Genetics and Biomarkers 

The era of personalized medicine is here.  Genetics and the human genome project are offering unprecedented means of detecting and treating diseases like cancer, cardiovascular disease, and diabetes, as well as, chronic episodic conditions (e.g., depression, asthma) and less common diseases (e.g., inflammatory bowel disease). The vision is simple.  With a detailed understanding of a patient’s genetic profile and current physiologic status, we can accurately anticipate future risks and specifically choose the intervention that will be optimal. Geisinger Center for Health Research (GCHR) investigators, in collaboration with Sigfried and Janet Weis Center for Research laboratory science investigators, are conducting research in three areas relevant to personalized medicine:

  • Screening and diagnostics: we are testing a variety of next-generation genetic and proteomic predictors to identify the patient’s medical problems before they manifest as full-fledged disease.  Early warning = better prevention.
  • Genetically guided dosing and prognosis:  Once a disease had already manifested, we can weigh our treatment options based on a variety of genetic markers that help us predict the patient’s response to drugs and procedures.
  • Drug design: we can use clues from genetic studies to tell us what genes are causing the disease.  Once we know this, we can fit drugs and drug combinations that target the broken physiological pathways and fix them.

Active areas of research interest include abdominal aortic aneurysm, morbid obesity, prescription opioid addiction, early detection of heart failure, colon cancer screening, and treatment response to use of asthma medications.

Development and Validation of a Panel of Breast Cancer Auto-antigens for Early Diagnosis of Breast Cancer

PI: Azadeh Stark, PhD

We have reported that a panel of autoantigens could distinguish breast cancer sera from normal controls and offers a promising test for the early diagnosis of breast cancer.  Our ongoing hospital-based case-control study, improves the accuracy of our previously reported data by focusing only on ductal carcinoma of the breast, and by expanding the diagnostic panel through the identification of new breast cancer associated phage-coded autoantigens and finally by validating the newly expanded panel in an independent group of women with BIRADS 4 or suspiciouos lesion diagnosis at their last screening mammographies.  The outcome of this project will be the development of a new diagnostic instrument, based on serum reactivity to an autoantigen panel constructed with phage-coded antigens, which may prove to be an accurate, relatively inexpensive and easy-to-adminster instrument for the early diagnosis of breast cancer.   This study is in collaboration with Dr. Fernandez-Madrid at the Karmanos Comprehensive Cancer Institute, Wayne State University.

Estrogen Receptor Polymorphism and Risk of Basaloid Breast Cancer in African-American Women

PI: Azadeh Stark, PhD

Lifetime breast cancer risk is lower for African-American compared to White-American women, yet African-Americans suffer from a higher disease specific mortality rate.  It is well accepted that the prevalence of basal-like breast cancer is significantly higher among African-American women.  Basal-like breast cancer are characterized by the absence of hormone receptors, with more advanced stages, poorly differentiated histologic grade, areas of necrosis and more propensity for metastasis to brain and lung.  A founder mutation effect has been proposed for the higher prevalence of basal-like breast cancer in African-American women.  We have implemented a multi-center research project to test the hypothesis that the genotypic structure of the estrogen receptors found in breast tissue of women with African heritage predisposes them to the basal-like breast cancer subtype.  The primary objective of this project is to sequence the estrogen receptors in breast tissue from African women, Ghana, African-American and White-American women.  This study is in collaboration with Dr. Lisa Newman at the University of Michigan Comprehensive Cancer Center.

