2018/3/27 Outline ◆ Heredity and Gene Precision Prediction ◆ Precision medicine Precision prediction and prevention Qianyi Xiao, Ph.D The ethic of genetic testin Outline Health ecological model ◆ Heredity and Gene on and pre Gene Gene has become the focus of media Gene is a region of DNA and is the molecular unit of heredity Genetic traits (genoty pe )phenotypic traits (phenotype) TM夏 fe
2018/3/27 1 Qianyi Xiao, Ph.D. Precision Prediction Outline Heredity and Gene Precision medicine Precision prediction and prevention The ethic of genetic testing Outline Heredity and Gene Precision medicine Precision prediction and prevention The ethic of genetic testing Health ecological model Gene DNA: hereditary materials Cell Chromsome Gene Gene is a region of DNA and is the molecular unit of heredity Genetic traits (genotype )——phenotypic traits （phenotype） 2010 Gene has become the focus of media
2018/3/27 Disease Gene Network Outline ◆ Precision medicine Precision Medicine Precision Medicine 尺个 ◆ Precision medicine Precision medicine(PM) is a medical model that molecular testing proposos the personalized treatment. In this model cal features molecular testing is often employed to select appropriate and optimal therapies based on the context of a patient's genetic content, or other molecular or cellular featrues. Precision Medicine Precision Medicine ◆ Molecular diagnosis ◆ Molecular diagnosis Disease stratification Hereditary cancer syndromes, rare hereditary disease. Approximately 5-10% of all cancers are inherited. Mainly caused by inherited gene mutations, which have Complicated disease treatment
2018/3/27 2 Disease Gene Network Disease Gene Outline Heredity and Gene Precision medicine Precision prediction and prevention The ethic of genetic testing Precision Medicine molecular testing Pathological features Imaging Analytics… Precision medicine Precision medicine (PM) is a medical model that proposes the personalized treatment. In this model, molecular testing is often employed to select appropriate and optimal therapies based on the context of a patient’s genetic content, or other molecular or cellular featrues. Precision Medicine Precision Medicine Molecular diagnosis Disease stratification Precision Therapy Complicated disease treatment Precision Medicine Molecular diagnosis Hereditary cancer syndromes, rare hereditary disease. Approximately 5–10% of all cancers are inherited. Mainly caused by inherited gene mutations, which have highly penetrance
2018/3/27 Clinical diagnosis for hereditary diseases Lynch Syndrome diagnosis Lynch Syndrome is caused by a germline mutation in any one of five DNA mismatch repar genes (MLH1, MSH2, MSH6, PMS1, and PMS2) Patients met Amsterdam criterial or Bethesda criteria test tumor tissue should further pursue germline DNA mutational analysis. Once a specific mutation is Mechanism of MMR carcinoge I Hereditary cancer syndrome ereditary breasta BRCA1, BRCA2 Breast cancer syndrome(HBOC) Ovarian cancer Regular DNA damage DNA damage repair LH1, MSH2, MSH6. Colorectal cance repair system Cancer PMS2, ECAP (HNPC amilial adenomatous polypr olorectal adenomatous polyposis gastric cancer CDH1 Gastric cancer Precision Medicine Molecular typing of lung cancer Traditional classification Disease stratification sP色 Molecular typing
2018/3/27 3 13 Clinical diagnosis for hereditary diseases Lynch Syndrome , also known as HNPCC (Hereditary Non-Polyposis Colorectal Cancer), is the most common hereditary colorectal cancer with a penetrance of 85–90%. Lynch Syndrome is caused by a germline mutation in any one of five DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS1, and PMS2) Half E, et al. Orphanet J Rare Dis. 2009 Colorectal cancer – Patients met Amsterdam criterial or Bethesda criteria test tumor tissue for MSI/IHC – MSI (microsatellite instability )and IHC testing can define which patients should further pursue germline DNA mutational analysis. – Once a specific mutation is identified, the diagnosis of Lynch syndrome is confirmed. Amsterdam criteria/ Bethesta criteria met? Test cancer for MSI/IHC Genetic testing for germline gene mutation Lynch Syndrome diagnosis About 39% of families with mutations in an HNPCC gene do not meet the Amsterdam criteria. 