Katherine S. Hunt

Essential Elements of Genetic Cancer Risk Assessment, Counseling, and Testing: Updated Recommendations of the National Society of Genetic Counselors

Updated from their original publication in 2004, these cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of counseling at-risk individuals through genetic 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 Familial Cancer Risk 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. Essential components include the intake, cancer risk assessment, genetic testing for an inherited cancer syndrome, informed consent, disclosure of genetic test results, and psychosocial assessment. 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.

Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.

Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC) to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50≈350 nM) was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50≈8 nM). In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X) in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations.

Outcome of Whole Exome Sequencing for Diagnostic Odyssey Cases of an Individualized Medicine Clinic: The Mayo Clinic Experience

OBJECTIVE To describe the experience and outcome of performing whole-exome sequencing (WES) for resolution of patients on a diagnostic odyssey in the first 18 months of an individualized medicine clinic (IMC). PATIENTS AND METHODS The IMC offered WES to physicians of Mayo Clinic practice for patients with suspected genetic disease. DNA specimens of the proband and relatives were submitted to WES laboratories. We developed the Genomic Odyssey Board with multidisciplinary expertise to determine the appropriateness for IMC services, review WES reports, and make the final decision about whether the exome findings explain the disease. This study took place from September 30, 2012, to March 30, 2014. RESULTS In the first 18 consecutive months, the IMC received 82 consultation requests for patients on a diagnostic odyssey. The Genomic Odyssey Board deferred 7 cases and approved 75 cases to proceed with WES. Seventy-one patients met with an IMC genomic counselor. Fifty-one patients submitted specimens for WES testing, and the results have been received for all. There were 15 cases in which a diagnosis was made on the basis of WES findings; thus, the positive diagnostic yield of this practice was 29%. The mean cost per patient for this service was approximately

Predicting BRCA1 and BRCA2 gene mutation carriers: comparison of PENN II model to previous study

8000. Medicaid supported 27% of the patients, and 38% of patients received complete or partial insurance coverage. CONCLUSION The significant diagnostic yield, moderate cost, and notable health marketplace acceptance for WES compared with conventional genetic testing make the former method a rational diagnostic approach for patients on a diagnostic odyssey.

Developing a Reproductive Life Plan

A number of models have been developed to predict the probability that a person carries a detectable germline mutation in the BRCA1 or BRCA2 genes. Their relative performance in a clinical setting is variable. To compare the performance characteristics of a web-based BRCA1/BRCA2 gene mutation prediction model: the PENNII model (www.afcri.upenn.edu/itacc/penn2), with studies done previously at our institution using four other models including LAMBDA, BRCAPRO, modified PENNI (Couch) tables, and Myriad II tables collated by Myriad Genetics Laboratories. Proband and family cancer history data were analyzed from 285 probands from unique families (27 Ashkenazi Jewish; 277 female) seen for genetic risk assessment in a multispecialty tertiary care group practice. All probands had clinical testing for BR.CA1 and BRCA2 mutations conducted in the same single commercial laboratory. The performance for PENNII results were assessed by the area under the receiver operating characteristic curve (AUC) of sensitivity versus 1-specificity, as a measure of ranking. The AUCs of the PENNII model were higher for predicting BRCA1 than for BRCA2 (81 versus 72%). The overall AUC was 78.7%. PENN II model for BRCA1/2 prediction performed well in this population with higher AUC compared with our experience using four other models. The ease of use of the PENNII model is compatible with busy clinical practices.

Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome

The purpose of this article is 2-fold: to emphasize the importance of a reproductive life plan and to define its key elements. We review the 2006 recommendations from the Centers for Disease Control and Prevention (CDC) regarding ways to improve the delivery of preconception health care to women in the United States, with particular focus on encouraging individual reproductive responsibility throughout the life span and on encouraging every woman to develop a reproductive life plan. We propose recommendations for the content of a reproductive life plan and explore ways to incorporate the guidelines from the CDC into clinical practice. By encouraging women to consider their plans for childbearing before they become pregnant, clinicians have the opportunity to influence behavior before pregnancy, which may decrease the incidence of unintended pregnancies and adverse pregnancy outcomes.

