer. Sixty-five percent of the patients had a family history of breast cancer. Breast cancers were triple negative in 26% of the patients; 70% of the patients presented with Stage II or greater disease. Positive control mutations in BRCA1, BRCA2, PALB2, CHEK2, MSH2 and BRCC3 were identified using the targeted panel. In analysis of the first 98 study patients, 46+/8 total variants were identified on average per patient with a median read depth of 131. Of the 4,483 total variants identified in the 98 patients, ten variants that are known to be or are likely functionally significant were identified in ten patients (10%). One patient had the CHEK2 1100delC mutation, and another the known deleterious TP53 mutation, P151T. Four of the functionally significant variants are novel frameshift or nonsense mutations in ATM, BRIP1, BARD1 and MRE11A. Four variants predicted to affect splicing, located within the first two nucleotides within the intron, were identified in CHEK2 (3) and MUTYH (1) and are therefore likely to be functionally significant. In addition, 29 patients (29%) were found to carry 27 variants predicted to be deleterious missense variants by multiple variant calling software programs and found at less than 1% frequency in the control population, but are of unclear functional significance as they are either novel or functionally untested. These potentially deleterious variants were identified in ATM (4), RAD50 (3), BRCA2 (3), BARD1 (2), BRCA1 (2), MLH1 (2), NBS (2), BRIP1 (1), CHEK2 (1), MCPH1 (1), MRE11A (1), MSH6 (1), PMS1 (1), and PMS2 (1). These data show that massively parallel sequencing has the ability to identify multiple potentially causative variants in known breast cancer susceptibility genes in patients who present with early onset breast cancer. However, only rare patients, 1% in our initial sample, which will be reported in full, have actionable mutations given current clinical management guidelines. Given the difficulty in determining the functional significance of novel variants, outside of truncating mutations, there is a great deal of uncertainty about how these findings can be translated into improvements in patient care. Citation Format: Kara N. Maxwell, Bradley Wubbenhorst, Richard Letrero, Kurt D'Andrea, Jacqueline Powers, Jill E. Stopfer, Susan M. Domchek, Katherine L. Nathanson. Targeted massively parallel sequencing identifies a limited number of clinically actionable variants in women with early onset breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2280. doi:10.1158/1538-7445.AM2013-2280