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Development of the clinical next-generation sequencing industry in a shifting policy climate

Background Effectively educating families about the risks and benefits of genomic tests such as whole exome sequencing (WES) offers numerous challenges, including the complexity of test results and potential loss of privacy. Research on best practices for obtaining informed consent (IC) in a variety of clinical settings is needed. The BASIC3 study of clinical tumor and germline WES in an ethnically diverse cohort of newly diagnosed pediatric cancer patients offers the opportunity to study the IC process in the setting of critical illness. We report on our experience for the first 100 families enrolled, including study participation rates, reasons for declining enrollment, assessment of clinical and demographic factors that might impact study enrollment, and preferences of parents for participation in optional genomics study procedures. Methods A specifically trained IC team offered study enrollment to parents of eligible children for procedures including clinical tumor and germline WES with results deposited in the medical record and disclosure of both diagnostic and incidental results to the family. Optional study procedures were also offered, such as receiving recessive carrier status and deposition of data into research databases. Stated reasons for declining participation were recorded. Clinical and demographic data were collected and comparisons made between enrolled and non-enrolled patients. Results Over 15 months, 100 of 121 (83%) eligible families elected to enroll in the study. No significant differences in enrollment were detected based on factors such as race, ethnicity, use of Spanish interpreters and Spanish consent forms, and tumor features (central nervous system versus non-central nervous system, availability of tumor for WES). The most common reason provided for declining enrollment (10% of families) was being overwhelmed by the new cancer diagnosis. Risks specific to clinical genomics, such as privacy concerns, were less commonly reported (5.5%). More than 85% of parents consented to each of the optional study procedures. Conclusions An IC process was developed that utilizes a specialized IC team, active communication with the oncology team, and an emphasis on scheduling flexibility. Most parents were willing to participate in a clinical germline and tumor WES study as well as optional procedures such as genomic data sharing independent of race, ethnicity or language spoken. Electronic supplementary material The online version of this article (doi:10.1186/s13073-014-0069-3) contains supplementary material, which is available to authorized users.

As genome sequencing technologies increasingly enter medical practice, genetics laboratories must communicate sequencing results effectively to nongeneticist physicians. We describe the design and delivery of a clinical genome sequencing report, including a one-page summary suitable for interpretation by primary care physicians. To illustrate our preliminary experience with this report, we summarize the genomic findings from 10 healthy participants in a study of genome sequencing in primary care.

The current emphasis on broad sharing of human genomic data generated in research in order to maximize utility and public benefit is a significant legacy of the Human Genome Project. Concerns about privacy and discrimination have led to policy responses that restrict access to genomic data as the means for protecting research participants. Our research and experience show, however, that a considerable number of research participants agree to open access sharing of their genomic data when given the choice. General policies that limit access to all genomic data fail to respect the autonomy of these participants and, at the same time, unnecessarily limit the utility of the data. We advocate instead a more balanced approach that allows for individual choice and encourages informed decision making, while protecting against the misuse of genomic data through enhanced legislation.

Much has been written about how we understand, teach and evaluate professionalism in medical training. Less often described are explicit responses to mild or moderate professionalism concerns in medical students. To address this need, Baylor College of Medicine created a mechanism to assess professionalism competency for medical students and policies to address breaches in professional behavior. This article describes the development of an intervention using a guided reflection model, student responses to the intervention, and how the program evolved into a credible resource for deans and other educational leaders.

The current model for conducting genome-wide association studies (GWAS) is primarily phenotype-driven. In this “top-down” approach, the model is the case-control study, where participants are enrolled based on the presence or absence of a clinical phenotype, for example, cardiovascular disease or breast cancer (Pennisi 2007; Wellcome Trust Case Control Consortium 2007). The International HapMap Project has identified a large number of single nucleotide polymorphisms (SNPs) in the human population that enable investigators to genotype subjects for these various polymorphisms and determine associations with a phenotype of interest (Fig. 1A) (International HapMap Consortium et al. 2007).

The routine use of genomic sequencing in clinical medicine has the potential to dramatically alter patient care and medical outcomes. To fully understand the psychosocial and behavioral impact of sequencing integration into clinical practice, it is imperative that we identify the factors that influence sequencing-related decision making and patient outcomes. In an effort to develop a collaborative and conceptually grounded approach to studying sequencing adoption, members of the National Human Genome Research Institute's Clinical Sequencing Exploratory Research Consortium formed the Outcomes and Measures Working Group. Here we highlight the priority areas of investigation and psychosocial and behavioral outcomes identified by the Working Group. We also review some of the anticipated challenges to measurement in social and behavioral research related to genomic sequencing; opportunities for instrument development; and the importance of qualitative, quantitative, and mixed-method approaches. This work represents the early, shared efforts of multiple research teams as we strive to understand individuals' experiences with genomic sequencing. The resulting body of knowledge will guide recommendations for the optimal use of sequencing in clinical practice.

Recent advances in genetic analysis especially DNA sequencing technology open a new strategy for adult disease prevention by genetic screening. Physicians presently treat disease pathology with less emphasis on disease risk prevention/reduction. Genetic screening has reduced the incidence of untreatable childhood genetic diseases and improved the care of newborns. The opportunity exists to expand screening programs and reduce the incidence of adult onset diseases via genetic risk identification and disease intervention. This article outlines the approach, challenges, and benefits of such screening for adult genetic disease risks.

The future clinical applications of whole genome sequencing come with speculation and enthusiasm but require careful consideration of the true system costs and health benefits of the clinical uses of this exciting technology., Summary The cost of whole genome sequencing is dropping rapidly. There has been a great deal of enthusiasm about the potential for this technological advance to transform clinical care. Given the interest and significant investment in genomics, this seems an ideal time to consider what the evidence tells us about potential benefits and harms, particularly in the context of health care policy. The scale and pace of adoption of this powerful new technology should be driven by clinical need, clinical evidence, and a commitment to put patients at the centre of health care policy.

Thousands of patents have been awarded that claim human gene sequences and their uses, and some have been challenged in court. In a recent high-profile case, Association for Molecular Pathology, et al. vs. Myriad Genetics, Inc., et al., the United States Supreme Court ruled that genes are natural occurring substances and therefore not patentable through “composition of matter” claims. The consequences of this ruling will extend well beyond ending Myriad's monopoly over BRCA testing, and may affect similar monopolies of other commercial laboratories for tests involving other genes. It could also simplify intellectual property issues surrounding genome-wide clinical sequencing, which can generate results for genes covered by intellectual property. Non-invasive prenatal testing (NIPT) for common aneuploidies using cell-free fetal (cff) DNA in maternal blood is currently offered through commercial laboratories and is also the subject of ongoing patent litigation. The recent Supreme Court decision in the Myriad case has already been invoked by a lower district court in NIPT litigation and resulted in invalidation of primary claims in a patent on currently marketed cffDNA-based testing for chromosomal aneuploidies.

