Genes and Cancer

• A defect of a gene that functions in repair of damaged DNA increases cancer risk.
• Failure to remove T=T dimers caused by UV light increases skin cancer
• People who have a genetic defect in one step of DNA repair have Xeroderma Pigmentosum and skin cancer
• Xeroderma pigmentosum people have sandy hair and freckles and increased risk of skin cancer
• Ataxia telangiectsia: inability to move (ataxia) and spider veins; inability to repair double strand breaks in DNA as might occur from radiation
• Ataxia telangiectsia greatly increases the risk of leukemia and lymphoma
• tumor suppressor genes: genes whose normal function is to turn off cell division when it should be turned off
• If both copies in a cell are defective, the cell does not stop dividing and the result is cancer
• Inherited cases of cancer often involve the inheritance of only one defective allele
• If no somatic cells have a mutation in the functional tumor suppressor gene, the individual will escape cancer but can pass the high risk on. This can explain "lack of penetrance"
• Retinoblastoma is typically a childhood cancer
• Retinoblastoma is the Rb gene
• If one defective allele is inherited about 85% of individuals will develop retinoblastoma before the age of 5, often in both eyes
• If retinoblastoma goes untreated, the tumor will grow into the brain and be lethal
• It is rare for a person who inherits two normal functional Rb alleles to develop retinoblastoma
• If a defective Rb gene is inherited and the "good" allele mutates in a dividing somatic cell, it will not stop dividing
• A local case in the Battallion: a little girl lost both her eyes to retinoblastoma in 2007
• Defects in the gene coding p53 are present in over half of human tumors
• p53 functions at a key checkpoint in cell division

  • If DNA damage has not been completely repaired, mitosis should not begin
  • If damage is too severe, the cell should undergo natural cell death (apoptosis)
• If mitosis occurs with still-damaged DNA, the damage becomes permanent
• FAP: familial adenomatous polyposis
• FAP: lots of polyps develop in the intestine; increases the risk of colon cancer
• Polyps can be removed by colonoscopy
• FAP is dominant inheritance with less than 100% penetrance; second mutation occurs in an intestinal polyp cell
• Multiple gene defects are common in cancer cells
• Those with no family history should get a colonoscopy at 45 every 5 years to age 75
• In 1910, Francis Peyton Rous found an oncogenic (cancer causing) agent that caused sarcomas in chickens
• Rous Sarcoma Virus could be recovered from the filtrate of homogenized cancer calls by passage through a filter that only a virus was small enough to pass through
• Rous was awarded a Nobel prize for showing that tumor cells can be "transplanted" and that a virus could transmit oncogenes
• RSV is a retrovirus, meaning its infectious stage is RNA
• RSV has only 3 genes, between long terminal repeats:

  • one gene makes a coat protein
  • another makes a spike protein
  • the 3rd encodes reverse transcriptase, a gene that can make a DNA copy of the RNA
• Normal copies of RSV do not create tumors, but could disrupt a gene
• Copies that have a "v-onc" gene can turn on cell division in infected cells, those cells are transformed into cancer cells
• Retrovirus-carried V-onc genes do not seem to be a problem in humans compared to birds and felines
• HIV is a retrovirus but it destroys immune cells that also function to eliminate abnormal cells such as cancer cells and has not been shown to carry any v-onc genes
• sarcoma tumor: muscle tumor
• By putting infected tumor cells in other muscles, Rous found that it infected the new cells, making it a virus
• Genes whose normal function is to turn on cell division can cause tumors if "turned on" when or in cells where they should not be active
• Many oncogenes are critical for normal development
• C-onc are cellular oncogenes