Flashcards in Lecture 64 Deck (29)
What are 3 categories of genetic alterations associated with the progression of cancer?
1) Activation of proto-oncogenes - normal role is to promote regulated cell growth
2) Loss of tumor suppressor genes - normal role is to suppress cell growth at inappropriate times
3) Chromosomal instability genes - normal role is to maintain the integrity of the genome
What is the difference between a proto-oncogene and an oncogene?
1) Proto-oncogene is a normal, wild-type gene
2) An oncogene is an altered (mutant or inappropriately expressed) version of a proto-oncogene
What are 3 characteristics of an alteration in an oncogene?
1) Generally associated with a gain of function
2) Functionally dominant to normal allele
3) Often involved in cancer progression through somatic mutations
What quantitative changes does an alteration in an oncogene lead to?
1) An increase in unaltered product by increased gene expression or decreased protein degradation
2) Expression not regulated in response to normal signals
What qualitative changes does an alteration in an oncogene lead to?
Production of a modified product due to point mutations, deletions, fusions, etc. leading to loss of control of activity
Normally, proto-oncogenes are involved with what two things?
1) Cell-cycle entry
2) Cell-cycle regulation
What are examples of proteins that contain proto-oncogenes?
1) Secreted growth factors
2) Cell surface receptors
3) Intracellular signal transduction
4) Transcription factors
5) Cyclins, CDKs, CDKIs
6) Oncogene-encoded proteins have aberrant function
What are three pathways that lead to the conversion of a proto-oncogene to an oncogene?
1) Point mutation
What occurs in the common c-H-Ras protein point mutation converting a proto-oncogene to an oncogene?
1) There is a G-->T point mutation in codon 12
2) Point mutation causes normal Glycine to change to abnormal Valine
3) This point mutation inactivates GTPase activate protein (GAP)
4) When the Ras protein is phosphorylated (GDP-->GTP) by GEF (Guanine nucleotide exhange factor) to produce the active form, it cannot be dephosphorylated because GAP is no longer active
5) Activated Ras induces cellular proliferation
What are point mutations in RET tyrosine kinase usually linked to?
1) Multiple endocrine neoplasia
2) Thyroid cancer
What occurs in the RET tyrosine kinase point mutation converting a proto-oncogene to an oncogene?
1) Normally, RET tyrosine kinases are inactive in monomeric form
2) Normally, they can only be activated when a ligand dimer binds to two kinases, causing dimer formation
3) In a RET tyrosine kinase point mutation, mutant kinases are formed that can dimerize without ligand binding
4) This causes the mutant receptor to be constitutively active
What occurs in a chromosomal translocation that results in chronic myelogenous leukemia?
1) Translocation breakpoint 1: the abl gene breakpoint (homologous to a gene encoded by Abelson leukemia virus) on chromosome 9
2) Translocation breakpoint 2: the bcr gene breakpoint ("break cluster region") on chromosome 22
3) Results in a longer long arm (q arm) in chromosome 9 & a shorter chromosome 22 long arm (q arm) (Philadelphia chromosome)
What is dysfunctional in the chromosomal translocation that results in chronic myelogenous leukemia?
1) The larger translocated chromosome 9 is missing the abl gene regulatory protein on chromosome 9
2) When the fusion protein product is expressed, it is going to be permanently activated causing over production of the abl protein
(p210 fusion protein with constitutively active tyrosine kinase)
What occurs in a chromosomal translocation that results in chronic Burkitt's Lymphoma (B-cell tumor of the jaw)?
2) Translocation breakpoint 1: chromosome 8 contains normal c-myc proto-oncogenes in which exons 2 and 3 regulate expression of myc protein
3) Translocation breakpoint 2: chromosome 14 has a highly activate IgH promoter region
4) When these two parts come together through a translocation, exons 2 and 3 are over expressed, causing increased expression of myc protein, resulting in Burkitt's Lymphoma
What are two things that DNA amplification within an abnormally reduplicated region of a chromosome can result in?
1) Chromosomal excision
2) Chromosomal integration
What occurs in chromosomal integration?
1) The amplified region of DNA maintains its incorporation in the chromosome
2) Can be detected using a homogeneous staining region (HSRs)
What occurs in chromosomal excision?
1) The amplified region of DNA is removed from the chromosome
2) Results in Double Minutes (DMs) - small pieces of reduplicated DNA
How does gene amplification result in breast cancer (erbB2 or HER2)?
1) EGF receptor is affected by gene amplification
2) Inactive monomer is converted to the dimer form because of the overexpression of gene product without dimer ligand activation
3) Causes a signal to be expressed when it is not needed
What is the function of Herceptin?
Herceptin (Trastuzumab) binds & blocks Her2 receptors
What are two examples of cells resistant to chemotherapeutic drugs?
1) Methotrexate cells with amplified dihydrofolate reductase genes (produces cloud of double minutes (DMs) - excision)
2) PALA cells with amplified CAD genes - integration (homogenous staining region (HSRs))
What does the telomerase gene ("hTERT") encode for?
Encodes a specialized DNA polymerase that lengthens telomeres
What happens to telomerase during normal cell development?
1) During development, normal cells progressively lose telomerase activity, and suffer progressive shortening of telomeres
2) Loss of telomerase is associated with senescence, and replicative mortality (cell death)
a) Erosion of telomeres can lead to end-to-end joining of chromosomes to create dicentric chromosomes, and cell death due to karyotype
What happens to telomerase in cancer cell development?
Unlike normal non-growing cells, tumor cells and transformed cells in culture have telomerase activity; thus inappropriate reactivation of telomerase expression leads to “replicative immortality”
What is are exceptions to oncogenic mutations?
1) Generally, oncogenic mutations are somatic mutations, however a germline mutation can occur in RET & MET
2) RET - Multiple endocrine neoplasia-thyroid carcinoma - constitutively active thyroid trans-membrane Tyr kinase
3) MET - Hereditary papillary renal carcinoma - constitutively active tyrosine kinase receptor for hepatocyte growth factor
What are two types of tumor suppressor genes?
1) Gatekeepers (GTSGs) - Direct involvement in regulaiton of cell cycle, or in growth inhibition by cell-to-cell contact - directly regulates cell growth
2) Caretakers (CTSGs) - Involved in repairing DNA damage and maintaining genomic integrity - indirectly lead to cancer by allowing secondary mutations to accumulate in proto-oncogenes or other tumor suppressor genes
What is a gatekeeper tumor suppressor gene?
1) Encode proteins whose normal function is to suppress proliferation at inappropriate times, or, to induce apoptosis
2) Loss-of-function mutations lead to tumorigenesis
3) Mutations behave in a recessive manner at the molecular level
4) Both copies of the gene must be inactivated to get the abnormal phenotype since it is recessive
What is retinoblastoma?
1) The most common primary eye tumor in children
2) Hereditary cases (40%); Sporadic cases (60%)
3) Familial: highly penetrant AD trait, with multiple independent tumors in both eyes
4) Curative therapy: removal of tumors and/or eye. Incidence of nonocular tumors increases with age
5) Sporadic: single tumor in one eye, no family history and no secondary tumors
6) pRB controls transcription required for cell cycle progression
What is the two-hit hypothesis?
1) First “hit” is a mutant gene inherited from a parent that is present in all cells of the child at birth
2) Second “hit” is a somatic change occurring in specific cells that then give rise to the eye tumor
3) Familial susceptibility displays dominant inheritance; development of tumor cells is a genetically recessive event