Next-generation sequencing (NGS) is commonly used for researching the causes of genetic disorders. However, its usefulness in clinical practice for medical diagnosis is in early development. In this report, we demonstrate the value of NGS for genetic risk assessment and evaluate the limitations and barriers for the adoption of this technology into medical practice. We performed whole exome sequencing (WES) on 81 volunteers, and for each volunteer, we requested personal medical histories, constructed a three-generation pedigree, and required their participation in a comprehensive educational program. We limited our clinical reporting to disease risks based on only rare damaging mutations and known pathogenic variations in genes previously reported to be associated with human disorders. We identified 271 recessive risk alleles (214 genes), 126 dominant risk alleles (101 genes), and 3 X-recessive risk alleles (3 genes). We linked personal disease histories with causative disease genes in 18 volunteers. Furthermore, by incorporating family histories into our genetic analyses, we identified an additional five heritable diseases. Traditional genetic counseling and disease education were provided in verbal and written reports to all volunteers. Our report demonstrates that when genome results are carefully interpreted and integrated with an individual’s medical records and pedigree data, NGS is a valuable diagnostic tool for genetic disease risk.

The American College of Medical Genetics and Genomics (ACMG) recently issued a statement ( 1 ) recommending that all laboratories conducting clinical sequencing seek and report pathogenic and expected pathogenic mutations for a short list of carefully chosen genes and conditions. The recommendations establish a baseline for reporting clinically relevant incidental findings and articulate ethical principles relevant to their disclosure. The ACMG acknowledged that the list will evolve over time and is developing a mechanism for community input ( 2 ). This paper focuses on the ethical framework for the recommendations, rather than on the choice of which genes to include on the list.

Approaches to return individual results to participants in genomic research variably focus on actionability, duty to share, or participants' preferences. Our group at Boston Children's Hospital has prioritized participants' preferences by implementing the Gene Partnership, a genomic research repository, based on the "Informed Cohort" model that offers return of results in accordance with participant preferences. Recognizing that ethical oversight is essential, the Gene Partnership Informed Cohort Oversight Board was convened in 2009.Over 3 years, the Informed Cohort Oversight Board developed guidelines for the return of individual genomic research results.The Informed Cohort Oversight Board defined its guiding principles as follows: to respect the developing autonomy of pediatric participants and parental decision-making authority by returning results consistent with participants' preferences and to protect participants from harm. Potential harms and strategies to eliminate harm were identified. Guidelines were developed for participant preferences that consider the child's development and family dynamics. The Informed Cohort Oversight Board agreed that to prevent harm, including harms related to interfering with a child's future autonomy, there will be results that should not be returned regardless of participant preferences.The Informed Cohort Oversight Board developed guidelines for the return of results that respect the preferences of parents, children, and adult participants while seeking to protect against harm.

In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the patient to the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including an open forum at the 2012 Annual Meeting and review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. The ACMG recommends that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the "normal" of tumor-normal subtractive analyses in all subjects, irrespective of age but excluding fetal samples. We recognize that there are insufficient data on penetrance and clinical utility to fully support these recommendations, and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.

Whole-genome sequencing and whole-exome sequencing (WGS/WES) have become increasingly affordable and accessible to individuals. There are currently 3 main pathways through which a person can receive WGS/WES: as a research participant in a genomic study; through a direct-to-consumer personal genome company; or as part of clinical care. In the research context, the extent to which findings from WGS/WES are communicated to study participants and used to inform their clinical care is a topic of much debate, but guidelines suggest that investigators may have an obligation to offer at least some results to study participants.1

Background: Human microbiome research has the potential to transform the practice of medicine, fundamentally shifting the ways in which we think not only about human health, illness and disease, but also about clinical practice and public health interventions. Drawing from a larger qualitative study on ethical, legal and social dimensions of human microbiome research, in this article, we document perspectives related to the translation of human microbiome research into clinical practice, focusing particularly on implications for health, illness and disease. Methods: We conducted 60 in-depth, semi-structured interviews (2009-2010) with 63 researchers and National Institutes of Health project leaders (‘investigators') involved with human microbiome research. The interviews explored a range of ethical, legal and social implications of human microbiome research, including investigators' perspectives on potential strategies for translating findings to clinical practice. Using thematic content analysis, we identified and analyzed emergent themes and patterns. Results: We identified 3 themes: (1) investigators' general perspectives on the clinical utility of human microbiome research, (2) investigators' perspectives on antibiotic use, overuse and misuse, and (3) investigators' perspectives concerning future challenges of translating data to clinical practice. Conclusion: The issues discussed by investigators concerning the clinical significance of human microbiome research, including embracing a new paradigm of health and disease, the importance of microbial communities, and clinical utility, will be of critical importance as this research moves forward.

Importance Whole-exome sequencing (WES) has the potential to reveal tumor and germline mutations of clinical relevance, but the diagnostic yield for pediatric patients with solid tumors is unknown. Objective To characterize the diagnostic yield of combined tumor and germline WES for children with solid tumors. Design Unselected children with newly diagnosed and previously untreated central nervous system (CNS) and non-CNS solid tumors were prospectively enrolled in the BASIC3 study at a large academic children’s hospital during a 23-month period from August 2012 through June 2014. Blood and tumor samples underwent WES in a certified clinical laboratory with genetic results categorized on the basis of perceived clinical relevance and entered in the electronic health record. Main Outcomes and Measures Clinical categorization of somatic mutations; frequencies of deleterious germline mutations related to patient phenotype and incidental medically-actionable mutations. Results Of the first 150 participants (80 boys and 70 girls, mean age, 7.4 years), tumor samples adequate for WES were available from 121 patients (81%). Somatic mutations of established clinical utility (category I) were reported in 4 (3%) of 121 patients, with mutations of potential utility (category II) detected in an additional 29 (24%) of 121 patients. CTNNB1 was the gene most frequently mutated, with recurrent mutations in KIT , TSC2 , and MAPK pathway genes ( BRAF , KRAS , and NRAS ) also identified. Mutations in consensus cancer genes (category III) were found in an additional 24 (20%) of 121 tumors. Fewer than half of somatic mutations identified were in genes known to be recurrently mutated in the tumor type tested. Diagnostic germline findings related to patient phenotype were discovered in 15 (10%) of 150 cases: 13 pathogenic or likely pathogenic dominant mutations in adult and pediatric cancer susceptibility genes (including 2 each in TP53 , VHL , and BRCA1 ), 1 recessive liver disorder with hepatocellular carcinoma ( TJP2 ), and 1 renal diagnosis ( CLCN5 ). Incidental findings were reported in 8 (5%) of 150 patients. Most patients harbored germline uncertain variants in cancer genes (98%), pharmacogenetic variants (89%), and recessive carrier mutations (85%). Conclusions and Relevance Tumor and germline WES revealed mutations in a broad spectrum of genes previously implicated in both adult and pediatric cancers. Combined reporting of tumor and germline WES identified diagnostic and/or potentially actionable findings in nearly 40% of newly diagnosed pediatric patients with solid tumors.