Predicting BRCA1 and BRCA2 gene mutation carriers: comparison of LAMBDA, BRCAPRO, Myriad II, and modified Couch models

Raskin L, Schwenter F, Freytsis M, Tischkowitz M, Wong N, Chong G, Narod SA, Levine DA, Bogomolniy F, Aronson M, Thibodeau SN, Hunt KS, Rennert G, Gallinger S, Gruber SB, Foulkes WD. Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome.

Clinical Implementation of Integrated Genomic Profiling in Patients with Advanced Cancers

ContextModels have been developed to predict the probability that a person carries a detectable germline mutation in the BRCA1 or BRCA2 genes. Their relative performance in a clinical setting is unclear.ObjectiveTo compare the performance characteristics of four BRCA1/BRCA2 gene mutation prediction models: LAMBDA, based on a checklist and scores developed from data on Ashkenazi Jewish (AJ) women; BRCAPRO, a Bayesian computer program; modified Couch tables based on regression analyses; and Myriad II tables collated by Myriad Genetics Laboratories.Design and settingFamily cancer history data were analyzed from 200 probands from the Mayo Clinic Familial Cancer Program, in a multispecialty tertiary care group practice. All probands had clinical testing for BRCA1 and BRCA2 mutations conducted in a single laboratory.Main outcomes measuresFor each model, performance was assessed by the area under the receiver operator characteristic curve (ROC) and by tests of accuracy and dispersion. Cases “missed” by one or more models (model predicted less than 10% probability of mutation when a mutation was actually found) were compared across models.ResultsAll models gave similar areas under the ROC curve of 0.71 to 0.76. All models except LAMBDA substantially under-predicted the numbers of carriers. All models were too dispersed.ConclusionsIn terms of ranking, all prediction models performed reasonably well with similar performance characteristics. Model predictions were widely discrepant for some families. Review of cancer family histories by an experienced clinician continues to be vital to ensure that critical elements are not missed and that the most appropriate risk prediction figures are provided.

Predictive testing for Alzheimer's disease: suicidal ideation in healthy participants.

DNA focused panel sequencing has been rapidly adopted to assess therapeutic targets in advanced/refractory cancer. Integrated Genomic Profiling (IGP) utilising DNA/RNA with tumour/normal comparisons in a Clinical Laboratory Improvement Amendments (CLIA) compliant setting enables a single assay to provide: therapeutic target prioritisation, novel target discovery/application and comprehensive germline assessment. A prospective study in 35 advanced/refractory cancer patients was conducted using CLIA-compliant IGP. Feasibility was assessed by estimating time to results (TTR), prioritising/assigning putative therapeutic targets, assessing drug access, ascertaining germline alterations, and assessing patient preferences/perspectives on data use/reporting. Therapeutic targets were identified using biointelligence/pathway analyses and interpreted by a Genomic Tumour Board. Seventy-five percent of cases harboured 1–3 therapeutically targetable mutations/case (median 79 mutations of potential functional significance/case). Median time to CLIA-validated results was 116 days with CLIA-validation of targets achieved in 21/22 patients. IGP directed treatment was instituted in 13 patients utilising on/off label FDA approved drugs (n = 9), clinical trials (n = 3) and single patient IND (n = 1). Preliminary clinical efficacy was noted in five patients (two partial response, three stable disease). Although barriers to broader application exist, including the need for wider availability of therapies, IGP in a CLIA-framework is feasible and valuable in selection/prioritisation of anti-cancer therapeutic targets.

