What is New in Genetic Testing Steven D. Shapiro MS, DMD, MD
18th Annual Primary Care Symposium Financial and Commercial Disclosure I have a no financial or commercial interest in my presentation. 2
Genetic Testing Topics History of DNA Testing Diagnostic Carrier Screening Prenatal Preimplantation Predictive and Pre-symptomatic Pharmacogenetic Cancer Management Forensic Consumer Directed Testing 3
History of DNA Testing 1920-1930 s - Blood Typing, HLA, Other Antigens 1953 Double Helix of DNA Watson, Crick, and Franklin 1956 46 Chromosomes in Man 1959 Down syndrome 47 Chromosomes 1977 - Rapid DNA Sequencing Sanger 1990 - Polymerase Chain Reaction Mullis 2000 Single Nucleotide Polymorphorism (SNP) 2010 Next Generation Sequencing Whole Exome Sequencing Whole Genome Sequencing 4
Diagnostic Identify or rule out a specific genetic disease Chromosomal Tests Gene Tests 5
Diagnostic Chromosomal Karyotypes - Looks for number and large rearrangements: i.e. Down Syndrome 6
Diagnostic Chromosomal Microarray 7
Diagnostic Chromosomal Microarray Primary screening test for diagnosis of persons with dysmorphic features, birth defects, intellectual disability/developmental delay, autism spectrum disorder, multiple congenital anomalies, seizures or any suspicion of chromosomal imbalance. Determine breakpoints of chromosomal rearrangements previously detected. CMA cannot detect: 1. balanced chromosomal rearrangements 2. genomic alterations in regions that are not represented 3. variants of single or small stretches of nucleotides 4. CMA cannot detect low-level mosaicism 8
Diagnostic Single Gene tests Confirm or rule out a genetic diagnosis based on signs and symptoms of the patient. 9
Diagnostic Single Gene tests In a study from March 2017 59,531 single gene tests available 8535 Panel tests available 10 new tests per day Hundreds of laboratories offering these tests. Internet Resources: Genetic Testing Registry GeneReview 10
Diagnostic Whole Exome Sequencing Looks for variations in the protein-coding region of a gene 11
Diagnostic Whole Exome Sequencing The phenotype or family history data strongly implicate a genetic etiology, but the phenotype does not correspond with a specific disorder for which a genetic test targeting a specific gene is available on a clinical basis. A patient presents with a defined genetic disorder that demonstrates a high degree of genetic heterogeneity, making WES or WGS analysis of multiple genes simultaneously a more practical approach. A patient presents with a likely genetic disorder, but specific genetic tests available for that phenotype have failed to arrive at a diagnosis. American College of Medical Genetics 12
Carrier Screening 100 + diseases Autosomal Recessive X-linked Recessive 13
Carrier Screening Indications High risk groups i.e. Ashkenazi Jews Positive family history Affected individuals Prenatal testing of couples Cystic Fibrosis Spinal Muscular Atrophy Fragile X if developmental delays in the family 14
Prenatal Testing of fetus for genetic diseases Amniocentesis Chorionic Villi Sampling 15
Prenatal Testing of the fetus for genetic diseases Non-Invasive Prenatal Testing (NIPT) Cell-free DNA 16
Preimplantation Testing embryos using assisted reproductive techniques Chromosomal testing Single gene testing 17
Predictive and Pre-symptomatic Predictive Identify mutations that increase risks for a genetic disease. i.e. Breast/Ovarian Cancer Pre-symptomatic determine whether one will develop a genetic disorder before any signs or symptoms. i.e. Hemochromatosis 18
Predictive and Pre-symptomatic Breast/ Ovarian Cancer Syndrome Risks Factors: Breast cancer under 50 Triple negative breast cancer Ovarian cancer Ashkenazi Jewish Positive Family history of breast or ovarian cancer 19
Predictive and Pre-symptomatic Breast/ Ovarian Cancer Syndrome New Indications: Metastatic Breast disease High Grade Prostate disease(gleason Score 7 or higher) Metastatic Prostate Cancer Pancreatic Cancer 20
Predictive and Pre-symptomatic Principles: Breast/ Ovarian Cancer Syndrome Provide genetic counseling Pedigree Patient education Risk management Test an affected individual first if possible Choose the best test (Single gene vs Panel) Understand the results 21
Predictive and Pre-symptomatic 22
Predictive and Pre-symptomatic 23
Pharmacogenetics Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways. These differences can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects 24
Pharmacogenetics 25
Pharmacogenetics Clopidogrel Hepatic cytochrome P450 oxidase system responsible enzyme, CYP2C19 Intermediate metabolizer: Use alternative antiplatelet therapy if no contraindications. Poor metabolizer: Use alternative antiplatelet therapy if no contraindications 26