Mutational load of susceptibility variants has not been studied on a genomic scale in a clinical population, nor has the potential to identify these mutations as incidental findings during clinical testing been systematically ascertained. Array comparative genomic hybridization, a method for genome-wide detection of DNA copy-number variants, was performed clinically on DNA from 9,005 individuals. Copy-number variants encompassing or disrupting single genes were identified and analyzed for their potential to confer predisposition to dominant, adult-onset disease. Multigene copy-number variants affecting dominant, adult-onset cancer syndrome genes were also assessed. In our cohort, 83 single-gene copy-number variants affected 40 unique genes associated with dominant, adult-onset disorders and unrelated to the patients’ referring diagnoses (i.e., incidental) were found. Fourteen of these copy-number variants are likely disease-predisposing, 25 are likely benign, and 44 are of unknown clinical consequence. When incidental copy-number variants spanning up to 20 genes were considered, 27 copy-number variants affected 17 unique genes associated with dominant, adult-onset cancer predisposition. Copy-number variants potentially conferring susceptibility to adult-onset disease can be identified as incidental findings during routine genome-wide testing. Some of these mutations may be medically actionable, enabling disease surveillance or prevention; however, most incidentally observed single-gene copy-number variants are currently of unclear significance to the patient. Genet Med 2013:15(1):45–54

The aim of this study was to explore specific conditions and types of genetic variants that specialists in genetics recommend should be returned as incidental findings in clinical sequencing.Sixteen specialists in clinical genetics and/or molecular medicine selected variants in 99 common conditions to return to the ordering physician if discovered incidentally through whole-genome sequencing. For most conditions, the specialists independently considered three molecular scenarios for both adults and minor children: a known pathogenic mutation, a truncating variant presumed pathogenic (where other truncating variants are known to be pathogenic), and a missense variant predicted in silico to be pathogenic.On average, for adults and children, respectively, each specialist selected 83.5 and 79.0 conditions or genes of 99 in the known pathogenic mutation categories, 57.0 and 53.5 of 72 in the truncating variant categories, and 33.4 and 29.7 of 72 in the missense variant categories. Concordance in favor of disclosure within the adult/known pathogenic mutation category was 100% for 21 conditions or genes and 80% or higher for 64 conditions or genes.Specialists were highly concordant for the return of findings for 64 conditions or genes if discovered incidentally during whole-exome sequencing or whole-genome sequencing.Genet Med 2012:14(4):405-410.

Return of individual genetic results to research participants, including participants in archives and biorepositories, is receiving increased attention. However, few groups have deliberated on specific results or weighed deliberations against relevant local contextual factors.The Electronic Medical Records and Genomics (eMERGE) Network, which includes five biorepositories conducting genome-wide association studies, convened a return of results oversight committee to identify potentially returnable results. Network-wide deliberations were then brought to local constituencies for final decision making.Defining results that should be considered for return required input from clinicians with relevant expertise and much deliberation. The return of results oversight committee identified two sex chromosomal anomalies, Klinefelter syndrome and Turner syndrome, as well as homozygosity for factor V Leiden, as findings that could warrant reporting. Views about returning findings of HFE gene mutations associated with hemochromatosis were mixed due to low penetrance. Review of electronic medical records suggested that most participants with detected abnormalities were unaware of these findings. Local considerations relevant to return varied and, to date, four sites have elected not to return findings (return was not possible at one site).The eMERGE experience reveals the complexity of return of results decision making and provides a potential deliberative model for adoption in other collaborative contexts.

Published guidelines suggest that research results and incidental findings should be offered to study participants under some circumstances. Although some have argued against the return of results in research, many cite an emerging consensus that there is an ethical obligation to return at least some results; the debate quickly turns to issues of mechanics (e.g., which results? who discloses? for how long does the obligation exist?). Although commentators are careful to distinguish this as an ethical rather than legal obligation, we worry that return of results may unjustifiably become standard of care based on this growing “consensus,” which could quickly lead to a legal (negligence-based) duty to offer and return individualized genetic research results. We caution against this and argue in this essay that the debate to date has failed to give adequate weight to a number of fundamental ethical and policy issues that should undergird policy on return of research results in the first instance, many of which go to the fundamental differences between research and clinical care. We confine our comments to research using data from large biobanks, the topic of the guidelines proposed in this symposium issue.

Author Manuscript date: 2013 February 05., Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81–99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome.

The recently announced 1000 Genomes Project is an international collaboration to sequence 1000 individuals in an effort to produce the most complete catalog of human genetic variation to date. Building on the International HapMap Project, the 1000 Genomes Project will utilize new sequencing technologies to catalog genetic variants that are present in the human population across most of the genome at a rate of 1 percent or greater frequency. Investigators will not only look for single letter changes in the genome (called single nucleotide polymorphisms or SNPs), but will also look for differences in structural variants in the genome (segments of the genome that have been rearranged, deleted, or duplicated) (1). The first phase of the Project will involve three pilot studies. The first will sequence the genomes of two nuclear families (an adult child and both parents) at deep coverage (20x). The second will sequence the genomes of 180 people at low coverage (2x). The third will sequence the coding regions (exons) of about 1000 – 2000 gene regions in 1000 people at deep coverage (20x) (2). The 1000 Genomes Project represents a major step forward on the road to personalized genomic medicine. By creating an important scientific resource, the Project will help advance understanding of the complex relationship between genetic variation and human health and disease. The promise of personalized genomics is not new; it was almost twenty years ago that the New York Times published an article that predicted: “In the not-so-distant future, we can expect to walk into a physician's office for an annual physical and walk out with a blueprint of our genetic inheritance - and with the knowledge of the most likely cause of our own death.” (3) In the past year, individual genome sequencing has become possible (4–5) but it is still a long way from becoming a routine part of medical care. In order to achieve its fullest potential, the 1000 Genomes Project, like other large scale sequencing projects that came before it, will have to be carefully designed to ensure adequate protection and respectful treatment of research participants. In addition to addressing the research ethics issues involved, however, this new initiative creates an opportunity to reflect on the larger health system challenges that will have to be addressed before the knowledge that is gained through genome research can be integrated into routine clinical care.

Background: Technological advancements are rapidly propelling the field of genome research forward, while lawmakers attempt to keep apace with the risks these advances bear. Balancing normative concerns of maximizing data utility and protecting human subjects, whose privacy is at risk due to the identifiability of DNA data, are central to policy decisions. Research on genome research participants making real-time data sharing decisions is limited; yet, these perspectives could provide critical information to ongoing deliberations. Methods: We conducted a randomized trial of 3 consent types affording varying levels of control over data release decisions. After debriefing participants about the randomization process, we invited them to a follow-up interview to assess their attitudes toward genetic research, privacy and data sharing. Results: Participants were more restrictive in their reported data sharing preferences than in their actual data sharing decisions. They saw both benefits and risks associated with sharing their genomic data, but risks were seen as less concrete or happening in the future, and were largely outweighed by purported benefits. Conclusion: Policymakers must respect that participants’ assessment of the risks and benefits of data sharing and their privacy-utility determinations, which are associated with their final data release decisions, vary. In order to advance the ethical conduct of genome research, proposed policy changes should carefully consider these stakeholder perspectives.