15 Mutation Defect of DNA damage repair T C T A C A G C T G T C G A C A G C T G A G A T G T C T A C T C T A C A G C T G Regular DNA damage repair system Mechanism of MMR carcinogenesis ——DNA damage repair Hereditary cancer syndrome Disease Gene Related cancer Hereditary breast-ovarian cancer syndrome (HBOC) BRCA1，BRCA2 Breast cancer Ovarian cancer Lynch Syndrome，/ Hereditary Non-Polyposis Colorectal Cancer （HNPCC） MLH1,MSH2,MSH6, PMS2，ECAP Colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, Familial adenomatous polyposis （FAP） APC Colorectal cancer, Colorectal adenomatous polyposis Hereditary diffuse gastric cancer (HDGC) CDH1 Gastric cancer Precision Medicine Molecular diagnosis Disease stratification Molecular typing Molecular typing of lung cancer 1987 unknown KRAS EGFR KRAS unknown Traditional classification 2004 Nature. 2014 Jul 31;511(7511):543-50 2014 Adenocarcinoma Squamous Small-cell Large-cell
2018/3/27 Precision Medicine Precision Therapy EGFR mutation in tumor is a strong predictor of a better outcome with gefitinib. ◆ Precision Therapy he design of drugs that target specific pathogenic mutations ve the success of precision medicine Precision Medicine Complicated disease treatment che aeu d]ork cimes 加kgm healthy ceNs for comparison. And they found that Complicated disease treatment (FLT3) was wildly active in the How precision prediction might work Outline ◆ Heredity and Ge t Precision prediction and prevention Prevention and screening Precision prediction
2018/3/27 4 Precision Medicine Molecular diagnosis Disease stratification Precision Therapy The design of drugs that target specific pathogenic mutations may improve the success of precision medicine Mok, NEJM 2009 Precision Therapy Lung adenocarcinoma EGFR mutation in tumor is a strong predictor of a better outcome with gefitinib. Precision Medicine Molecular diagnosis Disease stratification Precision Therapy Complicated disease treatment In Washington University， Dr. Lukas Wartman had acute lymphoblastic leukemia (ALL). He was deteriorating fast. No known treatment could save him. Dr. Timothy Ley performed the DNA sequencing the RNA sequencing of both his cancer cells and healthy cells for comparison. And they found that a normal gene (FLT3) was wildly active in the leukemia cells. Even better, there was a new drug, that approved for treating advanced kidney cancer, could shut down the malfunctioning gene. Gene may be the primary factor in the treatment of cancer, not just on the basis of cancer tissue or organ itself. Complicated disease treatment How precision prediction might work？ Precision Medicine Precision Prediction Disease Outline Heredity and Gene Precision medicine Precision prediction and prevention The ethic of genetic testing
2018/3/27 Three Stage of Prevention ◆ In predisease stage◆ Primary prevention How precision prediction might work factors in a favorable direction Genetic marker can be used in precision prediction ◆ In latent disease◆ Scondary prevention Methods to detect and address (1) Primary prevention(modifing the risk factors an existing disease prior to the (2)Secondary prevention (screening program) ◆ In symptomatic ◆ Tertiary prevention disease stage Methods to reduce the harm of Precision Prediction Interaction between Genetic and Environmenta/ risk Factors Complicated disease are caused by the interaction (1)Primary prevention between genetic predisposition and modifiable helping to predict a person s susceptibility to environmental factors adverse lifestyle exposures Chemical Factor r(intemal cause Life Style Interaction between Genetic and Environmental risk Factors Chemical factor at were determined by genetic factors at were influenced by both the genetic factors and D向 factors. They all play important roles in disease 3. Disease that depends entirely on environmental factors
