CANCER Chapter 26 (3th edition) Chapter 24 (3th edition)

Genetic alterations and the progression of colorectal cancer Genetic alterations and the progression of colorectal cancer. The major signaling pathways that drive tumorigenesis are shown at the transitions between each tumor stage. One of several driver genes that encode components of these pathways can be altered in any individual tumor. Patient age indicates the time intervals during which the driver genes are usually mutated. Note that this model may not apply to all tumor types. TGF-β, transforming growth factor–β. Vogelstein Bert et al. (2013) Science 29 March vol 339 p1546-1558.

Total alterations affecting protein-coding genes in selected tumors Total alterations affecting protein-coding genes in selected tumors. Average number and types of genomic alterations per tumor, including single-base substitutions (SBS), small insertions and deletions (indels), amplifications, and homozygous deletions, as determined by genome-wide sequencing studies. For colorectal, breast, and pancreatic ductal cancer, and medulloblastomas, translocations are also included. Vogelstein Bert et al. (2013). Science 29 March vol 339 p1546-1558.

JB Weitzmann and Nosh Yaniv Nature 1999, 400 p401

FISH of chromosome 4 HSR DNA amplification: Homogeneously Staining Regions

DNA amplification: double minute chromosomes.

Rous sarcoma virus

J. Michael Bishop (1936 - ) and Harold E J. Michael Bishop (1936 - ) and Harold E. Varmus (1939 - ) won the Noble Prize in 1989 for proving that viruses contain a cancer-causing gene derived from the genome of the organism they infect. Specifically, they showed that chicken Rous Sarcoma Virus (RSV) carried an oncogene called v-src and this gene was an intronless version of a normal chicken gene called c-src Nobel Prize 1989

Chicken Rous Sarcoma Virus (RSV) carried an oncogene called v-src and this gene was an intronless version of a normal chicken gene called c-src.

Active tumor suppressor gene(s) Inactive tumor suppressor gene(s) DNA Damage + DNA Repair Active tumor suppressor gene(s) Proto-oncogene(s) MUTATIONS Oncogene(s) Inactive tumor suppressor gene(s) Gain-of-function Dominant phenotype Loss-of-function CANCER Recessive phenotype

Retinoblastoma. S-phase EF2 Rb Cdk2-cyclin E DNA mRNA DNA polymerase P + DNA mRNA DNA polymerase S-phase

Loss of heterozygosity

Loss of heterozygosity

Conditional mouse models.

Promotors regulated by tetracyclines: transcription factors: transactivator (tTA) and reverse transactivator (rtTA). Response Element: Tet(racycline) Operator (tetO)

v-SIS: retroviral oncogene coding for PDGF homolog.

Activation of the Epo receptor by erythropoietin or gp55 from Spleen focus-forming virus (SFFV): erythroleukemia.

Papillomavirus E5 (44AA transmembrane protein) forms a complex with a endogenous PDGF receptor protein thereby aggregating and activating two or more receptor proteins.

EGF receptor oncogenes Overexpression of Her2 (human) Mutation of valine to glutamine in transmembrane domain: constitutively active (mice) Loss of extracellular domain: constitutively active (mice.

See also: Overexpression of Her2 receptors in many human breast cancers. The cells respond and proliferate to very small concentrations of EGF. Anti-Her2 mAb (Herceptin).

Domain structure of the normal Trk receptor and tropomyosin and the chimeric Trk oncoprotein. (Neurotrophin protein tyrosine kinase receptor)

Tyrosine kinase. The bcr-abl oncogene. Philadelphia chromosome: Chronic myelogenous leukemia (Gleevec: STI-571) and acute leukemia (in combination with a mutation in p53 or Rb).

c-fos (c-Jun) and c-myc are early response genes of many growth factors.

p14ARF: a key activator of p53

Risk of cancer increases: 1. p53 is defective. 2. MDM2 is over-active. 3. MDM2 is not enough sequestered (inactive p14ARF)

What causes cancer? 1. Environmental carcinogens - chemical (e.g., cigarette smoke) - physical (e.g., UV radiation) 2. Host carcinogens (e.g., inflammation) 3. Viruses:

HTLV Leukemia

TUMOR VIRUSES Papiloma virus Hepatitis B virus Human Herpes virus 8 (Kaposi) Human Herpes virus 4 (Epstein Bar) Human T lymphotropic virus

DNA viruses.

This woman has hepatitis B and is suffering from liver cancer This woman has hepatitis B and is suffering from liver cancer. She was a Cambodian refugee and died 4 months after she arrived in a refugee camp (average life expectancy after diagnosis of liver cancer is 6 months)

Kaposi syndrome: Human Herpes Virus 8)

Cutaneous B cell lymphoma

Retroviruses

The formation of a transducing retrovirus.

Base excision repair of a mismatch.

Mismatch repair of newly replicated DNA

Repair of double-strand breaks by homologous recombination.

Error-prone repair by end-joining.