There is an emerging consensus that when investigators obtain genomic data from research participants, they may incur an ethical responsibility to inform at-risk individuals about clinically significant variants discovered during the course of their research. With whole-exome sequencing becoming commonplace and the falling costs of full-genome sequencing, there will be an increasingly large number of variants identified in research participants that may be of sufficient clinical relevance to share. An explicit approach to triaging and communicating these results has yet to be developed, and even the magnitude of the task is uncertain. To develop an estimate of the number of variants that might qualify for disclosure, we apply recently published recommendations for the return of results to a defined and representative set of variants and then extrapolate these estimates to genome scale. We find that the total number of variants meeting the threshold for recommended disclosure ranges from 3955–12,579 (3.79%–12.06%, 95% CI) in the most conservative estimate to 6998–17,189 (6.69%–16.48%, 95% CI) in an estimate including variants with variable disease expressivity. Additionally, if the growth rate from the previous 4 yr continues, we estimate that the total number of disease-associated variants will grow 37% over the next 4 yr., National Library of Medicine (U.S.) (grant LM010470-01), Boston Children's Hospital. Manton Center for Orphan Disease Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (training grant HD040128), Baylor College of Medicine (BCM Clinical and Translational Research program), Baylor College of Medicine (Baylor Annual Fund), Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (AG027841), Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (HG02213), Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (HG005092)

Summary Genomic structural variants (SVs) are abundant in humans, differing from other variation classes in extent, origin, and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (i.e., copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analyzing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies.

Direct-to-consumer personal genome testing is now widely available to consumers. Proponents argue that knowledge is power but critics worry about consumer safety and potential harms resulting from misinterpretation of test information. In this article, we consider the health system implications of direct-to-consumer personal genome testing, focusing on issues of accountability, both corporate and professional.

The falling cost of sequencing means that we are rapidly approaching an era in which access to personalized genomic information is likely to be widespread. Here, four experts with different insights into the field of genomic medicine answer questions about the prospects for using this type of information. Their responses highlight the diverse range of issues that must be addressed - ranging from scientific to ethical and logistical - to ensure that the potential benefits of personal genomic information outweigh the costs to both individuals and societies.

Over the last decade there has been vast interest in and focus on the implementation of personalized genomic medicine. Although there is general agreement that personalized genomic medicine involves utilizing genome technology to assess individual risk and ensure the delivery of the "right treatment, for the right patient, at the right time," different categories of stakeholders focus on different aspects of personalized genomic medicine and operationalize it in diverse ways. In order to move toward a clearer, more holistic understanding of the concept, this article begins by identifying and defining three major elements of personalized genomic medicine commonly discussed by stakeholders: molecular medicine, pharmacogenomics, and health information technology. The integration of these three elements has the potential to improve health and reduce health care costs, but it also raises many challenges. This article endeavors to address these challenges by identifying five strategic areas that will require significant investment for the successful integration of personalized genomics into clinical care: (1) health technology assessment; (2) health outcomes research; (3) education (of both health professionals and the public); (4) communication among stakeholders; and (5) the development of best practices and guidelines. While different countries and global regions display marked heterogeneity in funding of health care in the form of public, private, or blended payor systems, previous analyses of personalized genomic medicine and attendant technological innovations have been performed without due attention to this complexity. Hence, this article focuses on personalized genomic medicine in the United States as a model case study wherein a significant portion of health care payors represent private, nongovernment resources. Lessons learned from the present analysis of personalized genomic medicine could usefully inform health care systems in other global regions where payment for personalized genomic medicine will be enabled through private or hybrid public-private funding systems.

Purpose: This study explores social networkers' interest in and attitudes toward personal genome testing (PGT), focusing on expectations related to the clinical integration of PGT results. Methods: An online survey of 1,087 social networking users was conducted to assess 1) use and interest in PGT; 2) attitudes toward PGT companies and test results; and 3) expectations for the clinical integration of PGT. Descriptive statistics were calculated to summarize respondents' characteristics and responses. Results: Six percent of respondents have used PGT, 64% would consider using PGT, and 30% would not use PGT. Of those who would consider using PGT, 74% report they would use it to gain knowledge about disease in their family. 34% of all respondents consider the information obtained from PGT to be a medical diagnosis. 78% of those who would consider PGT would ask their physician for help interpreting test results, and 61% of all respondents believe physicians have a professional obligation to help individuals in...

The early days of the genomic revolution—from the Asilomar Conference on Recombinant DNA in 1975 to the founding of the Human Genome Project in 1990—were marked by awareness among researchers, government officials, and policy makers that emerging scientific knowledge raised a host of ethical, legal, and social challenges. Scientists now undertaking research on the human microbiome—including those engaged in the National Institutes of Health’s (NIH) latest Roadmap initiative, the Human Microbiome Project (HMP)—confront a similarly uncharted ethical landscape. Not only does the conduct of human microbiome research raise important ethical considerations, but the long-term implications of the HMP also present the possibility of fundamental shifts in understandings of human life and health. The HMP is one of several international efforts to use metagenomic analysis to study human health. It is estimated that there are 10 times as many microbial cells than human cells in and on our bodies (Turnbaugh et al. 2007). We already know that human microbiota (i.e., all the microorganisms that inhabit the skin and mucous membranes) in certain sites of the body play an essential role in maintaining health and normal function (e.g., synthesis of vitamin K in the intestinal tract) (Lupp and Finlay 2005). The HMP aims to create a reference catalogue of microbial DNA that can be used as a resource to explore whether or not humans have a “core” microbiome (i.e., a microbiome that is common to all humans); whether there is stability in an individual’s microbiota through different periods in that individual’s life; whether there are similarities in microbiomes within families, communities, and different environments (Palmer et al. 2007); and ultimately, whether or not changes in the human microbiome can be correlated with changes in human health. A total of $8.2 million was awarded in 2007 to four institutions (Baylor College of Medicine, The Broad Institute, The J. Craig Venter Institute, and Washington University) to conduct the first phase of human sampling in the HMP. Samples are being collected from ∼250 healthy adults from five body sites: the oral cavity, skin, nasal cavity, gastrointestinal tract, and vagina, for a total of 18 subsites for women and 15 subsites for men. Peripheral blood is also being collected for human DNA sequencing and serum banking (to evaluate possible immune responses to the microbiome). Subjects will be screened using a general health questionnaire. Exclusion criteria for conditions that may influence the stability of the microbial environment, including taking specific medications (e.g., antibiotics, immunosuppressive agents), major dietary changes, history of cancer (exception of certain skin cancers) or chronic immune-mediated disorders (e.g., inflammatory bowel disease, psoriasis), history of chronic candidiasis (yeast infection), or active sexually transmitted diseases (e.g., gonorrhea) within the previous 2 mo for females. Children under the age of 18 and adults beyond the age of 40 will be excluded because of the need for a relatively uniform human population, especially considering the sample size and extent of potential variation within the human microbiome. Concerns about profound physiologic changes during adolescence and menopause in women also necessitate tighter boundaries to the age range. Each subject will provide at least one set of specimens within the first year, and at least 50% of these individuals are expected to participate in follow-up sampling within 12 mo of the initial sampling at all body sites. At least 10 subjects will be invited back for more extensive and invasive sampling at all body sites. All microbial DNA sequence data will be coded and released into publicly accessible databases. Clinical information that is collected will be coded and stored in a controlled-access database so that it can be correlated with analyzed data. Human DNA will be coded and stored for future analysis. Individual human DNA data will be released into controlled-access databases; aggregate data will be released into public databases. As the first phase of the HMP gets underway, it is important that the ethical, legal, and social implications of this research are carefully studied and responsibly managed. It is also essential that the research itself is conducted according to the highest ethical standards. Drawing on the significant body of scholarship that has amassed over the past two decades, and based on the involvement of two of the authors (A.L.M. and J.V.) with the first phase of the HMP, we identify five major ethical issues associated with conducting the HMP. This list is not exhaustive, and many of these issues are implicated in other areas of genetic research, but the complexity and exploratory nature of the HMP may, in some instances, necessitate modified resolutions.

