Genetics of Cancer - Lecture IV

transcript

Dr. Steven J. Pittler

VH375BOffice 4-6744Cell 612-9720

Suggested Reading: Lewis 2nd Edition

Chapter on Genetics of Cancer

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 (mutagens).

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

Cancer

• Is a complication of being a multicellular organism• All specialized cells must follow the cell cycle• If a cell escapes it forms a growth called a tumor

• In the blood such a cell will take over the population of blood cells

• A benign tumor grows in place• It is malignant or cancerous when it infiltrates the

nearby tissues• A malignant tumor invades locally and it also sends

parts of itself into the bloodstream and gets transported to other areas. This process of spread is called metastasis

Cancer

• 10% of cancer cases are single-gene disorders• More often mutations in cancer-causing genes

occur in somatic cells over a lifetime• Cancer is a genetic disease at the cellular level and

not the whole-body level• It is likely that combinations of particular gene

variants sum to increase the risk of cancer- run in families

• Takes years to develop as a sequence of genes mutate in the affected tissue

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.

Origin of cancer• There are more than 100 oncogenes

– Cause cancer when they are inappropriately activated• More than 30 tumor suppressor genes whose deletion or inactivation

causes cancer• Cancer is a consequence of disruption of the cell cycle

– The cell divides more frequently or more times– Timing, rate, and number of mitoses depends on protein growth

factors from outside the cell, and on transcription factors from within– The immune system destroys most cancer-cells

• A mutation in a gene that normally halts or slows the cell cycle can lift the constraint, leading to inappropriate mitosis

• Failure to pause long enough to repair DNA is another cell-cycle-related cause of cancer

• Loss of control over telomere length may also contribute to cancer– Human telomeres consists of the DNA sequence TTAGGG repeated

thousands of times– Normally lost as the cell matures– Specialized cells have shorter telomeres

Control of the cell cycle

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.

Telomeres affect the cell cycle

When telomerase is absent, telomeres are not added.

Lack of telomeres signals cessation of cell division.

Inherited Versus Sporadic cancer• Most cancers are isolated or sporadic-the causative

mutation occurs only in cells of the affected tissue: Somatic mutation– May result from a single dominant mutation, or from two

recessive mutations in the same gene– Inherited or germline cancer susceptibility is directly passed

to future generations because it is present in every cell, including gametes

• Inherited or germline cancer susceptibility is directly passed to future generations because it is present in every cell, including the gametes– Cancer develops when a second mutation occurs in the

somatic cell– The cancer site in the body is the site of the second mutation

Germline versus sporadic cancer

Characteristics of Cancer Cells

• A cell divides or if it stops dividing or whether it expresses the sets of genes that make it special depends upon biochemical signals from surrounding cells

• A cancer cell stops listening to these signals• Mutations that affect any stage of signal

transduction or gene expression can send a cell toward unrestrained division

Cell division rates of normal and cancer cells

Normal cellsHours between

cell division

Bone marrow precursors

Lining cells of large intestine

Lining cells of rectum

Fertilized ovum 36-60

Cancer cellsHour between cell divisions

Stomach 72

Acute myeloblastic leukemia

Chronic myeloid leukemia

Lung (bronchus carcinoma)

196-260

Some cancer cell types grow more slowly than some normal cell types.

Characteristics of Cancer Cells

• A cancerous tumor eventually grows faster than the surrounding tissue because of its greater proportion of cells that are dividing

• A cancer cell looks different than a normal cell– Rounder: does not adhere to normal cells– Plasma membrane is more fluid, different substances

can cross it

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

Characteristics of cancer cells• Divide continually (given space and nutrients)• Heritable mutations: cells with mutations have daughter cells which

inherit the same mutations.• Transplantable: if a cancer cell is injected into a healthy animal of

the same species, the cell will proliferate • 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

Cancer can progress slowly over years

Cells starved for oxygen within a tumor secrete vascular endothelial growth factor which stimulates capillaries to extend branches toward the tumor

Genes that Cause Cancer

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, onco means cancer

• One copy of an oncogenic mutation is sufficient to promote cell division.

Oncogenes

• A single base change in a proto-oncogene causes bladder cancer

• A proto-oncogene may be moved near a gene that is highly expressed, then, it to becomes highly expressed

• Some proto-oncogenes encode transcription factors– That as oncogenes are too highly expressed

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.

Fusion Proteins with New Functions• Oncogenes are activated when a proto-oncogene moves

next to another gene, and the gene pair is transcribed and translated together, as if one gene– Double gene product: fusion protein activates or lifts controls

of cell division• The first cancer-causing fusion protein was found in

chronic myeloid leukemia– Most CML have a Philadelphia chromosome- tip of 9

translocated to chromosome 21– One gene from chromosome 9, the Abelson oncogene (abl)

and the other from chromosome 22, the breakpoint cluster region (bcr)

– Reciprocal translocation produces two different fusion genes• bcr-abl fusion gene causes CML• Encodes for BCR-ABL oncoprotein- a form of the tyrosine kinase • This cancer causing form of tyrosine kinase is active for too long,

stimulating the cell to divide for too long

Gleevec replaces the ATP in the oncoprotein’s pocketWithout phosphorylation of the tyrosine substrate division of the abnormal cells stops. As cancer progresses, some cells undergo mutations that make the shape of their pockets unable to bind the drug

Receiving an Overly Aggressive Division Signal

• 25% of woman affected with breast cancer have 1-2 million copies of a cell surface protein called Her-2/neu a product of an oncogene

• Her-2/neu proteins are receptors for epidermal growth factors

Oncogenes: new functions from oldRearrangement of the genome can create a novel gene from portions of the two original genes.

promoter coding region

Proto-oncogene protein signals cell division

Gene expressed in brain

Fusion gene: Protein signals cell division in brain inappropriately

Tumor suppressor genes

• Cancer can be caused by loss of genes that inhibit cell division.

• Tumor suppressor gene mutation that causes cancer is typically a deletion, removal of function

• A point mutation can cause loss of function as well but this is rare

• DNA viruses (SV40, adenovirus, and human papilloma virus) interact with the normal products of tumor suppressor genes

• 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.

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.

Knudson’s two hit hypothesisKnudson 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.

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.

• Reading on page 368

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.

Multiple genes contribute to cancer progressionMultiple genetic changes in astrocytes, nerve support cells, cause in cancer growth.

Colon cancer results from genetic alterations in multiple genes

Inherited mutations in the APC gene dramatically increase risk of colon cancer

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.

Cruciferous vegetables can lower cancer risk

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.

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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

Genetics of Cancer - Lecture IV

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