2018/3/27 5 Three Stage of Prevention In predisease stage Primary prevention Method to modify the risk factors in a favorable direction. In latent disease stage In symptomatic disease stage Scondary prevention Methods to detect and address an existing disease prior to the appearance of symptom. Tertiary prevention Methods to reduce the harm of symptomatic disease through rehabilitation and treatment. Genetic marker can be used in precision prediction (1) Primary prevention (modifing the risk factors) (2) Secondary prevention (screening program) (3) Tertiary prevention (disability limitation ) How precision prediction might work？ Precision Prediction (1) Primary prevention helping to predict a person’s susceptibility to adverse lifestyle exposures. Interaction between Genetic and Environmental Risk Factors Complicated disease are caused by the interaction between genetic predisposition and modifiable environmental factors Environmental factors (internal cause） Genetic factors (external cause) Chemical Factor Physical factor Life Style Biotic Factor Risk factor Chemical Factor Smoke Automobile exhaust Indoor formaldehyde Genetic Factor metabolism Immune DNA damage repairement Hormone Biotic Factor Virus infection Parasite and Bacteria infection 3 Risk Factor for Tumor Phisical factor Ionizing radiation Ultraviolet rays Life Style Drinking、smoking Lack of physical activity Stress Interaction between Genetic and Environmental Risk Factors 3. Disease that depends entirely on environmental factors Nuclear radiation 2. Disease that were influenced by both the genetic factors and environmental factors. They all play important roles in disease pathogenesis. Complicated disease, such as sporadic cancer 1. Disease that were determined by genetic factors Hereditary syndrome
2018/3/27 Genetic marker Single nucleotide polymorphism (SNP) Complicated disease have genetic predisposition SNP is a variation in a single nucleotide that occurs at a specific position in the DNA. SNPs have no observable impact on the phenoty pe. High penetrance genes It just influence the predisposition Single nucleotide polymorphism (SNP) b Identifiability Smoking and Lung cancer re than 4000 compounds. most of which are carcinogenic substance he probability of lung nitrosamine. et al. Aerosol: carbon monoxide, benzene, acrolein, et al cancer in smokers was Mechanism of tobacco carcinogenesis 10-20% ccumulation of harmful gene The lung cancer mortality 8.4 times 18 times Drinking and Esophageal Cancer Hereditary susceptibility to lung cancer Polymorphism(SNP)in metabolic enzyme gene 2, Risk genotype. ADHB1(G/A)and ALDH2(G/A) CYPA1 activates some chemical substances in tobacco. such 3, Interaction between alcohol use and genetic variation genotype polycyclic aromatic hydrocarbons, to form active Non-risk genetic marker(G)+ non-drinking CST, coding the detoxifying enzyme, helps excrete toxic sk genetic marker(A) non-drinking metabolite by catalyzing it to form combination with glutathione Risk genetic marker (A) drinking 2-2-45times at is hop stant for individuals carrying high-risk alleles to reduce
2018/3/27 6 31 Genetic marker Varghese & Easton, 2010 Complicated disease have genetic predisposition Genetic markers High penetrance genes Single nucleotide polymorphism (SNP) Genetic markers have two basic characteristics Heredity Identifiability. Single nucleotide polymorphism (SNP) SNP is a variation in a single nucleotide that occurs at a specific position in the DNA. SNPs have no observable impact on the phenotype. It just influence the predisposition. Tobacco smoke contains more than 4000 compounds, most of which are carcinogenic substance. Particles：nicotine, PAHs (Polycyclic Aromatic Hydrocarbons), nitrosamine, et al. Aerosol：carbon monoxide, benzene, acrolein, et al. Mechanism of tobacco carcinogenesis Induce DNA damage——accumulation of harmful gene mutation——induce cancer Research by Hammond team： Smoking per day： 10-20 cigarettes 20-40 cigarettes The lung cancer mortality (smoker Vs non-smoker) 8.4 times 18 times Smoking and Lung cancer 34 The probability of lung cancer in smokers was 10-20% ? Polymorphism (SNP) in metabolic enzyme gene CYPA1 activates some chemical substances in tobacco, such as polycyclic aromatic hydrocarbons, to form active carcinogens. CST, coding the detoxifying enzyme, helps excrete toxic metabolite by catalyzing it to form combination with glutathione. Hereditary susceptibility to lung cancer 3、Interaction between alcohol use and genetic variation genotype lifestyle ESCC risk Non-risk genetic marker (G) + non-drinking reference Non-risk genetic marker (G) + drinking 1.15 times Risk genetic marker (A) + non-drinking 1~1.4 times Risk genetic marker (A) + drinking 2.2~4.5 times 1、Risk lifestyle: drinking Drinking and Esophageal Cancer (ESCC) It is important for individuals carrying high-risk alleles to reduce alcohol use. 2、R Nat Genet. 2012 Oct;44(10):1090-7. isk genotype: ADHB1(G/A) and ALDH2(G/A)
