Chapter 18 The Genetics of Cancer

Cancer- loss of cell cycle control Begins as single abnormal cell divides & produce more like itself Grow into a mass called a malignant tumor Is genetically controlled (because the biochemical which controls mitosis are under genetic control) Control of telomere length is another function which when lost, causes cancer

Telomeres Chromosome tips that consist of DNA sequence TTAGGG, repeated thousands of times. Repeats are normally lost as a cell matures (rate of about 15-40 nucleotides per cell division). The more specialized the cell, the shorter the telomeres (skin, nerve, & muscle-short telomeres; gametes-long telomeres) Control of telomere length is another function which when lost, causes cancer.

3 Factors Explain the Role Genes Play in Cancer Cancer may develop only after several genes mutate. A gene may confer a cancer susceptibility that is only realized in the presence of an environmental trigger. Cancer-causing mutations may be present in every cell or only in affected somatic cells.

Origin of Cancer Mutations can occur: In somatic cells - sporadic cancer only affecting the individual In germline cells - mutations that are inherited (usually require second somatic mutation)

General Characteristics of Cancer Cells Smallest detectable fast growing tumor is half a centimeter in diameter and contains a billion cells. These cells divide at a rate that produces a million or so new cells in an hour. If 99% of the tumor’s cells are destroyed, a million would still be left to multiply. Other cancers are very slow to develop and may not be noticed for years.

6 Characteristics of Cancer Cancer is heritable because it is passed from parent cell to daughter cells. Cancer is transplantable. If cancer cells are injected into healthy animal, the disease spreads as more cancer cells divide from the original. Cancer is dedifferentiated. Less specialized than the cell it descends from. Cancer cells lack control inhibition. Cancer cells lack the ability to stop dividing once it touches other cells. Cancer displays invasiveness. An invasive malignant tumor grows irregularly, sending tentacles in all directions. In fact the word “cancer” means crab in Latin because malignant tumors resemble a crab. Cancer can metastasize- means that it can spread and move to a new location in the body. After cancer spreads, it becomes more difficult to treat, because the DNA of secondary tumor cells often mutate many times causing chromosome abnormalities.

Loss of Cell Cycle Control Timing, rate, and number of cell divisions depend on Protein growth factors Signaling molecules from outside the cell Transcription factors within Checkpoints control the cell cycle Loss of control of telomere length may contribute

Figure 18.3

Cancer-Causing Genes Oncogenes More than 100 Cause cancer when inappropriately activated Tumor suppressor genes Deletion or inactivation causes cancer

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

Figure 18.4

Germline vs Sporadic Cancer Figure 18.5

Characteristics of Cancer Cells Divide continually (given space and nutrients) Contain heritable mutations Transplantable Dedifferentiated: lose their specialized identity Different appearance: reflects dedifferentiation Lack contact inhibition Induce angiogenesis (local blood vessel formation) Increased mutation rate Invasive: squeeze into any space available Metastasize: move to new location in the body

Figure 18.7

Cell Division Rates for Normal and Cancer Cells Table 18.1 Some cancer cell types grow more slowly than some normal cell types

Cancer Can Progress Slowly over Years Figure 18.6

Cancer Stem Cells Figure 18.8

Cancer by Loss of Specialization Specialized cells lose some of their distinguishing features Result is dedifferentiation A chemical “reversine” may stimulate differentiated cells to divide and produce progenitor cells in mice

Figure 18.9

Cancers from Shifting Balance of Cell Types in a Tissue Figure 18.10

Uncontrolled Tissue Repair May Cause Cancer Figure 18.11

Table 18.3

Oncogenes Proto-oncogenes are normal versions of genes that 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

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

Translocation Can Cause Cancer Figure 18.12

Fusion Proteins Oncogenes are activated when a proto-oncogene moves next to another gene The gene pair is transcribed together The double gene product is a fusion protein Example: chronic myeloid leukemia (CML)

Chronic Myeloid Leukemia (CML) Most patients have a translocated Philadelphia chromosome (tip of 9 on 22) Abl gene (from Chromosome 9) and bcr (from chromosome 22) gene produce fusion protein BCR-ABL oncoprotein is a form of tyrosine kinase that excessively stimulates cell division Understanding cellular changes allowed development of new drug, Gleevec, for treatment

Figure 18.13

Acute Promyelocystic Leukemia Translocation of chromosome 15 and 17 Combination of retinoic acid cell surface receptor and an oncogene, myl Fusion protein functions as a transcription factor; when overexpressed causes cancer Some patients respond to retinoid drugs

Her-2/neu Product of an oncogene Excessive levels in approximately 25% of breast cancer patients Too many receptors Too many signals to divide Monoclonal antibody drug, Herceptin, binds to receptors, blocking signal to divide

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 Examples include Wilms’ tumor, retinoblastoma gene, p53 gene, and BRCA1

Retinoblastoma A rare childhood eye cancer Alfred Knudson, 1971, examined cases of retinoblastoma 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 Frequently, boys and girls were affected equally Children with bilateral (both eyes) tumors were diagnosed earlier

Knudson’s Two Hit Hypothesis 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 Creates a dominant “susceptibility” to cancer in the family

p53 p53 acts as a cell cycle protein 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 Family members have many different types of cancer at early ages.

Figure 18.14

BRCA1 Gene A breast cancer susceptibility gene Tumor suppressor gene Increases risk of developing breast and ovarian cancer Within families a mutation in BRCA1 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

Complexities in Genetic Counseling for Familial Breast Cancer Table 18.5

Other Genes BRCA2 encodes for a nuclear protein Functions in cytokinesis Increases risk of breast, ovarian, colon, prostate, pancreas, gallbladder, and stomach cancers–also melanomas Acts with other genes Table 18.7 in textbook lists other cancer genes

Lifetime Risk Table 18.6

Types of Genes Gatekeeper Genes directly control mitosis and apoptosis Caretaker Genes control mutation rates and may have an overall effect, when mutant destabilizing the genome

An Example of a Series of Changes in a Rapidly Dividing Astrocytoma Rapidly growing Loss of both p53 alleles Mutations of both alleles of several genes on chromosome 9 (an interferon-producing and tumor suppression genes) An oncogene is activated on chromosome 7 Final stage–loss of chromosome 10, in end-stage tumor cells

Figure 18.15

Familial Adenomatuous Polyposis FAP 5% of colon cancer cases are inherited 1 in 5000 in U.S. has FAP Causes multiple polyps at an early age Several mutations contribute APC genes mutate Activation of oncogenes Mutations in TGF, p53, and other genes PRL-3 triggers metastasis Caretaker genes cause instability

Figure 18.16

Environment Impacts on Cancer Exposure to carcinogens increases risk Smoking increases 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 “Chemopreventative” nutrients may help decrease risk

Cruciferous Vegetables Can Lower Cancer Risk Figure 18.17

Table 18.8

Revealing Correlations between Environmental Exposure and Cancers Population Study Compares incidence of a type of cancer among different groups of people Case Control Identify differences between patients with a type of cancer and healthy individuals matched for multiple characteristics Prospective Studies Two or more groups of individuals follow a specific regimen ( e.g., diet or activity plan) and are checked regularly for cancer

Human Genome Data and Cancer Predict risk May tailor diagnosis and treatment Specialized drugs Identifying specific characteristics of cancer cells

Table 18.9