1. Human Genetics: concepts and applications 6th edition Ricki Lewis Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Chapter 18 The Genetics of Cancer

2. 18-2 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. Many genes that can mutate to cause cancer control the cell cycle or DNA maintenance (repair).

3. 18-3 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Control of the cell cycle

4. 18-4 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.

5. 18-5 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.

6. 18-6 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Germline versus sporadic cancer

7. 18-7 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Telomeres affect the cell cycle When telomerase is absent, telomeres are not added. Lack of telomeres signals cessation of cell division.

8. 18-8 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cell division rates of normal and cancer cells Normal cells Hours between cell division Bone marrow precursors 18 Lining cells of large intestine 39 Lining cells of rectum 48 Fertilized ovum36-60 Cancer cells Hour between cell divisions Stomach72 Acute myeloblastic leukemia 80-84 Chronic myeloid leukemia 120 Lung (bronchus carcinoma) 196-260 Some cancer cell types grow more slowly than some normal cell types.

9. 18-9 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cancer can progress slowly over years

10. 18-10 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Types of cancer genes Types of proteinsMutated functionNormal functionType of gene Enzymes for mismatch or excision repair Fail to repair DNA mutations Repair DNA mutations DNA repair gene mutation Checkpoint molecules Fails to suppress division Suppresses cell division Tumor suppressor gene Growth factorsPromotes division - abnormal time or cell type Promotes division Oncogene

11. 18-11 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

12. 18-12 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.

13. 18-13 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. Moving a proto-oncogene next to a highly transcribed gene can lead to erroneous transcription of the proto-oncogene.

14. 18-14 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Oncogenes: new functions from old Rearrangement of the genome can create a novel gene from portions of the two original genes. promoter coding region Proto-oncogene protein signals cell division promotercoding region Gene expressed in brain promoter coding region Fusion gene: Protein signals cell division in brain inappropriately

15. 18-15 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.

16. 18-16 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Retinoblastoma A rare childhood eye cancer Alfred Knudson, 1971 examined cases of retinoblastoma in Houston 1944-69 and determined: –One eye or two with tumor –Age of diagnosis –Relatives with retinoblastoma –Number of tumors per eye Observed that 50% of children of an affected parent were affected. Boys and girls were equally frequently affected. Children with bilateral (both eyes) tumors were diagnosed earlier.

17. 18-17 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Knudson’s two hit hypothesis Knudson proposed: Two mutations are required, one in each copy of the RB gene. For sporadic cases, retinoblastoma is a result of two somatic mutations. For familial cases, retinoblastoma is inherited as an autosomal recessive mutation followed by a somatic mutation in the normal allele. The chance of a second somatic mutation is high and creates a dominant “susceptibility” to cancer in the family.

18. 18-18 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.

19. 18-19 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. BRCA1, a breast cancer susceptibility gene Within families a mutation in BRCA1 leads to breast cancer susceptibility, inherited as a dominant trait. One mutation in the BRCA1 gene is inherited. Tumors in people acquire a second mutation in the normal allele of BRCA1. Lack of any functional BRCA1 leads to cancer cells. At the level of the cell, BRCA1 acts in a recessive manner.

20. 18-20 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Complexities in genetic counseling for familial breast cancer Many mutations are known but not all are associated with disease. (Some are polymorphisms.) Individuals with inherited predisposition and individuals with sporadic cancer can be found within the same family. BRCA1 and BRCA2 are not fully penetrant. Occasionally individuals with a mutation do not develop cancer.

21. 18-21 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Multiple genes contribute to cancer progression Multiple genetic changes in astrocytes, nerve support cells, cause in cancer growth.

22. 18-22 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Colon cancer results from genetic alterations in multiple genes Inherited mutations in the APC gene dramatically increase risk of colon cancer

23. 18-23 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.

24. 18-24 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cruciferous vegetables can lower cancer risk

25. 18-25 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Methods for evaluating environmental impacts of cancer Population studies compare incidence of a cancer trait among different populations. Case-control studies compare individuals with cancer to healthy individuals matched for characteristics such as age, sex, and ethnic background. Prospective studies follow the outcome of individuals placed in two or more groups who have different treatments, conditions, or procedures.

26. 18-26 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cancer treatments for breast cancer Radiation or chemotherapy to kill dividing cells Destroy cancerous tissue Gene expression profile on DNA microarray to guide drug choice Genomic level Her-2/neu positive cancers targeted with herceptin MAb Use genotype to select drug Estrogen receptor positive women take tamoxifen Use phenotype to select drug SurgeryRemove cancerous tissue ExamplesStrategy