Cancer Genetics lect

*most cancer involves more than one genes

  • Viruses

    • Non-living—cannot make energy for themselves, maintain a steady internal envionrment homeostasis), do independent prod

  • Retroviruses & Oncogenes

    • Oncogene - a gene that causes unregulated cell proliferation—transmitted by RNA tumor viruses (retroviruses) into genome of host

      • Retroviruses duplicate RNA genomes via DNA intermediate using reverse transcriptase

      • Ex. HIV, causes AIDS

    • Transducing retrovirus - pick up cellular DNA genes (often oncogenes) into NRA genome, transfer them to new host genomes

      • Cannot se;f replicate—require helper viruses if cell is infected with viruses that have replication genes

      • Carcinoma: epithelial origin (breast, colon)

      • Sarcoma: A cancer of the connective or supportive tissue and soft tissue

    • Rous Sarcoma Retrovirus

      • When retroviruses invade a cell, RNA is released, and reverse transcriptase makes a double-stranded DNA copy of the RNA genome called a provirus genome

      • Self-replicating retroviruses include 3 protein coding genes

        • gag - proteins of virus particle

        • pol - reverse transcriptase/integrase

        • env - envelope glycoproteins

      • Long-terminal repeats are ligated together to form a circular, viral cDNA molecule by reverse transcriptase

      • Staggered nicks made in host and viral genomes, becoming integrated into the host with the enzyme integrase

    • Non-oncogenic Retroiruses

      • Not all retroviruses cause cancer

      • Non-oncogenic retroviruses direct own life cycle but do not change growth properties of cells they infect

        • ex. HIV — synthesis of DNA from reverse transcriptase is very error prone, which causes many mutations, allowing drug resistance to evolve quickly

  • DNA tumor viruses

    • can cause cancer but do not carry oncogenes like RNA tumor viruses

    • Normally don’t induce cancer, makes protein that causes host cell to replicate DNA virus genome, causing cell lysis

    • If DNA virus genome is not replicated but is incorporated into host genome by mistake—host expresses viral gene for protein that can cause cancer via DNA replication and cell cannot stop replicating

      • Ex. Papovaviruses (HPV), hepatitis B

  • Oncogenes v. Tumor suppressor genes

    • Cancer pathways

    • Oncogenes — can cause cancer if incorporated into genome

    • Tumor suppressor genes — if malfunctions, can allow cancer to spread

      • produce factors that inhibit cell division

      • mutant alleles are recessive (both alleles must be mutated to produce excessive cell proliferation)

  • Proto-oncogenes

    • Michael Bishop & Harold Varmus, 1975

    • When p-oncogenes mutate, they can become ibcogenes that induce cancer in normal cells

    • Only one p-oncogenes on a homologous pair of chromosomes is necessary to induce cancer so the mutations are dominant

    • Proto-oncogene proteins are involved in cell growth and division

    • Proteins

      • growth factors - causes cells to grow and divide

      • Protein kinase - Enzymes that add phosphate groups to target prteins, thus altering their function

        • Protein kinases known to affect signaling pathways of cells, that are involved with growth factors

      • Membrane-associated G proteins - activated by growth factors to cell membrane receptors—involved in signaling cascade that activates transcription factors for specific genes

  • Tumor-Suppressor genes

    • 1960s, Henry Harris, normal rodent cells fused with cancer cells

    • Found normal cells had tumor suppressor genes, suppresses uncontrolled growth of cancerous cells

    • Mutations of tumor suppressor genes are recessive, both mutant alleles must be present to deactivate uncontrolled growth

  • TP53 Tumor suppressor gene

    • Involved in 50% of all cancers

    • Elephants & TP53

      • Every cell had the potential to become transformed, bigger animals with more cells have a higher risk of getting cancer in theory

      • Elephants 5x less likely to get cancer than humans

      • Most mammals have 2 alleles of the p53 gene, but elephants have 40, some with slightly varied structures that interact with Mdm2 differently

  • Retinblastoma

    • Retinoblastoma - chidhood cancer of the eye before 4 years, 90% treatable

    • Alfred Knudson, cancer genetics researcher

    • 1971, hypthesis (tqo-hit mutational model) explain 2 forms of retinoblastoma

      • In sporadic, two mutations occur in eye cell—-rare, only happens in one eye

      • Hereditary form — one mutation is passed on by hereditary

    • Breast cancer tumor suppressor genes

      • Cam aflict both sexes, 46,000 women a year

  • Mutator genes

    • Any gene that increases spontaneous mutation rate

      • Wild type form of mutator genes, involved DNA replication & repair

      • Mutations of mutator genes impair DNA replication and repair, allowing mutations to accumulate quickly

  • Carcinogens

    • A natural or artificial agent (chemical, radiation) that increases a cell’s risk of becoming cancerous

      • Chemicals cause more cancer than viruses—smoking 50-60& of cancer deaths

    • direct-acting carcinogens: bind to DNA and mutate it

    • Procarcinogens: must be converted by the body’s metabolism to become carcinogenic

      • both kinds of carcinogens induce point mutations—leading to cancer in some cases

    • Cigarettes and vaping

      • cigarettes contain 7,000 chemicals, including radioactive materials (polonium-210 & lead-210)

      • Damage every organ in body, especially

      • E-cigs and vaping - smoking liquid forms of nicotine is NOT safe and highly addictive

        • Fewer toxic chemicals but causes lung injury & death, not effective to quit smoking

  • Radiation & cancer

    • 2% of cancer deaths caused from radiation

    • Skin cancer most common in US (2 ppl die every hr) easy to treat if caught early

    • UV light causes thymine dimers (T^T) disrupts A-T pairing, bulge in DNA, disrupts DNA replication at bulge, can lead to cell death (skin cancer)

  • Herpes Simplex Virus (HSV)

    • Two strains:

      • HSV-1 - usually oral herpes—50-80% of adults in USA infected by age 20

        • commonly transmitted within families by kissing or sharing utensils (cold sores)

        • can infect partner via oral sex

      • HSV-2 - Usually gential herpres—causes painful sores that last for several days or weeks-not correlated with cancer, but can increase chance of HIV

      • Potentially fatal infection can transfer to baby of pregnant women

      • 1 in 5 women and 1 in 9 men have HSV-2

      • 90% of people infected with HSV not aware of it