BIOL 2416 Chapter 20: Genetics of Cancer

Cancer Genetic disease (due to DNA mutations) Not usually inherited (mutations in somatic, not germ cells)

Different kinds of cancer: (Names assigned According to Where cancer Started) See http://www.cancer.gov

Tumor Clonal (descendants of single cell gone wrong) Transformed cells: Neoplastic (grow too fast, cannot stop dividing) No longer show contact inhibition Are round and do not stick together immortal

Transformation can be seen in tissue culture: Normal Transformed

foci

Tumorigenesis: Transformation / immortalization Deregulated proliferation Suppressed apoptosis Angiogenesis Invasion Metastasis

Whereas normal cells can do damage control: Detect cellular DNA damage Arrest cell division to prevent proliferation of damaged cells Activate damage repair systems - if successful, return to cell cycle Activate apoptosis (cell-mediated cellular suicide) if damage cannot be repaired = critical part of damage control in normal cells (why suicide? Mostly b/c necrotic cell death would trigger inflammation - bacterial (infection) magnet)

Genes implicated in cancer: Oncogenes Mutated (or amplified) versions of normal proto-oncogenes; act as stuck gas pedal; e,g, myc, ras, HER2, or may block apoptosis (e.g. Bcl-2) Oncogenes are usually (1) growth factors, (2) growth factor receptors, (3) transcription factors, or (4) intracellular messengers (signals no longer turned off; many are protein kinases)

Cyclins: Proteins that act as triggers for progression through the cell cycle Growth factors may upregulate cyclins Growth inhibitors may downregulat cyclins High cyclin concentration activates cyclin-dependent kinases (Cdk’s) to stimulate cell division (see iGenetics animation)

Genes implicated in cancer, cont’d: Tumor suppressor genes Mutated versions act as lost brakes; e.g Retinoblastoma (Rb), P53, APC, DCC P53 mutated in over half of cancers = “guardian angel” of the cell - coordinator of repair systems - mutated P53 makes damage responses much more likely to fail; defects also lead to increased cell division rates > domino effect > more mutations, chromosome breakages DNA repair genes (mutator genes) E.g. xeroderma pigmentosum, heredirtary nonpolyposis colon cancer

View two iGenetics animations on normal cell growth and P53

Knudson’s 2-hit Hypothesis for Tumor suppressors: Only 1-hit Fig. 18.12 Comparison of the effects of tumor suppressor gene and proto-oncogene mutations Knudson’s 2-hit Hypothesis for Tumor suppressors: Only 1-hit Required for Oncogenes… Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

How can an oncogene (e.g. myc) become deregulated? Insertion of myc oncogene into cell genome by a retrovirus Insertion of a retrovirus near cellular myc, disrupting normal control of myc gene expression; get overexpression of myc Translocation of part of chromosome with myc into trasncriptionally active chromatin (immunoglobulin locus - Burkitt’s Lymphoma) Myc gene amplification

Fig. 18.15 A multistep molecular event model for the development of hereditary adenomatous polyposis (FAP), a colorectal cancer Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

What kinds of viruses can cause cancer? DNA viruses (e.g. Hepatitis B) Can become provirus that causes infected cells to divide more rapidly Do not carry oncogenes Retroviruses Reverse transcriptase helps produce viral dsDNA that becomes inserted as a prophage Typical genome includes LTRs and gag, pol, env

RSV was 1st identified cancer-causing retrovirus Encodes src Src is really a virla version of a normal cellular proto-oncogene picked up by the virus long ago Src may have been inserted near the viral LTRs that contain powerful enhancers, causing elevated expression at the wrong times, I.e. too much growth and cancer (similar to myc story - insertional mutagenesis)

Fig. 18.10 The chicken c-src proto-oncogene and its relationship to v-src in Rous sarcoma virus Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings. Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

Fig. 18.11 Model for the formation of a transducing retrovirus Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

Cancer vaccines Prophylactic Prevent viral infections that might lead to cancer (e.g. Hepatitis B vaccine) Therapeutic By presenting extra antigens to body, boost immune system’s effectiveness to fight the virus and the infected cells

What other targets? Surgery Chemotherapy/radiation to attack rapidly growing cells unfortunately also attacks gut cells, hair follicles Causes DNA mutations so devastating to kill cells Problem: cancer cells may fail to react/lose ability to detect DNA damage - may make things worse Another potential side effect: drug resistance (e.g. by upregulation of P-glycoprotein pumps to pump poisons out of cells) Telomere replication Cancer cells overproduce telomerase (lose internal clock - divide more than normal ~60 times. Angiogenesis Pancreatic cancers particularly angiogenic Idea is to starve tumor cells of O2 and nutrients Boost immune system E.g. by giving interferons