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 typing2018/3/27 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