可遗传体细胞突变.PPT

Genetics of  Gastrointestinal Neoplasia 张咸宁 zhangxianning@ Tel Office: A705, Research Building 2014/05 Learning Objectives 掌握结直肠癌为模型的恶性肿瘤的多步骤发生模式。 了解APC等相关癌基因。 Required Reading Thompson Thompson Genetics in Medicine, 7th Ed （双语版，2009） ● pp.396-401； ● Clinical Case Studies-19 Hereditary Nonpolyposis Colon Cancer Cancer is a group of genetic diseases affecting fundamental aspects of cellular function, including DNA repair, cell-cycle regulation, apoptosis, and signal transduction. LOH (loss of heterozygosity) Loss of a normal allele from a region of one cs of a pair,allowing a defective allele on the homologous cs to be clinically manifest. A feature of many cases of retinoblastoma, breast cancer, and other tumors due to mutation in a TSG. LOH (loss of heterozygosity) Tumour suppressor gene (TSG) Caretaker genes: TSGs that are indirectly involved in controlling cellular proliferation by repairing DNA damage and maintaining genomic integrity, thereby protecting proto-oncogenes and gatekeeper TSGs from mutations that could lead to cancer. E.g., ATM, BRCA1/2, MLH1, MSH2, XPA. Gatekeeper genes: Tumor-suppressor genes that directly regulate cell proliferation. E.g., APC, CDKN2A, RB, TP53, VHL. “Two-hit” hypothesis: Knudson,1971. This explains why hereditary retinoblastoma usually has an earlier age of onset and exhibits bilateral or multifocal occurrence more often than sporadic retinoblastoma. Colorectal Cancer (CRC) Factors associated with increased risk Age (90% diagnoses in individuals 50 years old) Personal or first-degree family history of CRC, or adenomas, polyps or inflammatory bowel disease Hereditary conditions Familial adenomatous polyposis (FAP) Lynch syndrome (Hereditary nonpolyposis colorectal cancer, HNPCC) Ulcerative colitis Obesity, physical inactivity High-fat or low-fiber diet, inadequate intake of fruits and vegetables Genetic predisposition to CRC Familial adenomatous polyposis (FAP) Or adenomatous polypo