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