Opioid Addiction and Chronic Pain: Genetic & Environmental Factors

PI: Joseph Boscarino, PhD

This study is assessing the genetic and environmental risks for addiction to prescription opioids. It is based on a candidate-gene study design among 705 chronic back-pain patients seen at Geisinger Health System (GHS). Altogether, 18 candidate genes are being investigated, including brain-derived neurotrophic factor, catechol-O-methyltransferase, corticotropin releasing hormone, dopamine receptors (D1, D2, D3, D4), monoamine oxidase A, neuropeptide Y, opioid receptor - mu 1, serotonin transporter, cholinergic receptor nicotinic alpha polypeptide, FK binding protein 5, and gamma-aminobutyric acid A receptor alpha, among other. The main environmental exposure of interest in this study is early life exposure to psychological trauma. Data analyses of completed patient interviews suggest that 35% of subjects meet DSM-IV criteria for opioid dependence (25% meet current dependence). In addition, 34% of subjects meet lifetime criteria for depression, 12% anxiety disorder, 24% anti-social personality, 14% PTSD, and 13% for lifetime alcohol dependence. Demographically, 67% are female, 77% less than 65 years old, and 63% are married. Preliminary analyses support G x E and G x G interaction for several genes of interest. This study is funded by the Geisinger Clinic Research Fund Endowment.

Integration of HPV16 and 18 and Smoking

 PI: Azadeh Stark, PhD

Cervical cancer arises parly as a consequence of persistent infection of the cervical epithelium by high-risk human papilloma virus (HPV) types.  HPV infection of the uterine cervix, especially high-risk types, results in the development of squamous intraepithelial lesion (SIL) of the cervix that progresses through a series of less differentiated lesions, leading to the development of cervical cancer.  The precipitating event in cancer development is a change in the physical state of virus DNA from an episomal to an integrated from.  Transcripts derived from integrated sequences are more stable than those derived from episomal sequences, thus producing relatively large amounts of virus oncoproteins E6 and E7 compared to episomally derived transcripts.  E6 promotes the degradation of p53 and E7 binds to pRB inhibiting its function for G1 arrest.  Cells with high levels of E6 and E7 are unable to detect DNA damage and fail to recognize cell cycle check points.  Additional cofactors such as smoking and methylenetrahydrofolate reductase (MTHFR), gene polymorphism contribute to the risk of cancer.  Therefore, we have hypothesized that one or more of these cofactors play a role in integration of the HPV genome in SIL, a precipitating event for the development of cervical cancer.  To test this hypothesis, we have implemented a case series study to determine the association between smoking, MTHFR and gene polymormism, HPV-16 variants in a series of women diagnosed with abnormal squamous cells of undetermined signficance.  The association of these cofactors in women who have episomal HPV-16 DNA in their lesions will be compared with those with integrated HPV-16 DNA sequences in their lesions.   This study is in collaboration with Dr. Wayne Lancater at the Department of Molecular and Genomic Medicine, Wayne State University.

Biomarkers of Tumor Aggressiveness for Guiding Prostate Cancer Therapy

Site PI: Porat Erlich, PhD, MSc

Prostate cancer screening currently relies on a two-tier sequential screening method, which consists of a PSA test followed by biopsy. While this strategy is sensitive for detection, its prognostic value is limited and there is a need for additional biomarkers that can discriminate slow from fast progressing prostate neoplasms.  In this study, we use surgical prostate tumor specimens from the Geisinger Surgical Pathology tissue archive to identify biomarkers of tumor aggressiveness. The results will help patients and providers make informed treatment choices based on the predicted rate of progression of identified tumor. 

Genetic Determinants of Persistent Nicotine Dependence

PI: Porat Erlich, PhD, MSc

In spite of intensive public health efforts, smoking remains the largest cause of preventable death in the US.  Approximately four in five individuals who try to stop smoking fail to meet sustained abstinence goals due to persistent nicotine dependence. Smoking, failure of attempts to quit smoking, and the development of lung cancer are significantly more common among individuals who have certain DNA variations in the CHRNA genes on chromosome 15q25.1. In this study, we examine the impact of these DNA variations on quit rates among Geisinger patients who were instructed by their primary care providers to stop smoking and were prescribed pharmacotherapic cessation aids. The results will help to identify cessation aids that work better for patients who have an inherited susceptibility to persistent nicotine dependence.