Biological samples are routinely collected and used in biomedical research. As Weir and Olick (2004) point out in their book The Stored Tissue Issue, there are four ways in which samples can be stored: “identified” (the name of the person from whom the sample came is included with the tissue); “linked or coded” (the sample has a numerical code that is linked to the name of the person from whom the sample came, most often by computer); “anonymous” (the sample is originally collected without any identifiers linking it to the person from whom it came); and “anonymized” (the sample was originally identified but the identifiers have been irreversibly stripped or disguised) (40). De-identification via linkage, coding, or anonymization has traditionally been considered sufficient to protect privacy, and special protections are only afforded for data or specimens that are readily identifiable. Consequently, research conducted by an investigator who obtains coded or anonymized biological specimens is not considered human subjects research and is not regulated under U. S. federal regulation (the Common Rule) (Federal Policy for the Protection of Human Subjects 2008; Office of Human Research Protections, U.S. Department of Health and Human Services 2004). Similarly, coded or anonymized biological specimens, in and of themselves, are not considered individually identifiable protected health information under the U. S. Health Insurance Portability and Accountability Act of 1996 (2002). We have challenged this regulatory distinction in the context of genome research, arguing that it is conceptually flawed because DNA is itself uniquely identifiable (McGuire and Gibbs 2006a, 2006b). In 2004, Zhen Lin and colleagues illustrated that access to just 30–80 statistically independent single nucleotide polymorphisms (SNPs) was sufficient to uniquely identify an individual (Lin, Owen, and Altman 2004). Last week, David Craig and colleagues demonstrated that an individual’s SNP profile could potentially be identifiable even when it is aggregated with 1,000 or more other samples (Homer et al. 2008). There have been several policy responses to these studies. Data security has become a top priority for most institutions as well as government agencies. There has also been a shift away from policy that calls for the full public release of all generated sequence data (National Human Genome Research Institute 2003). Newer policies call for the release of data into databases with restricted access and include heightened requirements for informed consent (10). Finally, many individuals and groups have advocated strongly for federal legislation that would protect against the discriminatory use of genetic information in insurance and employment, which recently resulted in the enactment of the Genetic Information Nondiscrimination Act of 2008 (HR 493, Genetic Information Nondiscrimination Act of 2008). Implicit in these policy responses is the recognition that DNA data are potentially identifiable and contain sensitive health information and are therefore deserving of special protection. Yet, policymakers continue to promote an interpretation of identifiability that excludes coded and anonymized biological specimens and DNA data from existing regulatory protections (Lowrance and Collins 2007). In this issue of the American Journal of Bioethics, Sara Chandros Hull and colleagues (2008) offer a second reason for challenging this identifiability distinction: it does not seem to be consistent with patient preferences. In a survey of patients from academic medical centers, Hull and colleagues report that 72% of respondents felt that it was important for them to be informed about research using samples that were anonymized (“your name is removed from both the blood sample and from the information from your medical records so you cannot be identified by any of the researchers or anyone else”) and 81% felt it was important to be informed of research using samples that were coded, or “identifiable” (“your name will be replaced with a unique identification number that could be traced back to you and your medical records, if the researcher needs to do so”). Curiosity-based reasons were most commonly identified for those who wanted information about the research use of anonymized samples, while confidentiality concerns were more prevalent among those who only cared to know about the research use of coded samples (Hull et al. 2008). It is not clear whether the potential identifiability of anonymized samples was explained to participants or if they fully understood the privacy risks associated with each scenario. Regardless, as the authors point out, this desire for information about the future research use of biological specimens is consistent with other studies. An important additional contribution of this study lies in the distinction that is made between desire for information and desire for control over decision making. Although a majority of participants expressed a desire for control over decision making (requiring permission to use), 42–43% felt that notification was sufficient, regardless of the identity status of the sample. This suggests an important compromise that deserves further policy consideration. As Hull and colleagues (2008) point out, however, patient preferences are only one factor to be considered in developing responsible research policy. If conceptual discrepencies and patient preferences are not enough to convince, there is a third reason to abandon the identifiability distinction: it has led to inconsistent federal policy, where DNA data are treated as identifiable for some purposes and not others. For example, the new Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies (GWAS) calls for the release of all genotypic and some phenotypic data from NIH funded or supported GWAS into dbGAP, a restricted database maintained by the NIH (National Institutes of Health 2007). Depositing investigators who obtain the data either through direct interaction with participants or who obtain identifiable private information (linked to the subject’s name or other personally identifying information) are assumed to be conducting research involving human subjects and must obtain informed consent and IRB approval for the study and the subsequent data release. However, investigators who desire access to the data in dbGAP, which are coded or anonymized by the depositing investigator, are not conducting human subjects research and do not need IRB approval for their study. They need only to obtain approval from the NIH data access committee (DAC). At the same time, there is concern that since the NIH is a government agency data stored in dbGAP could be accessible to the public subject to a request made under the Freedom of Information Act (FOIA). To protect against this threat, the NIH maintains that because DNA is uniquely identifiable, complying with a FOIA request for that information would constitute a “clearly unwarranted invasion of personal privacy” and thus, the data in those databases are exempt from FOIA (Lowrance and Collins 2007). Regardless of the merits of this claim, it is problematic to treat DNA data as identifiable for the purposes of FOIA but not identifiable under the Common Rule. Conflicting interpretations of the identifiability distinction leads to incompatible policies that are confusing to investigators, IRBs, research participants, and even policymakers themselves. Worse, inconsistent policies are more susceptible to challenge. For example, the NIH’s assertion that the data in dbGAP are exempt from a FOIA request could be challenged in a court of law. There is no judicial precedent on this issue. Will the courts believe that coded DNA data are identifiable (making access under FOIA a “clearly unwarranted invasion of personal privacy”) when the Office of Human Research Protections (OHRP) has issued federal guidance to the contrary? Inconsistent interpretations of the identifiability of DNA data at a federal policy level threatens to discredit legitimate attempts to protect these data, which may ultimately undermine public trust and inadvertently harm research participants.