2018/3/27 Alcohol-metabolizing pathwa Precision Prediction M乙an (2)Secondary prevention Alcohol Acetic ac Facilitating the stratification of susceptibility that help to guide timing and intensity of screening programs and avoid overscreening Hereditary breast-ovarian cancer syndrome(HBOC) ng program o Mother died from breast cacer at German HNPCC Consortium recommends Screening Program for e She carries the same Brcal Annual screenng (age 25 onwards or begnning no later than 5 years mutation before the lowest age of onset in family o% risk for breast cancer and a ◆ Physical examination ANGELINA so% it to varan ance Abdominal ultrasound At age 37, opted for mastectomy Ful colonoscopy o Raise public awareness for genomic Gastroscopy (age 35 onwards) testing and prevention Gynecological examination including transvaginal ultrasound Endometrial pipelle biopsy (age 35 om Hereditary cancer syndrome oradic cancer related risk sNP iY BrCA1 muratore coloreetal Esophageal 组前! Thyroid eaneer7
2018/3/27 7 Alcohol Acetaldehyde (Toxic) ADH ALDH H2O+CO2 Fat Acetic aci Alcohol-metabolizing pathway Precision Prediction (1) Primary prevention (2) Secondary prevention Facilitating the stratification of susceptibility that help to guide timing and intensity of screening programs and avoid overscreening. Mother died from breast cacer at age 56, with a BRCA1 mutation She carries the same BRCA1 mutation 80% risk for breast cancer and a 50% risk for ovarian cancer At age 37, opted for mastectomy Raise public awareness for genomic testing and prevention Hereditary breast-ovarian cancer syndrome (HBOC) German HNPCC Consortium recommends Screening Program for Lynch Patients: Annual screening (age 25 onwards or beginning no later than 5 years before the lowest age of onset in family): Physical examination Abdominal ultrasound Full colonoscopy Gastroscopy (age 35 onwards) Gynecological examination including transvaginal ultrasound Endometrial pipelle biopsy (age 35 onwards) Screening program for Lynch Syndrome(HNPCC) Hereditary cancer syndrome Disease Gene Related cancer Risk Hereditary breast-ovarian cancer syndrome (HBOC) BRCA1， BRCA2 Breast cancer BRCA1 mutation: 44-78%； BRCA2 mutation: 33-54% Ovarian cancer BRCA1 mutation: 18-54%； BRCA12 mutation: 4%-18% Lynch Syndrome，/ Hereditary Non-Polyposis Colorectal Cancer （HNPCC） MLH1,MSH2, MSH6,PMS2， ECAP Colorectal cancer, endometrial cancer, gastric cancer, ovarian cancer, Colorectal cancer: 52-82% endometrial cancer: 25-60% gastric cancer: 6-13% ovarian cancer: 4%-12% Familial adenomatous polyposis （FAP） APC Colorectal cancer, Colorectal adenomatous polyposis 100% Hereditary diffuse gastric cancer,(HDGC) CDH1 Gastric cancer Men：67% Women：83% 42 Sporadic cancer related risk SNP Varghese & Easton, 2010 Cancer type Associated SNP Prostate cancer 103 Breast cancer 125 Colorectal cancer 41 Esophageal cancer 27 Lung cancer 18 Bladder cancer 14 Pancreatic cancer 11 Glioma 9 Thyroid cancer 7
2018/3/27 Genetic risk score Stratification of Susceptibility Each snP has modest effect size Cancer Genetic risk score(RGS) Based on multiple disease risk-associated SNPs, and weighted by their effect. New PSA Guidelines Discourage Stratification of Susceptibility Genetic risk score: based on risk-associated genotype Prostate Cancer Prevention Trial(PCPD Nearly 90% of men with PSA-detected prostate cancer undergo early treatment y Precision Prediction Aiding the prognosis that help to establish anagement strategy