Hereditary Risk for Cancer

The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) study1 showed that disclosure of apolipoprotein E (APOE) genotype, the most prevalent genetic risk factor for Alzheimer’s disease (AD),2 can be done safely, but with the caveats that participants in this study were carefully screened for psychiatric problems and those with suicidal ideation were excluded. Further, participants had extensive education, counseling, and followup, all steps that characterize a best practice but which are unlikely to occur outside of the protective walls of a research trial. In an effort to explore the perspectives of unscreened and unsheltered individuals who are likely to seek presymptomatic testing for AD we administered a questionnaire through an online website and found that nearly 12% of more than 4000 respondents (who had not undergone genetic testing), when asked how they might react if found to be a “high risk” for AD endorsed “seriously consider suicide.”3 With the advent of presymptomatic clinical trials, recruitment strategies include mass screening of individuals harboring genetic or biomarker evidence of high risk for AD.4–6 The present study explores possible demographic, cognitive, psychological, and personality characteristics that might identify a potential research participant as one at high risk of suicidal ideation by administering the same questionnaire to our longstanding research cohort, the Arizona APOE Cohort.7 METHODS As previously described3 this survey was developed from a 2-part interview with members of the Arizona APOE Cohort to get a sense of what features of presymptomatic AD testing seemed most relevant to them (eg, whether they felt any form of predictive testing for AD was appropriate, and how they might handle such information if it was disclosed to them). The final questionnaire comprised of yes/no and multiple choice questions addressing demographics, genetic testing, biomarker testing, and possible reactions to such information was then mailed to the remaining cognitively normal members of the cohort. Members of the Arizona APOE Cohort are cognitively normal residents of Maricopa County age 21 years and above recruited through local media ads, genotyped for APOE, and who undergo longitudinal neuropsychological assessment every 2 years.7 The participants agreed to have the results of the APOE test withheld from them as a precondition to their participation in this study. Neuropsychological tests encompassed general intellect, memory, executive, language, and visuospatial skills. Behavioral measures included the Personality Assessment Inventory (PAI), Hamilton Depression Scale, Beck Depression Rating Scale, Geriatric Depression Scale, and the Neuropsychiatric Inventory Questionnaire. Also included were paired subjective cognition questionnaires, the Multidimensional Assessment of Neurodegenerative Symptoms, self and informant versions.8 Personality was assessed with the Five Factor Neuroticism, Extraversion, and Openness (NEO) Inventory. Socioeconomic status was approximated in 3 ways. Income was estimated by zip code median income, major occupational background was quantified with the Dictionary of Occupational Titles General Educational Development (Reasoning, Mathematical, Language),9 and subjective community and socioeconomic standing was selfassessed by patients using the subjective scale of social status indicated on a 10 rung ladder (1 lowest, 10 highest). Members were asked 2 questions pertaining to consideration of suicide based on the following 2 scenarios. The first question addressed risk of AD based on genetic test results and a second question asked about presymptomatic AD based on biomarker test results. Members were eligible for analysis related to consideration of suicide if they answered both the genetic test and biomarker risk questions. Members not answering both questions were excluded from this analysis. Univariate analysis of responses to questions regarding reactions to presymptomatic testing including consideration of suicide was performed for each demographic and behavioral variable. Variables that were statistically significant on univariate Received for publication February 4, 2015; accepted April 10, 2015. From the *Department of Neurology; zCenter for Individualized Medicine; yClinical Studies Unit; 8Section of Biostatistics, Mayo Clinic Arizona, Scottsdale; wSandra Day O’Connor College of Law; #Center for Biology and Society, and School of Life Sciences, Arizona State University, Tempe, AZ; and zBanner Alzheimer Institute, Phoenix, AZ. Supported by NIA P30AG19610, R01AG031581, and the Arizona Alzheimer’s Research Consortium. In addition to these funding sources, R.J.C. also receives research funding support from Merck, and J.L. receives research support from Genentech and Novartis. The authors declare no conflicts of interest. Reprints: Richard J. Caselli, MD, Department of Neurology, Mayo Clinic Arizona, 13400 East Shea Blvd, Scottsdale, AZ 85259 (e-mail: Caselli.richard@mayo.edu). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.alzheimerjournal.com. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. BRIEF REPORT