浙江大学医学院：Genetics of Gastrointestinal Neoplasia（PPT讲稿）

Genetics of Gastrointestinal Neoplasia 张咸宁 zhangxianning@zju.edu.cn Tel:13105819271;88208367 Office: A709, Research Building 2012/04

Genetics of Gastrointestinal Neoplasia 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: A709, Research Building 2012/04

Learning Objectives 1.掌握结直肠癌为模型的恶性肿 瘤的多步骤发生模式。 2.了解APC等相关癌基因

Learning Objectives 1. 掌握结直肠癌为模型的恶性肿 瘤的多步骤发生模式。 2. 了解APC等相关癌基因

Required Reading Thompson &Thompson Genetics in Medicine,7hEd(双语版,2009) ●pp.396-401; O Clinical Case Studies-19 Hereditary Nonpolyposis Colon Cancer

Required Reading Thompson &Thompson Genetics in Medicine, 7th Ed （双语版，2009） ● pp.396-401； ● Clinical Case Studies-19 Hereditary Nonpolyposis Colon Cancer

MUTATION Mutations in Mutations disrupting Mutations affecting coding region RNA stabilit gene regulation RNA splicing Protein abnormal Protein structure normal Decreased Hb Hammersmith (if unstable->decreased amount) amount CAUSE OF DISEASE aE-thalassemias B-thalassemias Monosomies Increased Tumor-suppressor mutations Loss of protein function amount Hb Kempsey Achondroplasia the great majority) Trisomies Charcot-Marie- Toot Gain of function disease type 1A Novel property Many oncogenes (infrequent Inappropriate expression (wrong time, place) Ectopic or heterochronic expression (uncommon, except in cancer

Feature Tumor Suppressor Oncogenes G enes Function of normal Regulates cell growth Promotes cell growth version and proliferation; and proliferation some can induce apoptosis Mutation(at cell level) Recessive(both Dominant (only one copies of gene copy of gene mutated) inactivated) Effect of mutation Loss of function Gain of function Germline mutations Seen in most tumor Seen in only a few resulting in inherited suppressor genes oncogenes cancer syndromes

Feature Tumor Suppressor Genes Oncogenes Function of normal version Regulates cell growth and proliferation; some can induce apoptosis Promotes cell growth and proliferation Mutation (at cell level) Recessive (both copies of gene inactivated) Dominant (only one copy of gene mutated) Effect of mutation Loss of function Gain of function Germline mutations resulting in inherited cancer syndromes Seen in most tumor suppressor genes Seen in only a few oncogenes

Tumour suppressor gene(tsg) Caretaker genes: TSGs that are indirectly involved in controlling cellular proliferation by y 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, MLHI, MSH2, XPA Gatekeeper genes: Tumor-suppressor genes that directly regulate cell proliferation. E.g., APC, CDKN2A RB TP53 VHL

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

“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

Inheritance merited Sporadic First hit occurs of first hit in embryo Egg erm E RB1 mutation-tp Norma First mutation already present in germline First mutation is somatic Second mutation Second mutation is somatic s somatic Tumor development Tum development rey et al: Medical Genetics, 4th Edition

Colorectal Cancer is a Maior Cause of cancer deaths in the united states Men Women 289,550270,100 Lung and bronchus 31% 26% Lung and bronchus Colon and rectum 9% 15% Breast Prostate 9% 10% Colon and rectum Pancreas 6% 6% Pancreas Leukemia 4% 6% Ovary Esophagus 4% 4% Leukemia Liver/intrahepatic bile duct 4% 3% Non-Hodgkin's lymphoma Non-Hodgkin's lymphoma 3% 3% Uterine corpus Urinary bladder 3% 2% Liver/intrahepatic bile duct Kidney and renal pelvis 3% 2% Brain/nervous system 25% All other sites All other sites 24% Jemal et al. CA Cancer j clin. 2007: 57: 43

Men 289,550 Women 270,100 26% Lung and bronchus 15% Breast 10% Colon and rectum 6% Pancreas 6% Ovary 4% Leukemia 3% Non-Hodgkin’s lymphoma 3% Uterine corpus 2% Liver/intrahepatic bile duct 2% Brain/nervous system 25% All other sites Lung and bronchus 31% Colon and rectum 9% Prostate 9% Pancreas 6% Leukemia 4% Esophagus 4% Liver/intrahepatic bile duct 4% Non-Hodgkin’s lymphoma 3% Urinary bladder 3% Kidney and renal pelvis 3% All other sites 24% Colorectal Cancer is a Major Cause of Cancer Deaths in the United States Jemal et al. CA Cancer J Clin. 2007;57:43

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) ynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) -Ulcerative colitis -Obesity, physical inactivity High-fat or low-fiber diet, inadequate intake of fruits and vegetables American Cancer Society Cancer Facts Figures 2005 National Cancer Institute. PDQ Physician Statement

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 American Cancer Society. Cancer Facts & Figures 2005. National Cancer Institute. PDQ® Physician Statement