2018/3/27 8 Each SNP has modest effect size Multiple SNPs confer a stronger effect to disease Genetic risk score (RGS) Based on multiple disease risk-associated SNPs, and weighted by their effect. Genetic risk score All Family history 24% 29% 23% 18% 24% 33% 36% 0% 10% 20% 30% 40% All (N=4,528) FH+ (17%) FH- (83%) 1.4 (21%) >2.0 (8%) Detec on rate 24% 29% 23% 18% 24% 33% 36% 0% 10% 20% 30% 40% All (N=4,528) FH+ (17%) FH- (83%) 1.4 (21%) >2.0 (8%) Detec on rate Prostate Cancer Prevention Trial (PCPT) Stratification of Susceptibility All Family history 24% 29% 23% 18% 24% 33% 36% 0% 10% 20% 30% 40% All (N=4,528) FH+ (17%) FH- (83%) 1.4 (21%) >2.0 (8%) Detec on rate 24% 29% 23% 18% 24% 33% 36% 0% 10% 20% 30% 40% All (N=4,528) FH+ (17%) FH- (83%) 1.4 (21%) >2.0 (8%) Detec on rate Genetic risk score (GRS) Men without FH 24% 29% 23% 18% 24% 33% 36% 0% 10% 20% 30% 40% All (N=4,528) FH+ (17%) FH- (83%) 1.4 (21%) >2.0 (8%) Detec on rate Prostate Cancer Prevention Trial (PCPT) Stratification of Susceptibility Genetic risk score: based on risk-associated genotype Risk for prostate cancer Family history PSA level : Low-risk: PSA20 Only 30% of patients with high PSA have prostate cancer diagnosed after biopsy. Nearly 90% of men with PSA-detected prostate cancer undergo early treatment with surgery, radiation, or androgen-deprivation therapy. Precision Prediction (1) Primary prevention (2) Secondary prevention (3) Tertiary prevention Aiding the prognosis that help to establish appropriate clinical treatment decision and cancer management strategy
2018/3/27 How precision prediction Prognosis of treatment response might work Purine is a anti-tumor drug The answer: When given the standard dose of purine drugs, patients with (1)helping to predict a person's susceptibility to adverse lifestyle exposures. monitor sideeffect TPMT gene test (2)facilitating the stratification of susceptibility that help to guide timing and intensity of screening programs and avoid overscreening (3)aiding the prognosis that help to establish appropriate dinical treatment decision and cancer management strategy standard dose Outline The widespread use of Next generation sequencing(NGS) technology 90205年 3.8HlHioa dollan d on and pre The ethic of genetic testing 围江 ANFORD Broast cancer diagnoois Medical school to offer UC Berkeley Modin en DNA Testing Projec a.9■ Variant under
2018/3/27 9 Prognosis of treatment response Lower dose； monitor side-effect TPMT gene test standard dose Purine is a anti-tumor drug When given the standard dose of purine drugs, patients with TPMT deficiency suffered from severe toxicity. How precision prediction might work？ The answer: (1) helping to predict a person’s susceptibility to adverse lifestyle exposures. (2) facilitating the stratification of susceptibility that help to guide timing and intensity of screening programs and avoid overscreening. (3) aiding the prognosis that help to establish appropriate clinical treatment decision and cancer management strategy. Outline Heredity and Gene Precision medicine Precision prediction and prevention The ethic of genetic testing 1990年-2005年 Human Genome Project 13 years 3.8 billion dollars 2008年 The first individual genome sequencing was finished using the NGS 2 month about 1 million dollars Now Develped NGS 1day 1 thousands dollars The widespread use of Next generation sequencing (NGS) technology 53
2018/3/27 Discussion Returning results: bout actionable results Patients want information about all findings from sequencing Thanks standards for analytical validity, different testing platforms . In 2013, the FDA directed 23andMe to cease selling Personal In February 2015, the FDA reclassified these kits to enable a regulatory path exempt from premarket revie
2018/3/27 10 Discussion Returning results: Genome sequencing producing massive amounts of data of unknown medical and social impact. Return information about actionable results Patients want information about all findings from sequencing Privacy and confidentiality Patients do not want their sequencing results ‘filtered’ New technology need data sharing to achieve common standards for analytical validity, different testing platforms. Personal genetic testing: In 2013, the FDA directed 23andMe to cease selling Personal Genomic Testing (PGS) kits. In February 2015, the FDA reclassified these kits to enable a regulatory path exempt from premarket review. Thanks !