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Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Human Genetics: concepts and applications 6th edition Ricki Lewis Chapter 18 The Genetics of Cancer Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cancer Cancer is a group of diseases caused by loss of cell cycle control. Cancer is associated with abnormal uncontrolled cell growth. Carcinogens are substances which cause cancer by mutating DNA. 18-2 Many genes that can mutate to cause cancer control the cell cycle or DNA maintenance (repair). Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Origin of cancer Cancer begins from the growth of a single abnormal cell. • A mutation occurs allowing a cell to undergo cell division when it would not normally divide. • Division produces more abnormal cells. Mutations can occur: • In somatic cells => sporadic cancer only affecting the individual • In germline cells => mutations that are inherited • Germline mutations usually require second somatic mutation also. 18-4 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Telomeres affect the cell cycle Telomerase is the protein and enzyme complex that adds telomere sequences to the ends of chromosomes. Presence of telomerase and telomeres allows cells to pass a cell cycle checkpoint and divide. 18-5 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Germline versus sporadic cancer 18-6 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cancer can progress slowly over years 18-9 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Types of cancer genes Type of gene Normal function Mutated function Types of proteins Oncogene Promotes division Promotes Growth factors division abnormal time or cell type Tumor suppressor gene Suppresses cell division Fails to suppress Checkpoint division molecules DNA repair gene mutation Repair DNA mutations Fail to repair DNA mutations 18-10 Enzymes for mismatch or excision repair Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Characteristics of cancer cells • Divide continually (given space and nutrients) • Heritable mutations: cells with mutations have daughter cells which inherit the same mutations. • Transplantable • Dedifferentiated: cells lose their specialized identity • Different appearance: reflects dedifferentiation • Lack contact inhibition: will divide in a crowd of cells and pile on top of each other • Induce angiogenesis (local blood vessel formation) • Increased mutation rate • Invasive: squeeze into any space available • Metastasize: cells move to new location in the body 18-11 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Oncogenes • Proto-oncogenes are normal versions of genes which promote cell division. • Expression at the wrong time or in the wrong cell type leads to cell division and cancer. • Proto-oncogenes are called oncogenes in their mutated form. • One copy of an oncogenic mutation is sufficient to promote cell division. 18-12 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Oncogenes: overexpression of a normal function • Viruses integrated next to a proto-oncogene can cause transcription when the virus is transcribed. • Moving a proto-oncogene to a new location can separate the coding region from regulatory regions of the gene leading to incorrect expression. • 18-13 Moving a proto-oncogene next to a highly transcribed gene can lead to erroneous transcription of the proto-oncogene. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Tumor suppressor genes • Cancer can be caused by loss of genes that inhibit cell division. • Tumor suppressor genes normally stop a cell from dividing. • Mutations of both copies of a tumor suppressor gene is usually required to allow cell division. 18-15 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. p53 coordinates cell cycle regulation • p53 acts as a cell cycle protein which determines if a cell has repaired DNA damage. If damage cannot be repaired, p53 can induce apoptosis. • More that 50% of human cancers involve an abnormal p53 gene. • Rare inherited mutations in the p53 gene cause a disease called Li-Fraumeni syndrome in which family members have many different types of cancer at early ages. 18-18 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Colon cancer results from genetic alterations in multiple genes 18-22 Inherited mutations in the APC gene dramatically increase risk of colon cancer Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Environment impacts cancer Exposure to carcinogens • Carcinogens in tobacco smoke are correlated with lung cancer incidence. Exposure to radiation • Burns from overexposure to sunlight can cause skin cancer. Variation in diet • Fatty diets are correlated with increased estrogen and increased breast cancer. 18-23 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cruciferous vegetables can lower cancer risk 18-24