Ch. 25: Cancer genetics

cancer

• a disease that occurs in multicellular organisms

• characterized by uncontrolled cell division

carcinogens

• 80% of human cancers are related to these

• environmental agents that increase the likelihood of developing cancer

clonal

• cancer originating in a single cell

malignant

• classification of cancer one cellular growth becomes invasive and metastatic

invasive

• cancer cells can invade healthy tissues

metastatic

• cancer cells that can migrate to other parts of the body

oncogene

a mutant gene that is overexpressed and contributes to cancerous growth

tumor suppressor gene

• gene that prevents cancer

• a loss-of-function mutations in these genes allows for cancerous growth to occur

proto-oncogenes

• are normal cellular genes that can be mutated into an oncogene

  • expression becomes abnormally active

  • this is a gain-of-function muatation

formation of oncogenes

• typically occurs in three ways

  • The amount of the coded protein is greatly increased

  • A change occurs in the structure of the coded protein that causes it to be overly active

  • The coded protein is expressed in a cell type where it is not normally expressed.

growth factors

• regulates cell cycle

• bind to cell surface receptors and initiate a cascade of cellular events leading ultimately to cell division

oncogenes

• often code proteins that function in cell signaling pathways related to cell division

  • growth factor receptors

  • intracellular signaling proteins

  • transcription factors

genetic changes in proto-oncogenes coverting them to oncogenes

• missense mutations

• gene amplifications

• chromosomal translocations

• viral integration

gene amplification

• increase in copy number

  • expected to increase the amount of protein

• Examples

  • c-mycin a leukemia cell line

  • N-mycin neuroblastomas

  • erbB-2in breast carcinomas

viral integration

• Certain viruses integrate into host DNA as part of their life cycle

• This can cause activation of a cellular proto-oncogene

  • Direct transcription from viral promoter

  • Activation of cellular promoter by viral enhance

• Ex:In certain lymphomas in birds, avian leukosis virus is integrated next to the c-myc gene, enhancing its level of transcription

tumor suppressor genes

• prevent the proliferation of cancer cells

• If they are inactivated by mutation, it becomes more likely that cancer will occur

retinoblastoma

• a tumor of the retina of the eye

• involved in the first identification of human tumor-suppressor gene

inherited

• one form of retinoblastoma

• occurs in the first few years of life

non inherited

• one form of retinoblastoma

• occurs later in life

Rb protein

• prevents the proliferation of cancer cells

• its phosphorylated when the cell is about to divide

• Dissociates from E2F, a transcription factor that activates genes for cell cycle progression

• When both copies of are defective, the E2F protein is always active

  • This leads to uncontrolled cell division

two hit model

• retinoblastoma requires two mutations to occur

• People with the inherited form have already received one mutation from one of their parents

  • It is not unlikely that a second mutation occurs in one of the retinal cells at an early age, leading to disease

• People with the noninherited form, must have two mutations in the same retinal cell to cause the disease

  • Two rare events are much less likely to occur than a single event

p53 gene

• the second tumor-suppressor gene discovered

• About 50% of all human cancers are associated with defects in the gene

• A primary role for the protein it makes is to determine if a cell has incurred DNA damage

• If so, it will promote three types of cellular pathways to prevent the division of cells with damaged DNA

pathways p53 prevents division of cells with damage

• Activates genes that promote DNA repair

  • prevents accumulation of mutations

• activates genes that arrest cell division and repress other genes that are required for cell division

  • Stimulates the expression of p21, which inhibits the formation of cyclin/CDK complexes that are needed to advance the cell cycle

• Activates genes that promote apoptosis, or programmed cell death

types of tumor suppressor genes

• Proteins that negatively regulate cell division

  • ex: Rb negatively regulates E2F

• proteins that maintain genome integrity

  • prevent damaged cells from dividing (checkpoint proteins)

  • DNA repair

healthy tissues

• tumor suppressors = brake working

• proto-oncogenes = accelerator mostly off

cancer tissue

• tumor suppressors = brake defective

• oncogenes = accelerator jammed

chromosomal abnormalities leading to cancer

• missing chromosomes may have carried a tumor suppressor gene

• duplicated chromosomes may overexpress proto-oncogenes

• translocation fuse or disrupt genes

telomerase

• another gene involved in cancer

• activation allows cells to divide indefinitely

• apoptosis genes

• another gene involved in cancer

• genes involved in signaling programmed cell death are often mutated

cell adhesion genes

• another gene involved in cancer

• genes involved in intercellular interactions and attachments

• is cells don’t stick together—→ cells can spread (metastasis)

vascularization genes

• another gene involved in cancer

• genes that stimulate angiogenesis are often overexpressed

miRNAs

• another gene involved in cancer

• microRNAs are often mis regulated

epigenetic maintenance genes

• another gene involved in cancer

• genes involved in DNA methylation, histone modification and chromatin remodeling

physical methods

• removes or physically kills cancer cells

• includes surgery and ablation

killing actively dividing cells

• radiation and chemotherapy are usually used to kill cells that are actively dividing

targeted drug therapy

• a specific protein is targeted that has an abnormal structure and/or is overactive in cancer cells

hormone therapy

• decreases the level of hormones or blocks their effects to stop or slow the growth of cancer cells

immunotherapy

• uses the immune system or components from the immune system to fight cancer