The most popular current models of medical decision making, identified by names such as shared decision making, informed decision making, and evidence-based patient choice, portray an empowered patient actively involved in his or her medical choices and generally assume that patient and physician reach agreement. These models are limited to a specific type of decision (in which there is more than one choice) and a specific process (in which agreement is reached). The authors extend the model of medical decision making beyond shared decisions in 2 dimensions. First, the authors incorporate a class of medical decisions in which there is only one medically reasonable treatment option, such as the removal of a primary melanoma. Patient preferences are irrelevant to whether or not the melanoma should be removed, so there is no treatment choice in which the patient can share. When there is only one realistic treatment option, the clinician's job is not to offer alternatives but to explain why there is only one viable choice and move the decision-making process forward. The physician does not thereby abridge the patient's autonomy; rather, the disease process itself constrains both patient and physician. Second, the authors include decisions in which patient and physician do not reach agreement. Sometimes the patient insists on a particular treatment and the physician reluctantly yields, sometimes it is the other way around, but disagreement is commonplace in clinical medicine and its presence deserves inclusion in the way we think about medical decisions. Conflict resolution requires acknowledging the potential for conflict.

The recent completion of the first two individual whole-genome sequences is a research milestone. As personal genome research advances, investigators and international research bodies must ensure ethical research conduct. We identify three major ethical considerations that have been implicated in whole-genome research: the return of research results to participants; the obligations, if any, that are owed to participants' relatives; and the future use of samples and data taken for whole-genome sequencing. Although the issues are not new, we discuss their implications for personal genomics and provide recommendations for appropriate management in the context of research involving individual whole-genome sequencing.

Genome-scale sequencing methods such as whole exome sequencing (WES) have provided significant insight into the pathogenesis of cancer. However, experience with the use of these tests in the clinical care of cancer patients remains limited. Sequencing of tumor and matched normal samples can reveal multiple types of results with implications for clinical practice. The identification of somatic (tumor-specific) mutations has the potential to offer diagnostic and prognostic information and inform selection of therapies. Detection of germline mutations in cancer susceptibility genes may prompt further genetic testing and guide cancer surveillance strategies for both the patient and family members. Germline mutations may also explain non-cancer phenotypes, predict drug responses, or provide reproductive counseling information for parents. The goal of the BASIC3 (Baylor College of Medicine Advancing Sequencing into Childhood Cancer Care) study is to determine the clinical impact of incorporating clinical tumor and constitutional WES into the care of children with newly diagnosed solid tumors. This study follows pediatric patients with newly diagnosed CNS and non-CNS solid tumors at Texas Children's Cancer Center for two years after performing CLIA-certified WES of blood and frozen tumor samples. Results are deposited into the electronic health record and disclosed to families by their oncologist and a genetic counselor. The potential impact of tumor exome findings on clinical decision-making is assessed through review of the medical record over the two year follow-up period as well as through surveys of the oncologists regarding prioritization of treatment options in the hypothetical event of tumor recurrence before and after receiving tumor exome results. Preferences of patient families and oncologists for reporting this complex information are obtained by interviews and audio recording of the WES result disclosure visits. Since the study opened in August 2012, more than 210 subjects have been enrolled (~80% of potentially eligible patients), representing the expected distribution of both CNS and non-CNS tumors. WES results have been reported for 170 subjects, revealing potentially-clinically relevant germline and somatic mutations in cancer genes known to be related to pediatric solid tumors as well as others known to be mutated primarily in adult cancer patients. Data will be presented regarding the diagnostic yield of combined tumor and germline WES for children with newly-diagnosed solid tumors. These results demonstrate the feasibility of routine tumor WES in the pediatric oncology clinic and a significant level of parental interest in receiving WES results and have significant implications for the treatment of children with relapsed and refractory solid tumors and the design of clinical trials using precision oncology approaches for these patients. Further analyses of the clinical utility of the WES data and the preferences of oncologists and parents for reporting of these results are under study. The BASIC3 study is a Clinical Sequencing Exploratory Research (CSER) program project supported by NHGRI/NCI 1U01HG006485. Citation Format: D. William Parsons, Angshumoy Roy, Yaping Yang, Tao Wang, Sarah Scollon, Katie Bergstrom, Robin A. Kerstein, Stephanie Gutierrez, Abhishek Bavle, Frank Y. Lin, Dolores H. López-Terrada, Federico A. Monzon, Jed G. Nuchtern, Uma Ramamurthy, Amy L. McGuire, Susan G. Hilsenbeck, Jeffrey G. Reid, Donna M. Muzny, David A. Wheeler, Stacey L. Berg, Murali M. Chintagumpala, Christine M. Eng, Richard A. Gibbs, Sharon E. Plon. Clinical genomics for children with solid tumors: Current realities and future opportunities. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr IA16.

Next-generation sequencing technologies are revolutionizing human genomics, promising to yield draft genomes cheaply and quickly. One such technology has now been used to analyse much of the genetic code of a single individual — who happens to be James D. Watson. The procedure, which involves no cloning of the genomic DNA, makes use of the latest 454 parallel sequencing instrument. The sequence cost less than US$1 million (and a mere two months) to produce, compared to the approximately US$100 million reported for sequencing Craig Venter's genome by traditional methods. Still a major undertaking, but another step towards the goal of 'personalized genomes' and 'personalized medicine'. The DNA sequence of a diploid genome of a single individual, James D. Watson, sequenced to 7.4-fold redundancy in two months using massively parallel sequencing in picolitre-size reaction vessels is reported. The association of genetic variation with disease and drug response, and improvements in nucleic acid technologies, have given great optimism for the impact of ‘genomic medicine’. However, the formidable size of the diploid human genome1, approximately 6 gigabases, has prevented the routine application of sequencing methods to deciphering complete individual human genomes. To realize the full potential of genomics for human health, this limitation must be overcome. Here we report the DNA sequence of a diploid genome of a single individual, James D. Watson, sequenced to 7.4-fold redundancy in two months using massively parallel sequencing in picolitre-size reaction vessels. This sequence was completed in two months at approximately one-hundredth of the cost of traditional capillary electrophoresis methods. Comparison of the sequence to the reference genome led to the identification of 3.3 million single nucleotide polymorphisms, of which 10,654 cause amino-acid substitution within the coding sequence. In addition, we accurately identified small-scale (2–40,000 base pair (bp)) insertion and deletion polymorphism as well as copy number variation resulting in the large-scale gain and loss of chromosomal segments ranging from 26,000 to 1.5 million base pairs. Overall, these results agree well with recent results of sequencing of a single individual2 by traditional methods. However, in addition to being faster and significantly less expensive, this sequencing technology avoids the arbitrary loss of genomic sequences inherent in random shotgun sequencing by bacterial cloning because it amplifies DNA in a cell-free system. As a result, we further demonstrate the acquisition of novel human sequence, including novel genes not previously identified by traditional genomic sequencing. This is the first genome sequenced by next-generation technologies. Therefore it is a pilot for the future challenges of ‘personalized genome sequencing’.

