Quantitative Approaches to Understanding Cancer Genomes.

Recent advances in technology have enabled the systematic, genome-wide analysis of cancer genomes, providing greater insight into the genetic basis of cancer development and a deeper understanding of the human genome. The focus of the current work is to identify genomic alterations potentially conferring risk for developing colorectal and breast cancers by performing genome-wide analysis with single nucleotide polymorphism (SNP) genotyping and next-generation sequencing (NGS) platforms. My first dissertation project involves deeply sequencing the genomes of individuals from a single family to identify novel mutations in hereditary mixed polyposis syndrome, a rare form of colorectal cancer with no known genetic basis. A novel candidate gene, ZNF426, was identified and decreased expression was confirmed in tumors from affected individuals. The second part of my dissertation evaluates methods for detection of somatic copy number alterations in colorectal cancer on chromosome 18 and the application of statistical methods for utilizing poor quality tumor data. Using genotyping and expression data from tumors, a variety of structural alterations were identified on chromosome 18. Additionally, I demonstrated the utility of applying new statistical methods to identity copy number alterations in array data with high background noise. The goal of my third project was to evaluate the contribution of consanguinity to breast cancer risk in Arab women without mutations in the BRCA1 and BRCA2 genes. The hypothesis in this study is that an increase in autosomal recessive genes responsible for genetic susceptibility to breast cancer is expected among families with consanguinity due to the increase in probability of sharing alleles identical-by-descent. Six unrelated individuals with breast cancer shared a 200kb overlapping region of homozygous SNPs on chromosome 9q332-33.3, which harbors an important candidate gene for cancer risk, LHX2. Whole-genome analysis allows for greater depth and higher throughput sequencing at lower costs, adding a new dimension to our understanding of cancer genetics. Future progress in these technologies and bioinformatics methods will improve the costs, sensitivity and accuracy of detecting mutations.Ph.D.Human GeneticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/89716/1/gornickm_1.pd

Estimating probability of germline mismatch repair mutations in colorectal cancer patients with microsatellite stable tumors

http://deepblue.lib.umich.edu/bitstream/2027.42/112938/1/13053_2011_Article_206.pd

Interpretations of the Term “Actionable” when Discussing Genetic Test Results: What you Mean Is Not What I Heard

In genomic medicine, the familiarity and inexactness of the term “actionable” can lead to multiple interpretations and mistaken beliefs about realistic treatment options. As part of a larger study focusing on public attitudes toward policies for the return of secondary genomic results, we looked at how members of the lay public interpret the term “medically actionable” in the context of genetic testing. We also surveyed a convenience sample of oncologists as part of a separate study and asked them to define the term “medically actionable.” After being provided with a definition of the term, 21 out of 60 (35%) layperson respondents wrote an additional action not specified in the provided definition (12 mentioned “cure” and 9 mentioned environment or behavioral change) and 17 (28%) indicated “something can be done” with no action specified. In contrast, 52 surveyed oncologists did not mention environment, behavioral change, or cure. Based on our findings, we propose that rather than using the term “actionable” alone, providers should also say “what they mean” to reduce miscommunication and confusion that could negatively impact medical decision‐making. Lastly, to guide clinicians during patient‐ provider discussion about genetic test results, we provide examples of phrasing to facilitate clearer communication and understanding of the term “actionable.”Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149289/1/jgc41064.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149289/2/jgc41064_am.pd

Knowledge regarding and patterns of genetic testing in patients newly diagnosed with breast cancer participating in the iCanDecide trial

BackgroundThe current study reports rates of knowledge regarding the probability of a BRCA1 and/or S pathogenic variant and genetic testing in patients with breast cancer, collected as part of a randomized controlled trial of a tailored, comprehensive, and interactive decision tool (iCanDecide).MethodsA total of 537 patients newly diagnosed with early‐stage breast cancer were enrolled at the time of their first visit in 22 surgical practices, and were surveyed 5 weeks (496 patients; Response Rate [RR], 92%) after enrollment after treatment decision making. Primary outcomes included knowledge regarding the probability of carrying a BRCA1 and/or BRCA2 pathogenic variant and genetic testing after diagnosis.ResultsOverall knowledge regarding the probability of having a BRCA1 and/or BRCA2 pathogenic variant was low (29.8%). Significantly more patients in the intervention group compared with the control group had knowledge regarding the probability of a BRCA1 and/or BRCA2 pathogenic variant (35.8% vs 24.4%; P <.006). In multivariable logistic regression, the intervention arm remained significantly associated with knowledge regarding the probability of having a BRCA1 and/or BRCA2 pathogenic variant (odds ratio, 1.79; 95% confidence interval, 1.18‐2.70).ConclusionsThe results of the current study suggest that although knowledge concerning the probability of having a BRCA1 and/or BRCA2 pathogenic variant remains low in this patient population, the interactive decision tool improved rates compared with a static Web site. As interest in genetic testing continues to rise, so will the need to integrate tools into the treatment decision process to improve informed decision making.As interest in genetic testing increases, so will the need to integrate tools into the treatment decision process. Results from the current study suggest that although knowledge regarding the probability of a BRCA1 and/or BRCA2 pathogenic variant remains low in this patient population, the interactive decision tool improved rates compared with a static Web site.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146553/1/cncr31731.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146553/2/cncr31731_am.pd

Next‐generation sequencing in precision oncology: Patient understanding and expectations

