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