Physicians are encouraged to actively involve patients in clinical decision-making, but this expectation has not been adequately examined from the physicians' perspective. Our objective was to identify and characterize physicians' attitudes toward patient participation in decision-making and to gain insight into how they consequently think about and structure the decision-making process.This was a qualitative cross-sectional study of physicians' reported attitudes and practices.The study took place in private practice and academic physicians' practices.A total of 53 academic and private practice physicians from primary care and surgical specialties, ranging from first year residents to recently retired, participated in the study.We performed a qualitative analysis of semistructured individual interviews.The physicians in this study expressed consistently positive attitudes toward patient participation in medical decision-making. They identified patient autonomy as an essential justification for patient participation but often went beyond an autonomy-based rationale. Several were motivated by the fundamental principle of beneficence as well as their own self-interest in avoiding legal liability. Many physicians saw their role as an expert who educates the patient but retains control over the decision-making process; others took a more collaborative approach, encouraging patients to assume decisional priority. The decision-making process often was modified by patient, physician, and environmental factors.The physicians in this study demonstrated a positive, flexible approach toward including patients in decision-making. A one-dimensional model of shared decision-making based solely on the principle of autonomy fails to account for variability in how physicians allocate decisional priority and is therefore ethically inadequate.

In this issue, Weinberg and colleagues conclude that colorectal cancer screening uptake in average-risk persons was not positively associated with feedback from a single personalized GERA. The edit...

Advances in sequencing technologies allow for provision of genome-scale data to oncologists and geneticists caring for pediatric cancer patients but current experience with the clinical application of genomic sequencing is limited. The goal of the BASIC3 (Baylor Advancing Sequencing into Childhood Cancer Care) study is to determine the clinical impact of incorporating CLIA-certified tumor and constitutional whole exome sequencing (WES) into the care of children with newly diagnosed solid tumors. This study follows pediatric patients with newly diagnosed CNS and non-CNS solid tumors (target enrollment n=280) at Texas Children's Cancer Center for two years after performing CLIA-certified whole exome sequencing (WES) of blood and frozen tumor samples. Results are deposited into the electronic medical record and disclosed to families by their oncologist and a genetic counselor. The potential impact of tumor exome findings on clinical decision-making is assessed through review of the medical record over the two year follow-up period as well as through surveys of the oncologists regarding prioritization of treatment options in the hypothetical event of tumor recurrence before and after receiving tumor exome results. Preferences of patient families and oncologists for reporting this complex information are obtained by interviews and audiorecording of the exome result disclosure visits. Since the study opened in August 2012, ∼85% of potentially eligible families have consented to enrollment. The first 100 patients comprise a diverse representation of diagnoses, including 32 with CNS tumors (32%) and 68 with non-CNS tumors (68%). Despite limited diagnostic biopsies in many patents, snap-frozen tumor samples adequate for WES were obtained from 84 subjects (84%), including 62/68 non-CNS solid tumors (91%) and 22/32 (69%) CNS solid tumors. Tumor WES results have been reported for the first 55 patients, revealing a median of 9 (range of 0 to 78) protein-altering mutations per tumor and alterations of known cancer genes such as ALK, BRAF, DICER1, KIT, KRAS, NRAS, MET, JAK2, FGFR3, ARID1A, CTNNB1, and TP53. Fourteen of 55 tumors (25%) contained mutations classified as having proven or potential clinical utility. These results demonstrate the feasibility of routine tumor WES in the pediatric oncology clinic and a significant level of parental interest in receiving WES results. Potentially clinically-relevant mutations can be identified in a substantial minority of pediatric solid tumor patients but distinct from the medically actionable mutations seen in adult cancer patients. Data further assessing the clinical utility of the tumor exomes and the preferences of oncologists and parents for reporting of these results are under study. Supported by NHGRI/NCI 1U01HG006485. Citation Format: D. Williams Parsons, Angshumoy Roy, Federico A. Monzon, Dolores H. López-Terrada, Murali M. Chintagumpala, Stacey L. Berg, Susan G. Hilsenbeck, Tao Wang, Robin A. Kerstein, Sarah Scollon, Katie Bergstrom, Richard L. Street, Jr., Laurence B. McCullough, Amy L. McGuire, Uma Ramamurthy, David A. Wheeler, Christine M. Eng, Yaping Yang, Jeff G. Reid, Donna M. Muzny, Richard A. Gibbs, Sharon E. Plon. Evaluating the implementation and utility of clinical tumor exome sequencing in the pediatric oncology clinic: Early results of the BASIC3 study. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr IA16.

Background: Advances in sequencing technologies allow for provision of genome-scale data to physicians caring for pediatric cancer patients but current experience with the clinical application of genomic sequencing is limited and the diagnostic yield of these methods is unclear. Methods: The goal of the BASIC3 (Baylor Advancing Sequencing into Childhood Cancer Care) study is to determine the clinical impact of incorporating tumor and constitutional whole exome sequencing (WES) into the care of children with newly diagnosed solid tumors at Texas Children's Cancer Center (target enrollment n=280). WES of patient blood and frozen tumor samples is being conducted in the CLIA-certified Whole Genome Laboratory at Baylor College of Medicine using the VCRome 2.1 capture reagent and Illumina paired-end sequencing with reports incorporated in the medical record. Results: 120 patients have enrolled to date, including 39 (33%) and 81 (67%) with CNS and non-CNS tumors, respectively. Despite limited diagnostic biopsies in many patients, tumor samples adequate for WES have been obtained from 97 subjects (81%). WES results have been reported for 89 patients. Tumor WES (n=73) revealed 20 of 73 tumors (27%) to contain mutations classified as having proven or potential clinical utility, including recurrent alterations of CTNNB1, BRAF, KIT, and NRAS/KRAS. Notably, less than 50% of somatic mutations would have been detected on an adult-focused cancer panel, BCM Cancer Gene Mutation Panel v.2. Germline WES (n=89) identified diagnostic findings in 11 cases (12%) including 8 patients with pathogenic mutations in dominant cancer susceptibility genes (singletons except for 2 patients with TP53 mutations). Four of these 8 patients had genetic testing recommended clinically. There were 2 patients with mutations providing the genetic cause of non-cancer medical problems and 1 patient with a mutation which explained both liver disease and hepatocellular carcinoma. Downstream testing of at-risk relatives has occurred rapidly in several families and cancer screening recommendations implemented. Seven (8%) medically actionable incidental findings unrelated to phenotype were reported, predominantly in cardiovascular genes and mitochondrial DNA. Conclusions: These data demonstrate the feasibility of routine WES in the pediatric oncology setting. Early results demonstrate that clinically relevant findings are identified by tumor and germline WES in 38% of pediatric solid tumor patients. The yield of clinically relevant somatic and germline alterations would likely increase further by incorporation of complementary genomic methods (e.g. RNA-seq or copy number analysis). Assessment of the clinical utility of the tumor and germline exomes and preferences for reporting of these results to physicians and parents are under study. Supported by NHGRI/NCI 1U01HG006485. Citation Format: Donald W. Parsons, Angshumoy Roy, Federico A. Monzon, Yaping Yang, Dolores H. López-Terrada, Murali M. Chintagumpala, Stacey L. Berg, Susan G. Hilsenbeck, Tao Wang, Robin A. Kerstein, Sarah Scollon, Katie Bergstrom, Richard L. Street, Laurence B. McCullough, Amy L. McGuire, Uma Ramamurthy, Jeff G. Reid, Donna M. Muzny, David A. Wheeler, Christine M. Eng, Richard A. Gibbs, Sharon E. Plon. Diagnostic yield of clinical tumor and germline exome sequencing for newly diagnosed children with solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5169. doi:10.1158/1538-7445.AM2014-5169

