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Family members of individuals who have received secondary genomic findings after exome/genome sequencing

Individuals who have received secondary genomic findings after exome/genome sequencing

Julie Sapp

Leslie G Biesecker, M.D.

For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)

Background:

Genes are the instructions a person s body uses to function. Genome sequencing is a new way to look at genes that your main research team is using to learn the causes of the condition they are studying. When a new cause is found this way, it is called a primary variant. Each person has many variants. Most do not cause disease. Sequencing can also find secondary variants. These are not related to the condition your main research team is studying, but may show a person to be at high risk for cancer or another condition. Researchers want to learn more about what it means to have a secondary variant.

Objectives:

To find new gene changes that lead to certain medical conditions. To better understand the causes of certain diseases. To learn about how people understand their genetic test results.

Eligibility:

People with rare diseases who have already consented to and enrolled in another protocol run by a group other than the National Human Genome Research Institute.

Design:

DNA samples that were already collected will be studied.

Participants may be asked to send in a second DNA sample (blood or saliva). These will be used to verify any findings.

If a primary variant for the participant s health condition is found through genome sequencing, this will be shared with the participant by their primary research team.

If the participant has a secondary finding, it will be shared by phone call or videoconference by this research group in the National Human Genome Research Institute. Some participants may get their results in person at the clinic.

Three months after getting their secondary findings, participants will do an online survey and phone interview. They will be asked about how they have used the information.

Some people who do not receive a secondary finding from genome sequencing will be asked to do an online survey three months after they get that result.

Participants who have a secondary finding can get genetic counseling.

The implementation of genome and exome sequencing creates challenges and opportunities, particularly with respect to the return of medically-actionable secondary findings (SF). This study seeks to investigate the utility and effectiveness of returning SF generated via research or clinical sequencing by studying individuals who have received such findings. Our objectives with this protocol have evolved over time and have been substantially informed by our experiences in returning SF through sequencing initiatives such as the ClinSeq study, the Clinical Center Genomics Opportunity (CCGO), and the Secondary Genomic Findings Service (SGFS). Our work with these studies/initiatives suggests that much remains unknown about how recipients of SF understand these findings, communicate them to their health professionals and families, and whether they adhere to recommended health-preserving actions in both the short and long-term. As well, recipients of SF are an unselected population in which to investigate penetrance of disorders associated with SF genes. Thus, this protocol aims to explore important questions of clinical utility associated with SF return and penetrance of SF-related disorders. Healthcare actions and family communication (clinical utility) are assessed by interviews and surveys with SF recipients. This protocol also includes a pilot program in which selected participants will be invited to the NIH for bespoke phenotyping to uncover the presence of disease and explore avenues to develop interventions to enhance outcomes.

Genomic Services Research Program

We will assess affective responses and healthcare and behavioral changes to receiving positive SF results

We will assess penetrance using the family-based positive predictive value metric

We will assess what individual, community, and systemic factors influence recipients follow through on recommendations and how they communicate SF results with family members.

We will assess the health impacts of SF receipt and healthcare processes affecting outcomes in SF recipients.

National Human Genome Research Institute (NHGRI)

Blood samples and, for some patients, buccal (mouth cell) samples will be collected at diagnosis and/or relapse. Solid tumor samples will be collected in the normal course of treatment, from biopsy, blood or other specimens. For blood-based cancers such as leukemia, blood and bone marrow specimens will be collected before treatment begins, on day 29 and possibly at a later time point if relapse occurs.

Patients may meet, depending on test results, with their physician and a genetic counselor to discuss possible changes in their treatment options and/or lifestyle changes.

Cancer Treatment Options

Stuart S Winter, MD

The goal of this study is to develop a new, local system that will use special tests based on patients' genetic makeup to better tailor cancer care at the University of New Mexico Cancer Center.

The Food and Drug Administration has already approved over forty (40) drugs to treat cancer patients based on specific genetic makeup, and more agents are in development that will support this new approach to treatment, often referred to as "personalized medicine."

The goal of performing specific tests on patients' genetic material is to discover tumor-specific, single nucleotide variations (SNVs) and other forms of genetic changes (called epigenetic changes) that can be detected when comparing normal tissue and tumor tissue. This can help guide cancer care decisions that may be more effective for patients. These will be called clinically actionable findings, or CAF.

Additional health related findings may be made, not related to cancer but to other conditions, diseases or syndromes. These are called secondary findings (SF). In this study the investigators will also measure how often they find SF and will discuss their possible impact on other aspects of patients' health. If patients want to know about these findings, they will be discussed with a panel of experts including genetic counselors.

Finally, the investigators will compare how often CAF and SF differ from those identified in nationwide samples.

For brevity, the investigators include the approaches of whole genome sequencing, whole exome sequencing of just the protein-coding exons, enrichment and sequencing of methylated DNA and RNA or transcriptome-sequencing under the broad category term, Whole Genome Sequencing (WGS).

The development of rapid and low cost next-generation genome sequencing technologies brings the promise of a new era of precision therapeutics to clinical practice, but it is associated with significant challenges, including reproducible generation of high-quality sequence data and the need for comprehensive data analysis and interpretation that is translatable to clinical action. Equally critical are the ethical, legal, and social issues surrounding the introduction of WGS testing and its clinical application in multiethnic, multicultural populations, particularly those who have historically experienced discrimination or even unethical research practices. Of particular concern are issues surrounding the privacy, ownership, storage, and use of WGS data.

Genome Sequencing of Human Cancer Tissues

The investigators will utilize new genomics technologies in to identify potentially Clinically Actionable Findings (CAF) in patient tumor and other samples. Based on individual patient data, alternative treatment options will be offered to patients.

The investigators will measure the frequency with which clinically actionable findings (CAF) that could impact current patient care decisions occur in tumor and other samples.

Determine whether CAF identified in the unique patient populations treated at the University of New Mexico Cancer Center differ from those identified in nationwide data sets such as The 1000 Genomes Project or The Cancer Genome Atlas (TCGA) data collections.

Identify the numbers and types technological, social, ethical and/or legal barriers that might limit the use of genomics information in patient care at the University of New Mexico Cancer Center and the University of New Mexico Health Sciences Center. The investigators will assess the frequency of use of CAF by local treating physicians. They will assess how often cancer treatment choice is altered as a result of providing CAF to physicians and patients. The investigators will assess how often identified CAF are entered into patient medical records. They will assess the frequency with which patients choose to receive information about potentially detrimental SF unrelated to their cancer care.

Identify other genomics-based findings in patient samples unrelated to cancer care, but which might impact other aspects of patients' health. These will be referred to as Secondary Findings, or SF. For example, if a SF is identified that suggests an increased risk of diabetes, this would be considered a secondary finding. This will be discussed by a panel of medical experts, and if patients wish to have this information returned to them, their doctor and genetic counselor will discuss the SF. Patients can choose not to have SF returned to them.

Determine whether SF identified in the unique patient populations treated at the University of New Mexico Cancer Center differ from those identified in nationwide samples such as The 1000 Genomes Project or The Cancer Genome Atlas (TCGA).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Genomic Services Research Program	NCT02595957	Colon Cancer Breast Cancer		1 Month - 105 Years	National Institutes of Health Clinical Center (CC)
Genome Sequencing of Human Cancer Tissues	NCT02105545	Cancer	Cancer Treatmen...	-	New Mexico Cancer Care Alliance

Spots Global Cancer Trial Database for secondary findings