BackgroundImplementation of precision oncology interventions poses several challenges to informed consent and patient education. This study assessed cancer patients’ understanding, expectations, and outcomes regarding participation in research examining the impact of matched tumor and germline sequencing on their clinical care.MethodsA total of 297 patients (mean age: 59 years; 50% female; 96% white) with refractory, metastatic cancer were surveyed, including 217 who completed surveys both before and after undergoing integrated whole exome and transcriptome sequencing as part of a larger clinical research study.ResultsAt baseline, the vast majority of patients expected to receive several potential direct benefits from study participation, including written reports of sequencing findings (88%), greater understanding of the causes of their cancer (74%), and participation in clinical trials for which sequencing results would make them eligible (84%). In most cases, these benefits were not realized by study completion. Despite explanations from study personnel to the contrary, most participants (67%‐76%) presumed that incidental germline sequencing findings relevant to noncancerous health conditions (eg, diabetes) would automatically be disclosed to them. Patients reported low levels of concern about study risks at baseline and low levels of regret about study participation at follow‐up.ConclusionsFindings suggest that cancer patients participating in precision oncology intervention research have largely unfulfilled expectations of direct benefits related to their study participation. Increased focus on patient education to supplement the informed consent process may help manage patients’ expectations regarding the extent and likelihood of benefits received as a result of undergoing genomic sequencing.This study assessed cancer patients’ understanding and expectations regarding participation in research examining the impact of matched tumor and germline sequencing on their clinical care. Findings suggest that cancer patients participating in precision oncology intervention research have largely unfulfilled expectations of direct benefits related to their study participation. Increased focus on patient education to supplement the informed consent process may help manage patients’ expectations regarding the extent and likelihood of benefits received as a result of undergoing genomic sequencing.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147745/1/cam41947.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147745/2/cam41947_am.pd

Human papillomavirus is not associated with colorectal cancer in a large international study

Recent publications have reported an association between colon cancer and human papillomaviruses (HPV), suggesting that HPV infection of the colonic mucosa may contribute to the development of colorectal cancer. The GP5+/GP6+ PCR reverse line blot method was used for detection of 37 types of human papillomavirus (HPV) in DNA from paraffin-embedded or frozen tissues from patients with colorectal cancer (n = 279) and normal adjacent tissue (n = 30) in three different study populations, including samples from the United States (n = 73), Israel (n = 106) and Spain (n = 100). Additionally, SPF10 PCR was run on all samples (n = 279) and the Innogenetics INNO-LiPA assay was performed on a subset of samples (n = 15). All samples were negative for all types of HPV using both the GP5+/GP6+ PCR reverse line blot method and the SPF10 INNO-LiPA method. We conclude that HPV types associated with malignant transformation do not meaningfully contribute to adenocarcinoma of the colon

Effect of Public Deliberation on Attitudes toward Return of Secondary Results in Genomic Sequencing

The increased use of genomic sequencing in clinical diagnostics and therapeutics makes imperative the development of guidelines and policies about how to handle secondary findings. For reasons both practical and ethical, the creation of these guidelines must take into consideration the informed opinions of the lay public. As part of a larger Clinical Sequencing Exploratory Research (CSER) consortium project, we organized a deliberative democracy (DD) session that engaged 66 participants in dialogue about the benefits and risks associated with the return of secondary findings from clinical genomic sequencing. Participants were educated about the scientific and ethical aspects of the disclosure of secondary findings by experts in medical genetics and bioethics, and then engaged in facilitated discussion of policy options for the disclosure of three types of secondary findings: 1) medically actionable results; 2) adult onset disorders found in children; and 3) carrier status. Participants’ opinions were collected via surveys administered one month before, immediately following, and one month after the DD session. Post DD session, participants were significantly more willing to support policies that do not allow access to secondary findings related to adult onset conditions in children (Χ2 (2, N = 62) = 13.300, p = 0.001) or carrier status (Χ2 (2, N = 60) = 11.375, p = 0.003). After one month, the level of support for the policy denying access to secondary findings regarding adult‐onset conditions remained significantly higher than the pre‐DD level, although less than immediately post‐DD (Χ2 (1, N = 60) = 2.465, p = 0.041). Our findings suggest that education and deliberation enhance public appreciation of the scientific and ethical complexities of genome sequencing.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/1/jgc40122-sup-0006.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/2/jgc40122.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/3/jgc40122-sup-0005.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/4/jgc40122-sup-0007.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/5/jgc40122-sup-0002.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/6/jgc40122-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/7/jgc40122-sup-0003.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146892/8/jgc40122-sup-0004.pd

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Public’s Views toward Return of Secondary Results in Genomic Sequencing: It’s (Almost) All about the Choice

The therapeutic use of genomic sequencing creates novel and unresolved questions about cost, clinical efficacy, access, and the disclosure of sequencing results. The disclosure of the secondary results of sequencing poses a particularly challenging ethical problem. Experts disagree about which results should be shared and public input – especially important for the creation of disclosure policies – is complicated by the complex nature of genetics. Recognizing the value of deliberative democratic methods for soliciting informed public opinion on matters like these, we recruited participants from a clinical research site for an all‐day deliberative democracy (DD) session. Participants were introduced to the clinical and ethical issues associated with genomic sequencing, after which they discussed the tradeoffs and offered their opinions about policies for the return of secondary results. Participants (n = 66; mean age = 57 (SD = 15); 70% female; 76% white) were divided into 10 small groups (5 to 8 participants each) allowing interactive deliberation on policy options for the return of three categories of secondary results: 1) medically actionable results; 2) risks for adult‐onset disorders identified in children; and 3) carrier status for autosomal recessive disorders. In our qualitative analysis of the session transcripts, we found that while participants favored choice and had a preference for making information available, they also acknowledged the risks (and benefits) of learning such information. Our research reveals the nuanced reasoning used by members of the public when weighing the pros and cons of receiving genomic information, enriching our understanding of the findings of surveys of attitudes regarding access to secondary results.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147026/1/jgc41197.pd