Pharmacogenetics perceived lack of clinical utility, inadequate professional guidelines for pharmacogenetics based management, limited insurance reimbursement for testing 27
Cancer Management Circulating Tumor DNA (ctdna) Germ line Mutations Ovarian Cancer Somatic Mutations Breast Cancer Lung Cancer 28
Cancer Management Prognosis Recurrence Risks Treatment choices Research 29
Circulating Tumor DNA Cancer Management With cell death, DNA is released into circulation As small as 200 nucleotides(ctdna) Varies based on: Tumor type Location Cancer stage 30
Cancer Management Circulating Tumor DNA Detecting and diagnosis of a tumor Somatic mutations Reduce the need for biopsy Directing treatment (FDA approval limited) Monitoring Treatment Monitoring Remission 31
Cancer Management Ovarian Cancer Germline mutations are involved in more than one-fifth of ovarian cancer cases 10 15% of ovarian cancer are due BRCA mutation BRCA1gene mutation is 40 to 60 percent BRCA2gene mutation is 20 to 35 percent Eastern European women and women of Ashkenazi Jewish descent are at a higher risk Lynch syndrome: MLH1orMSH2gene and accounts for between 10 and 15 percent of hereditary ovarian cancers. 32
Cancer Management Ovarian Cancer BRCA mutations Some women with ovarian cancer are resistant to standard cancer treatments, such as chemotherapy, making them less effective Even if the cancer does respond to treatment, it can eventually return Treatment eligibility for targeted therapies 33
Cancer Management Ovarian Cancer BRCA mutations PARP - poly(adp-ribose) polymerase proteins is an enzyme used by cells to repair damage to their DNA Work by keeping cancer cells from repairing themselves once they've been damaged by chemotherapy, while sparing healthy cells. 34
Cancer Management Ovarian Cancer BRCA mutations Inhibition of PARP can result in preferential death of cancer cells when another mechanism for repairing DNA is defective. Inhibition of PARP can prevent the repair of single-strand breaks, which may then be converted to more cytotoxic double-strand breaks. In BRCAm ovarian cancer, PARP inhibition can potentiate the occurrence of double-strand breaks in DNA to help drive programmed cell death. 35
Cancer Management Breast Cancer Tumor Profiling Somatic mutations analyzed from the tumor Predicts the activity and interaction of genes and their role in certain diseases Uses Used to predict the response to chemotherapy Prognosis Recurrence Risks 36
Cancer Management Breast Cancer PersonalizedTreatment Genomic-based, comprehensive, individualized risk assessment for early-stage invasive breast cancer in adjuvant and neoadjuvant settings Chemotherapy or not Approved by clinical guidelines from the National Comprehensive Cancer Network (NCCN ) 37
Cancer Management Lung Cancer Many mutations have been found to recur in lung cancer Most of these genes are involved in the regulation of gene activity (expression), cell proliferation, the process by which cells mature to carry out specific functions (differentiation), and apoptosis. 38
Cancer Management Lung Cancer The NCCN NSCLC Guidelines Panel strongly advises broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials. Broad molecular profiling is a key component of the improvement of care of patients with NSCLC.. 39
Forensic 40
Direct to Consumer Testing 41
Direct to Consumer Testing 2017 - $10billion business 42
Direct to Consumer Testing 43
Direct to Consumer Testing 2017 Truven NPR survey Genetic testing done Reasons: Ancestry/genealogy: 24.9% Diagnostic: 23.7% Predictive: 15.9% Treatment: 9% Carrier testing: 7% 44
Direct to Consumer Testing 2017 Truven NPR survey Genetic testing physician directed Reasons: Ancestry/genealogy: 5.2% Diagnostic: 30.7% Predictive: 17.5% Treatment: 12% Carrier testing: 11.4% 45
Direct to Consumer Testing 2017 Truven NPR survey Genetic testing consumer directed Reasons: Ancestry/genealogy: 30.3% Diagnostic: 23.2% Predictive: 14.2% Paternity: 9.2% Treatment: 8.7% Lifestyle: 5.2% Carrier testing: 4.8% 46
Direct to Consumer Testing Type of testing: Ancestry Health Carrier status Wellness Traits Pharmacogenetic Paternity Others 47
Ancestry Direct to Consumer Testing Limited to the data base of the service Family issues Paternity Issues Privacy Issues 48
Direct to Consumer Testing Health Testing Issues Inherited Breast Cancer Testing usually only BRCA gene May not include full sequencing but limit to only a few mutation i.e. one company does only the three most common BRCA mutation associated with Ashkenazi Jews 49
Wellness Direct to Consumer Testing Alcohol Flush Reaction Caffeine Consumption Deep Sleep Genetic Weight Lactose Intolerence Muscle Composition Saturated Fat and Weight 50
Traits Bitter Taste Cheek Dimples Cleft chin Earlobe Types Fear of Heights Freckles Direct to Consumer Testing Mosquito Bite Frequency Photic Sneeze Reflex Unibrow 51
Genetic testing 52
Questions