Neoplasia Flashcards
Cyclins and Cyclin-Dependent Kinases
These gene products control the cells entrance into the cell cycle. Cyclin D and CDK4 mutations are the most common of this group.
Cyclin D1
Cyclins and Cyclin-Dependent Kinases
over expressed in mantle cell lymphoma t(11;14)
breast carcinoma, esophageal carcinomas and liver carcinomas
CDK4
Cyclins and Cyclin-Dependent Kinases
amplified in melanomas, sarcomas and glioblastomas
principle targets of genetic damage
Growth promoting proto-oncogenes
Growth inhibiting tumor suppressor genes
Apoptosis (cell death) regulating genes
DNA repair genes – accumulate mutation
Oncogenes
the ability to promote cell growth in the absence of normal growth-promoting signals
Oncogene products (oncoproteins)
activated within transformed cells without the presence of growth factors or other external factors
often devoid of important regulatory elements
Proto-oncogenes
(promote growth in a cell) undergo mutation to oncogenes
Growth Factor Production
Cancer cells can acquire the ability to produce the very growth factors that they normally respond to. The growth gene itself may not be altered mutated, but the products of other oncogenes (RAS) may cause over expression of growth factor genes
TGF-α
Growth Factor Production
sarcomas
Growth Factor Receptors
Oncogene expression can lead to increased numbers of growth receptors on the cell.
Mutations to receptors themselves can lead to continued growth signal activity, even in the absence of growth hormone presence.
Her2-neu (ErbB2)
Growth Factor Receptors
This is seen in high grade breast carcinomas causing over production of the receptor
RET
Growth Factor Receptors mutation
Multiple endocrine neoplasia syndromes 2A and 2B
PDGF
Growth Factor Receptors mutation
chronic monomyelocytic leukemia, t(5;12)
glioblastoma
FLT3
Growth Factor Receptors mutation
myeloid leukemias
Signal-Transducing Proteins
Alterations here are a common mechanism seen in malignancies that allows them to give continuous proliferation signals along the pathwayMany of these signaling proteins are associated with the inner aspect of the cell membrane
RAS
Signal-Transducing Proteins
≈20% of all cancers have RAS (KRAS, HRAS and NRAS) mutations, and the rate of this mutation is even higher in pancreatic and colonic cancers (the MOST COMMON oncogene abnormality known). This leaves the mutated RAS proteins in the ”activated” mode with continued signaling for cell growth. RAS gene mutations are commonly caused by point mutations in the “hot spots” around codons 12, 13 and 61
ABL
Signal-Transducing Proteins
A translocation in Chronic Myeloid Leukemia (CML) and several acute leukemias (t(9,22)
The Philadelphia Chromosome) removes the regulatory components and the BCR-ABL fusion product is a potent tyrosine kinase without the normal control components. The BCR-ABL fusion product also cannot enter the nucleus as the normal ABL product does. This results in a lack of apoptosis, another factor promoting abnormal cell accumulations.
Gleevec, an inhibitor of this tyrosine kinase, is used in the treatment of CML with great success.
Nuclear Transcription Factors
Mutations in genes controlling DNA transcription can result in autonomous cell growth.
The oncogene products MYC, MYB, JUN, FOS and REL have been localized to the nucleus
MYC
Nuclear Transcription Factors
Translocations like t(8;14), as seen in Burkitt lymphoma, remove the normal MYC inhibitory components. Amplification of MYC also occurs in breast, colon and lung cancers from formation of multiple gene copies, either homogeneous staining regions (HSR) or double minutes. Related N-MYC and L-MYC are amplified in neuroblastomas and lung carcinomas
Insensitivity to Growth-Inhibitory Signals
Loss of normal growth suppression gene products can lead to insensitivity to normal inhibitory signals
Adenomatous Polyposis Coli - β-Catenin Pathway
The active APC gene has anti-proliferative effects and acts to degrade β-Catenin which normally enters the nucleus and causes proliferation signals.
APC
Adenomatous Polyposis Coli - β-Catenin Pathway
Insensitivity to Growth-Inhibitory Signals -
The APC gene product is abnormal and not active, β-Catenin levels increase and the cell experiences increased proliferation signals. APC acts much like the RB gene and individuals with one abnormal gene are at risk for inactivation of the remaining APC gene.
APC mutations are seen in 70% to 80% of colon cancers. APC is a component of the WNT pathway.
Affected individuals develop hundreds to thousands of colon polyps when the second APC gene is mutated. Other additional mutations eventually lead to the development of invasive colon cancer.
TP53 (p53) Gene
Insensitivity to Growth-Inhibitory Signals -
A suppressor gene that is one of the most commonly mutated genes in human cancers. The gene has anti-proliferative actions and also exerts control on apoptosis (programmed cell death). p53 binds to damaged DNA and causes a cascade of actions that result in delay of the cell cycle, repair of damaged DNA (if possible) and resumption of the normal cell cycle
If the DNA cannot be repaired, p53 initiates the BAX apoptosis gene and cell death occurs. This defect is found in essentially all lung, colon and breast cancers. Inheritance of one mutant TP53 gene is found with the the Li-Fraumeni syndrome in which many types of cancer can develop. The TP53 gene and the RB gene can also be inactivated by viral proteins associated with HPV, HBV and +/- EBV. This may explain at least part of these viruses transforming properties.
Development of Sustained Angiogenesis -
Inactivation of TP53 leads to decreasing levels of thrombospondin-1, a potent inhibitor of angiogenesis.
Evasion of Apoptosis
Blocking normal apoptosis can lead to prolonged life of abnormal cells. Many genes have been associated control of apoptosis, including TP53, BAX, BAD, BID and BCL2. Therefore, many different mutations can effect apoptosis.
