Genetics of Cancer - Lecture IV. Dr. Steven J. Pittler VH375B Office 4-6744 Cell 612-9720. Suggested Reading: Lewis 2 nd Edition Chapter on Genetics of Cancer. Cancer. Cancer is a group of diseases caused by loss of cell cycle control. - PowerPoint PPT Presentation
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• Is a complication of being a multicellular organism• All specialized cells must follow the cell cycle• If a cell escapes it forms a growth called a tumor
• In the blood such a cell will take over the population of blood cells
• A benign tumor grows in place• It is malignant or cancerous when it infiltrates the
nearby tissues• A malignant tumor invades locally and it also sends
parts of itself into the bloodstream and gets transported to other areas. This process of spread is called metastasis
Inherited Versus Sporadic cancer• Most cancers are isolated or sporadic-the causative
mutation occurs only in cells of the affected tissue: Somatic mutation– May result from a single dominant mutation, or from two
recessive mutations in the same gene– Inherited or germline cancer susceptibility is directly passed
to future generations because it is present in every cell, including gametes
• Inherited or germline cancer susceptibility is directly passed to future generations because it is present in every cell, including the gametes– Cancer develops when a second mutation occurs in the
somatic cell– The cancer site in the body is the site of the second mutation
• A cell divides or if it stops dividing or whether it expresses the sets of genes that make it special depends upon biochemical signals from surrounding cells
• A cancer cell stops listening to these signals• Mutations that affect any stage of signal
transduction or gene expression can send a cell toward unrestrained division
Characteristics of cancer cells• Divide continually (given space and nutrients)• Heritable mutations: cells with mutations have daughter cells which
inherit the same mutations.• Transplantable: if a cancer cell is injected into a healthy animal of
the same species, the cell will proliferate • Dedifferentiated: cells lose their specialized identity• Different appearance: reflects dedifferentiation• Lack contact inhibition: will divide in a crowd of cells and pile on
top of each other• Induce angiogenesis (local blood vessel formation)• Increased mutation rate• Invasive: squeeze into any space available• Metastasize: cells move to new location in the body
Fusion Proteins with New Functions• Oncogenes are activated when a proto-oncogene moves
next to another gene, and the gene pair is transcribed and translated together, as if one gene– Double gene product: fusion protein activates or lifts controls
of cell division• The first cancer-causing fusion protein was found in
chronic myeloid leukemia– Most CML have a Philadelphia chromosome- tip of 9
translocated to chromosome 21– One gene from chromosome 9, the Abelson oncogene (abl)
and the other from chromosome 22, the breakpoint cluster region (bcr)
– Reciprocal translocation produces two different fusion genes• bcr-abl fusion gene causes CML• Encodes for BCR-ABL oncoprotein- a form of the tyrosine kinase • This cancer causing form of tyrosine kinase is active for too long,
Gleevec replaces the ATP in the oncoprotein’s pocketWithout phosphorylation of the tyrosine substrate division of the abnormal cells stops. As cancer progresses, some cells undergo mutations that make the shape of their pockets unable to bind the drug
Alfred Knudson, 1971 examined cases of retinoblastoma in Houston 1944-69 and determined:– One eye or two with tumor– Age of diagnosis– Relatives with retinoblastoma– Number of tumors per eye
• Observed that 50% of children of an affected parent were affected.
• Boys and girls were equally frequently affected.• Children with bilateral (both eyes) tumors were
• Two mutations are required, one in each copy of the RB gene.
• For sporadic cases, retinoblastoma is a result of two somatic mutations.
• For familial cases, retinoblastoma is inherited as an autosomal recessive mutation followed by a somatic mutation in the normal allele. The chance of a second somatic mutation is high and creates a dominant “susceptibility” to cancer in the family.
• p53 acts as a cell cycle protein which determines if a cell has repaired DNA damage. If damage cannot be repaired, p53 can induce apoptosis.
• More that 50% of human cancers involve an abnormal p53 gene.
• Rare inherited mutations in the p53 gene cause a disease called Li-Fraumeni syndrome in which family members have many different types of cancer at early ages.