BACKGROUND: Additional insight into the molecular alterations driving pediatric central nervous system (CNS) tumors is urgently needed, given the significant morbidity and mortality associated with these cancers and the relative paucity of effective chemotherapeutic options. Advances in sequencing technologies now allow for provision of genome-scale data to oncologists caring for pediatric cancer patients but current experience with the clinical application of genomic sequencing is limited. The goal of the BASIC3 (Baylor Advancing Sequencing into Childhood Cancer Care) study is to determine the clinical impact of incorporating CLIA-certified tumor and constitutional whole exome sequencing (WES) into the care of children with newly diagnosed solid tumors. METHODS: The study follows pediatric patients with newly diagnosed CNS and non-CNS solid tumors (target enrollment n = 280) at Texas Children's Cancer Center for two years after performing CLIA-certified whole exome sequencing (WES) of blood and frozen tumor samples. Results are deposited into the electronic medical record and disclosed to families by their oncologist and a genetic counselor. The potential impact of tumor exome findings on clinical decision-making is assessed through review of the medical record and through surveys of the oncologists regarding prioritization of treatment options in the hypothetical event of tumor recurrence. RESULTS: To date, 133 subjects have been enrolled, including 47 patients with CNS tumors (35%) comprising a diverse representation of diagnoses. Despite limited diagnostic biopsies in many patients, tumor samples adequate for WES were obtained from 33/47 (70%) patients. Tumor WES results have been reported for the first 22 CNS tumors, revealing a median of 7 (range of 0 to 25) protein-altering mutations per tumor, including alterations of known cancer genes such as ARID1A, SMARCA4, BRAF, CTNNB1, DDX3X, NF2, FANCA, and NOTCH3. Notably, 12/22 (55%) tumors were found to harbour mutations only in genes not known to be recurrently altered in human cancers. CONCLUSIONS: These results demonstrate the feasibility of routine tumor WES in the pediatric neuro- oncology clinic. Potentially clinically-relevant mutations can be identified in a substantial proportion of patients but early results suggest that integration of parallel genomic technologies (e.g. RNAseq) to identify genetic alterations not detectable by WES will be necessary; such studies are ongoing. Orthotopic xenograft models and cell lines are being established to allow in vitro and in vivo analysis of tumors containing alterations of interest. Data further assessing the clinical utility of the tumor exomes are under study. Supported by NHGRI/NCI 1U01HG006485. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.

In our Policy Forum “Regulating direct-to-consumer personal genome testing” (8 October, p. [181][1]), we recommend a risk-stratified regulatory approach for direct-to-consumer (DTC) genetic tests. If tests are low risk (as existing data indicate for the vast majority of tests sold DTC ) then the oversight should be minimal and should focus on ensuring that consumers have accurate and truthful information. Only high-risk tests would be subject to greater oversight and enhanced scrutiny by agencies such as the U.S. Food and Drug Administration (FDA). Williams argues that this type of risk-based strategy fails to account for the impact of benefit on the tolerability of risk. We agree that benefit is an important consideration. A high-risk test that has the potential to benefit consumers significantly, and thus has proven therapeutic utility, should be cleared or approved for distribution. In fact, the sort of external data-driven review that would be required to assess benefit is precisely what the FDA would provide when evaluating a high-risk new test product. However, the primary goal of regulatory oversight is to ensure consumer safety, so regardless of the potential for benefit, a test that poses significant risk ought to be subject to external review. The data required for the review in this circumstance allow regulators to take into account both risks and benefits. Williams also argues that delayed access to a new test may prevent the introduction of life-saving diagnostics. We are not aware of any evidence that life-saving genetic tests, such as those used in newborn screening, are being delayed, but we agree that waiting for robust effectiveness data could effectively regulate DTC companies out of existence and should be avoided. We therefore believe that the FDA's premarket oversight should focus on the legitimacy of claims made and that there should be enhanced postmarket data collection and surveillance. This approach is quite flexible in terms of the amount and type of evidence required for a test to move to market. It is more hospitable to innovative tests than is the case in many other countries, such as Germany, where DTC testing has been banned. Baskys believes that all individuals have a right to receive their genetic information. We do not necessarily disagree. We simply argue that consumers need access to accurate and truthful information in order to make informed decisions. For tests that have the potential to influence important medical decisions, this includes contextual information about the individual's other risk factors, including family history, environmental exposures, and biological symptoms. We agree that there is a dearth of scientific evidence on the potential risks associated with receiving genetic information DTC; there is also a lack of evidence of the potential benefits. As noted by Baskys, there are few, if any, DTC tests that have as much predictive value as a blood pressure test or a weight scale. Indeed, available evidence tells us that genetic risk information does little to motivate healthy behavior change ([ 1 ][2]). Given this reality, it seems appropriate that the vast majority of DTC tests will not require significant oversight, as per our stratified approach. 1. [↵][3] 1. T. M. Marteau 2. et al ., “Effects of communicating DNA-based disease risk estimates on risk-reducing behaviours” (Cochrane Database of Systematic Reviews, issue 10, 10.1002/14651858.CD007275.pub2, 2010). doi:10.1002/14651858.CD007275.pub2 [OpenUrl][4][CrossRef][5] [1]: /lookup/doi/10.1126/science.1194006 [2]: #ref-1 [3]: #xref-ref-1-1 "View reference 1 in text" [4]: {openurl}?query=rft.jtitle%253DCochrane%2BDatabase%2Bof%2BSystematic%2BReviews%26rft_id%253Dinfo%253Adoi%252F10.1002%252F14651858.CD007275.pub2%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [5]: /lookup/external-ref?access_num=10.1002/14651858.CD007275.pub2&link_type=DOI