Heart and Blood Diseases

Symptoms and General Pathology

All Conditions

Nutritional and Metabolic Diseases

Neoplasms

Skin and Connective Tissue Diseases

Gland and Hormone Related Diseases

Musculoskeletal Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Respiratory Tract (Lung and Bronchial) Diseases

Eye Diseases

Immune System Diseases

Digestive System Diseases

Myocardial Infarction

Infarction

Obesity

Breast Neoplasms

Diabetes Mellitus

Diabetes Mellitus, Type 2

Osteoarthritis

Prostatic Neoplasms

Lung Neoplasms

Atrial Fibrillation

Graves Disease

Celiac Disease

Arrhythmias, Cardiac

Heart Diseases

Ischemia

Necrosis

Coronary Artery Disease

Myocardial Ischemia

Vascular Diseases

Gastrointestinal Diseases

Intestinal Diseases

Syndrome

Malabsorption Syndromes

Metabolic Diseases

Glucose Metabolism Disorders

Endocrine System Diseases

Exophthalmos

Orbital Diseases

Goiter

Thyroid Diseases

Hyperthyroidism

Autoimmune Diseases

Those who will receive predictive genetic risk assessments

The patients in the intervention group will obtain genetic risk assessments based on genome-wide association studies.

SNP analysis

Kristina Tiedje, Ph.D.

Clayton T. Cowl, M.D.

Barbara A. Koenig, Ph.D.

This proof-of-principle clinical trial at Mayo Clinic studies how patients and their physicians understand and utilize predictive genetic risk assessment. A critical goal of this clinical trial is to understand how individual patients and their doctors perceive and respond to genetic risk information that is largely uncertain.

The prospect of personalized medicine is under heated debate at the Mayo Clinic and it is of interest across the world. A point of contention is the provision of individual genetic risk assessment to healthy patients, especially information predicting risk of common diseases like diabetes, cancer, or heart disease. While scientific debate continues, personal genetic testing is currently offered to the public by commercial firms using a "direct-to-consumer" (DTC) approach. At present, the number of private companies offering such services is growing (i.e. 23 and me, deCode genetics, etc.). Although many professionals hope that genetic risk information will prove to be valuable in the near future, there is little understanding of how this kind of predictive risk assessment will be interpreted and perceived by patients and their doctors. Due to the great attention given to predictive genetic testing in the popular press, one expects that patients will soon demand this testing as part of standard clinical practice. Yet, there is currently no effective regulatory oversight to guide clinicians and policy makers about how to incorporate results from predictive genetic testing into routine clinical use. In fact, no appropriate clinical trials assessing the impact of this type of testing have been completed. Indeed, a recent commentary in the New England Journal of Medicine recommended that all such testing be conducted in the context of a clinical trial.

How to protect human subjects during the early stages of development of a new technology is a classic dilemma in translational research. For that reason, we have developed a "proof-of-principle" clinical trial at Mayo Clinic to study how patients and their physicians understand and utilize predictive genetic risk assessment. A critical goal of this clinical trial is to understand how individual patients and their doctors perceive and respond to genetic risk information that is largely uncertain.

Our pilot study seeks to answer three fundamental questions: How will physicians deal with the uncertainty provided by the new technology of predictive genetic risk assessment? What hopes do patients have regarding the significance of predictive genetic testing? And how do they interpret their results? This proof-of-principle study will investigate the impact of direct-to-consumer, predictive genetic testing provided and sponsored by Navigenics, Inc., a private company advertising predictive genetic testing for common diseases or conditions. This study will allow Mayo Clinic to be proactive in researching the dynamics of this potential innovation in health care. The proof-of-principle study described herein is designed to collect preliminary data that will inform the development of a larger clinical trial and provide data for an application for federal funding.

Our study will be in collaboration with Navigenics, the industry sponsor of this project. Navigenics will use a high density, genome microarray for determining the gene variants-, and published disease-association studies, to calculate the relative risk of each patient for a few targeted common diseases. High density microarrays are genome chips that allow the assessment of one million single nucleotide polymorphisms (SNPs) at relatively low cost. The combination of particular SNPs are presumed to influence the risk of developing certain common diseases as shown from genome-wide association studies published in peer-reviewed scientific and medical literature. Navigenics will use these population-based association studies (studies that produce odds ratios for developing a disease given a certain SNP) to estimate the relative of an individual patient developing a disease, an approach that is used by most direct-to-consumer genetic testing companies. They claim that their testing has a role in preventive medicine in order to "Help people live healthier lives." Our study will allow us to examine how patients and doctors respond to and utilize Navigenics' risk assessments derived from microarray technology and published genome-wide association studies.

The role of information delivery to patients by physicians, genetic counselors or other health care professionals using predictive genetic risk assessment is unclear. Its acceptance by patients and health care professionals has also not been studied. Therefore, this study seeks to compare the perception of genetic risk estimations obtained from Navigenics' testing with the relative risk estimations obtained through a family history, the current Mayo standard of care.

Our study design includes two phases to be conducted over 18 months. The first phase is a "pre-pilot" study that will take place in 2008. In phase one, we will conduct structured interviews with 20 Executive Health (EH) Program patients who have obtained their disease risk assessments for common diseases or who have obtained a family history. In phase 2, we will conduct a quantitative phone survey with 150 EH patients randomized into two arms (genetic testing and standard of care). We will also conduct follow up qualitative interviews with 20 patients in phase 2. The study is anticipated to be completed in mid 2009.

