Cancer Genetics

cancer

diseases of unregulated cell proliferation

malignant

tumor consisting of cells that invade other tissues

metastasis

movement of cells that separate from malignant tumors to other sites where they establish secondary tumors

• associated with highly advanced cancers

genetic theory of cancer

• many causes of mutations

• some cancers are consistently associated with a particular chromosome abnormality

  • some cancers run in families

Knudsen model

cancer is a multistep process that requires multiple mutations in the same cell

• mutations can occur spontaneously or one mutation can be inherited

clonal evolution

mutations that enhance the ability of cells to proliferate predominantly in a clone of cells

• increasingly faster in growth

  • increasingly aggressive in proliferation properties

environmental causes

• most cancers are not inherited

• environmental exposure to carcinogens and mutagens

  • examples:

  • tobacco

  • diet

  • alcohol

  • UV

  • infections

  • obesity

  • occupation

• prevalence of cancers varies by location

  • some cancers have environmental and genetic predisposition interactions

oncogenes

mutates, dominant acting stimulatory genes that cause cancer

• mutation in proto-oncogene with or without viral infection

tumor suppressor genes

mutated recessive acting inhibitory genes that are inactive

• mutations lead to a loss of heterozygosity

haploinsufficiency

mutant phenotype in an individual cell or organism that is heterozygous for a normally recessive trait

cyclin dependent kinase

combines with cyclin to phosphorylate proteins

• phosphorylation can activate or inactivate protein

G1 to S transition

1. rb binds to transcription factor

2. cyclins increase in concentration

3. cyclins combine with CDK’s

4. rb phosphorylated by CDK’s

5. transcription factor released

   1. gene needed from replication transcribed

G2 to M transition

1. cyclin binds with CDK to create inactive MPF

2. MPF activated by dephosphosphorylation

3. MPF increases until critical level

4. MPF phosphorylated proteins for mitosis

   1. MPF decreases initiating anaphase

mutations

• RB mutations

• apoptosis genes (p53)

  • autophagy genes (p53)

signal transduction pathways

external signal triggers a cascade of intracellular reactions that produce a specific response

• ras proteins coded by oncogenes

receptor components

• extracellular domain

• transmembrane domain

• intracellular domain

levels of miRNA’s

more important in late stage tumor development

less miRNA= higher cancer c

cancer genome project

sequencing of tumors from various cancers

d

drivers

mutation that directly contributes to the development of cancer

• proto- oncogenes, tumor suppressor genes, telemorase genes, etc

passengers

mutations that arise randomly in the process of tumor development and do not contribute to cancer progression

evidence

• mutations in genes that regulate epigenetic changes in chromatin

• cancer cells have different DNA methylation problems

  • histone acetylation patterns differ

development of colorectal cancer

1. apc gene mutation= adenomatous polyp formation

2. mutation in ras gene in larger more advanced polyps

   1. malignant cells have mutation in p53 gene leading to higher mutation rates

deletions

loss of one or more tumor- suppressor genes

inversions and translocations

• disrupt function of tumor repressor gene

• bring together sequences of genes = fusion protein = increased cell division

• move cancer causing genes to new location = activated by new regulatory process