Genetics chp. 16 Cancer Genetics

Two main properties of cancer

• Uncontrolled Cell division

• Ability of cells to spread to other sites in the body (metastasis)

Age and cancer correlation

Proportional: As age goes up, cancer deaths increase

Predisposition for cancer

We have a predisposition for over 50 forms of cancer that are inherited

Chemicals causing cancer

Most are mutagens

Can viruses carry genes promoting cancer?

Yes

Ultimate cause of cancer?

Mutations

Process leading to cancer cell

One mutant cell accumulates specific mutations over a long period of time which will eventually escape control of cell cycle and divide continually

Non invasive vs invasive cancer cells

• Benign: Non invasive cancer cell (does not spread)

• Malignant or metastatic: Invasive cancer cell (spreads to other body parts)

Metastasis process

• 1) cancer cells break away from original tissue

• 2) Malignant cell attach to wall of blood vessel or lymph vessel where digestive enzymes are secreted and breach the wall

• 3) The cell enters the blood vessel and travels through the bloodstream, then leaves the same way it got in and looks for new tissue to bind to

Sporadic cancer

A mutation to a single somatic cell that then accumulates additional mutations that eventually cause cancer (Not inherited)

Inherited cancer syndromes

• cause a predisposition to cancer

• Mutations will be carried in all cells in a heterozygous state but in a cancer cell the normal allele is lost

How many gametes carry germ line mutation

Half the offspring will because mutations are carried in heterozygous state

Clonal evolution

Mutation that allows cell to proliferate is increased as clone of cell accumulates more somatic mutations.

Two ways to get cancer (discussed in previous flash cards)

inherited or sporadic

genes that contribute to cancer when mutated

• oncogenes and tumor suppressor genes

• Genes that control cycle of cell division

• DNA repair genes

• Genes that regulate telomerase

• Genes that promote vascularization and the spread of tumors

Tumor suppressor gene vs oncogene

• tumor suppressor gene: decreases cell division (recessive - need two mutated alleles)

• oncogene: increases cell division (dominant - need only one allele to be dominant)

Proto-oncogene vs oncogene

• Proto-oncogene: Gene that initiates or maintains cell div that can be mutated to become an oncogene

• Oncogene: Gene that induce or continue uncontrolled cell div

90% of cancers are thought to be dominant oncogenes

Why are people heterozygous for tumor suppressor genes predisposed to cancer?

A deletion can occur at wild type allele which will lead to loss of heterozygosity and the tumor suppressor gene will activate.

Tumor suppressor gene function

Encode proteins that suppress cell division and regulate the cell cycle. Gene products are control points at G1/S or G2/M. If these products are deleted or nonfunctional then cell div will be continuous.

Other 10% of cancer are tumor suppressor genes

Eukaryotic cell cycle phases

• G1: Cell growth before DNA replication

• S: DNA replication occurs and is completed

• G2: Cell prepares to divide

• M: Mitosis occurs

Checkpoints in cell cycle

• G1/S checkpoint: Cell proceeds to S phase and commits to chromosome replication

• G2/M checkpoint: Monitors DNA synthesis and damage

Genes controlling cell cycle

• Control of entire cell cycle: Cyclin-dependent kinases (CDK’s)

• G1/S transition: Retinoblastoma protein (Rb protein)

• G2/M transition: Mitosis-promoting factor (MPF)

CDKs and cyclins

• CDK: enzymes that phosphorylate other proteins, turning them on or off

• Cyclins: proteins that oscillate over the course of the cell cycle

Retinblastoma

Malignant tumor of the eye arising in retinoblasts

This will only occur in children as retinoblasts disappear around 2 years old and mature retinal cells do not become tumors.

Can be inherited or caused by sporadic mutation

RB protein

• CDK’s phosphorylate RB

• Regulates activity of protein called E2F

• Cell division is uncontrolled without RB

RB and CDK action example

Increase in cyclins cause more CDK’s to be produced. These CDK’s phosphorylate an RB protein bound to an E2F protein (it is inactivating it). The E2F protein is released and activated to induce transcription of DNA in nucleus.

Ras gene mutation

Mutation of ras gene turns it into an oncogene continuously signals cell division leading to tumor formation

What do cancer cells bypass

• Cell cycle checkpoints are bypassed which leads to continuous cell division

• Apoptosis (programmed cell death) is bypassed leading to uncontrolled cell div. of damaged or mutated cells that should be dead

Genes controlling cycle of cell division

• DNA-repair genes

• Genes regulating telomerase

• Genes that promote vascularization and spread of tumors

P53 gene

DNA-repair gene that will either stop cell cycle until damaged DNA is repaired or activate apoptosis if repairs cannot be made

Mutated P53 gene effect

DNA damage will not be repaired and apoptosis will not occur but cell cycle is not halted and checkpoints are bypassed leading to division of cancerous cell

What are BRCA 1 and BRCA 2

DNA repair genes

Process of DNA repair through BRCA1 and BRCA2

When a double stranded break occurs BRCA1 signals proteins to process the double stranded break to a single stranded tail. BRCA2 coordinates proteins to search for a template to synthesize missing info.

Mutation to BRCA1 and BRCA2 effect

Women will be predisposed to breast and ovarian cancer

Mutation to telomerase cause

Cancer cells usually have mutations to telomerase which is why chromosomes do not shorten even after many divisions

angiogenesis

Growth if new blood vessels

Process that promotes the growth of tumors

Oxygen and nutrients are needed by tumor cells to survive. Cancerous tumors will either overly express growth factors that stimulate angiogenesis or inhibitors of angiogenesis may be mutated.

Process that promotes the spread of tumors

Usually the primary tumor gives rise to secondary tumors which spread to other tissues and are a leading cause of cancer deaths. These arise due to mutations in genes for the EM, cytoskeleton, and adhesion proteins

Epigenetic changes causing cancer

• DNA methylation: Stimulates oncogenes and makes chromosomes unstable

• Histone modifications: Alters transcription of genes and makes chromosomes unstable

Chromosomal rearrangements associated with cancer

• Deletion: leads to loss of one or more tumor suppressor genes

• Inversions/translocations: Can generate fusion proteins that stimulate cancer processes like leukemia. Also transfer of gene to a new location can lead to lymphoma.

Fusion protein process

Two separate genes coding for different proteins go through translocation and are joined to produce a single fusion protein

What do fusion proteins lead to and how

By joining the c-ABL gene on chromosome 9 to the BCR gene on chromosome 22 the hybrid gene will encode a fusion protein that makes cell divide uncontrollably causing CML (Leukemia type)

Burkitt’s Lymphoma cause

translocation causes c-myc to stimulate division of B cells

How does Colon cancer arise

Starts as benign tumor that later becomes malignant

Two pathways to colon cancer related to genetic predisposition

• FAP

• HNPCC

Colon polyps

small clusters of dividing cells on lining of colon

Colon cancer process

mutation to the tumor suppressor APC gene forms a polyp. Another mutation to k-RAS gene activates oncogene and benign tumor grows rapidly. Another mutation occurs to P53 gene which turns benign tumor malignant. More mutations occur and cancer spreads to other tissue through bloodstream.

2 ways retrovirus causes cancer

• mutating and rearranging host gene can turn proto-oncogene into oncogene

• Insertion of strong promoter near a proto-oncogene leads to over expression