Predictive Genetic Risk Assessment Trial

Proof-of-Principle Trial of Communication to Patients Receiving Predictive Genetic Risk Assessment

Mayo Clinic

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Colonic Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Fluorouracil

Formaldehyde

Samples from patients with stage III colorectal cancer who are going to receive fluorouracil-based adjuvant chemotherapy will be used for gene mutations analysis, gene methylation analysis, gene expression analysis, SNP analysis, and protein expression analysis.

Genomic DNA extracted from paired fresh-frozen tumor and normal tissues is used for KRAS mutations, BRAF mutations, PIK3A mutations, and EGFR mutations, etc., by sequencing and for MSI analysis by PCR and capillary electrophoresis.

Gene mutations analysis

Genomic DNA extracted from paired fresh-frozen tumor and normal tissues is used for specific gene methylation or CIMP status analysis by MethyLight or bisulfite sequencing. Whole-genome bisulfite sequencing will be used to identify novel candidate set of predictive markers.

Gene methylation analysis

RNA extracted from paired fresh-frozen tumor and normal tissues or serum is used for specific gene expression analysis by real-time reverse-transcription PCR (RT-qPCR). RNA-seq will be used to identify novel candidate set of predictive markers.

Gene expression analysis

Genomic DNA extracted from serum is used for specific SNP analysis by using sequencing. GWAS with SNPs array will be used to identify novel candidate set of predictive markers.

Tissue microarray made from formalin-fixed paraffin-embedded (FFPE) paired tumor and normal tissues is used for specific protein expression analysis by immunohistochemistry staining.

Protein expression analysis

The goal of this laboratory research is to look for genetic and epigenetic markers that can predict which patients with stage III colorectal cancer will benefit from fluorouracil-based adjuvant chemotherapy.

This is a prospective project in collecting and assessing clinical outcomes data related to molecular profiling of tumors based on samples from peripheral blood, primary tumor, and adjacent normal colorectal tissue.

Objectives:

1. Validation of predictive value of known markers CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in the response to 5-fluorouracil-based chemotherapy in patients with stage III colorectal cancer.
2. Exploratory evaluation of the potential predictive values of known genetic variations including, but not limited to, KRAS mutations, BRAF mutations, PIK3A mutations, and EGFR mutations, etc.
3. Exploratory identification and evaluation of the predictive value of novel methylation aberrations identified by whole-genome bisulfite sequencing.
4. Exploratory identification and evaluation of the predictive value of novel genetic aberrations discovered by RNA-sequencing (RNA-seq) or genome-wide association study (GWAS).

Outline:

Blood is collected at baseline and examined for single-nucleotide polymorphisms (SNPs) and expression level of specific gene. Tumor and corresponding normal tissue at surgical resection and assessed for gene methylations, mutations, and expressions.

Blood, serum, tumor tissue, normal colorectal tissue

Genetic and Epigenetic Determinants of Response to Fluorouracil-based Adjuvant Chemotherapy in Patients With Stage III Colorectal Cancer

The Identification, Validation and Implementation of Molecular Markers to Predict Response to Fluorouracil-based Adjuvant Chemotherapy in Stage III Colorectal Cancer Patients - Prospective Clinical Observational Study

Time to any event, except non-cancer-related death. All recurrences, treatment-related deaths, second same or other primary cancers, and deaths from other cancers are considered to be events. Loss to follow-up and non-cancer-related deaths are censored. Associations between TTR and genetic and epigenetic markers will be analyzed.

Time to any event, irrespective of cause. All events are included, except loss to follow-up. Associations between DFS and genetic and epigenetic markers will be analyzed.

Time to death caused by the same cancer, whether due to the original tumor or to a second primary same cancer. The only event is death from the same cancer, without taking into account whether the death is caused by the primary tumor or a second same cancer. Locoregional recurrence, distant metastases, second primary same cancers, and second other primary cancers are ignored. Deaths from other cancers, non-cancer-related deaths, treatment-related deaths, and loss to follow-up are censored. Associations between CSS and genetic and epigenetic markers will be analyzed.

Time to death, irrespective of cause. There is no need to specify whether the death was due to cancer. Locoregional recurrence, distant metastases, second primary colorectal cancers, and second other primary cancers are ignored. Loss to follow-up is censored. Associations between OS and genetic and epigenetic markers will be analyzed.

Renmin Hospital of Wuhan University

Head of Department of GI Surgery II

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Predictive Genetic Risk Assessment Trial	NCT00782366	Colon Cancer Lung Cancer Atrial Fibrilla... Diabetes Type 2 Obesity Breast Cancer Graves Disease Osteoarthritis Celiac Disease Myocardial Infa... Prostate Cancer	SNP analysis	18 Years - 65 Years	Mayo Clinic
Genetic and Epigenetic Determinants of Response to Fluorouracil-based Adjuvant Chemotherapy in Patients With Stage III Colorectal Cancer	NCT03127111	Stage III Color...	Gene mutations ... Gene methylatio... Gene expression... SNP analysis Protein express...	18 Years - 70 Years	Renmin Hospital of Wuhan University
Predictive Genetic Risk Assessment Trial	NCT00782366	Colon Cancer Lung Cancer Atrial Fibrilla... Diabetes Type 2 Obesity Breast Cancer Graves Disease Osteoarthritis Celiac Disease Myocardial Infa... Prostate Cancer	SNP analysis	18 Years - 65 Years	Mayo Clinic

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