Download Genetics Objectives 20

Genetics Objectives 20
A.
Cancer Biology:
1.
Unique characteristics of cancer for malignant phenotype:
a.
Uncontrolled, limitless proliferation
b.
Impaired apoptosis pathways
c.
Differentiation arrest and clonal expansion
d.
Invasion and metastasis
e.
Angiogenesis
2.
Histopathologic classifications of human cancer:
a.
Carcinoma: epithelial tissues in adults
b.
Sarcoma: mesenchymal tissues in children
c.
Leukemia/lymphoma: hematopoietic tissues in both children and adults
3.
Differentiation arrest and clinical behavior: tumor progression occurs with
differentiation arrest, and clinically, this can be used to determine the tumor tissue
of origin. This can be advantageous in PCR screening because cancer cells will
all leave the same characteristic banding pattern, and can be detected in low
amounts with PCR amplification.
Clonal evolution and clinical behavior: as tumors progress from a single cell,
they become heterogeneous with higher than normal mutation rates. Cells that
have defects in DNA repair and an ability to tolerate severe chromosomal defects
are selected for by clonal evolution, and increases malignancy of the developing
tumor. However, this malignant phenotype also makes tumor cells more
susceptible to DNA damaging chemotherapeutic agents because they continue
progressing through the cell cycle with a fatal amount of damaged DNA.
4.
Mechanisms of cancer resulting in altered DNA: cancer causes alter DNA in
many fashions:
a.
Excision repair: Xeroderma Pigmentosa
b.
Mismatch repair: Hereditary Non Polyposis Colon Cancer
c.
Cell cycle checkpoint: Ataxia Telangiectasia
d.
Chromosome instability: Fanconi’s Anemia, Bloom’s Syndrome
e.
Mutagenicity: UV rays, X-rats, Aflatoxin, Tobacco smoke
f.
Stimulation of growth: Estrogen
g.
Chronic inflammaion: Asbestos
h.
Viral oncogenesis: Papillomaviruses, Hepatitis B and C, Epstein-Barr
virus, HTLV-1, HIV
B.
Oncogenes and Tumor Suppresor Genes:
1.
Oncogene: a gene that leads to tumorigenesis
Proto-oncogenes and contribution to oncogenesis: proto-oncogenes are
oncogene precursors that when overactivated, lead to increased susceptibility to
tumorigenesis
2.
Tumor suppressor gene identification: identified using RFLP analysis looking
for loss of heterozygosity
Tumor suppressor inactivation and cancer development: a tumor suppressor
gene prohibits uncontrolled proliferation; loss of function of this gene results in
uncontrolled proliferation and development of cancer
3.
Oncogenic tumorigenesis: oncogenic tumorigenesis occurs when a protooncogene is activated, and activity of a protein signaling cascade increases. This
occurs in humans in three manners: a mutation in the coding sequence leading to
a hyperactive protein made in normal amounts (RAS, RET), gene amplification of
a normal protein made in large amounts (MYC, ERB-B2), or a chromosomal
rearrangement leading to either hyperactive proteins or mass production of a
normal protein (BCR-ABL, MYC, BCL-2)
Tumor suppressor tumorigenesis: caused when a tumor suppressor gene is
inactivated, and activity of a protein signaling cascade increases. This occurs in
humans in many ways: transcriptional regulation (Rb), transcription factor loss
(p53, BRCA-1), altered cadherin signaling (APC), GTP-ase activator (NF-1),
inhibition of transcription elongation (VHL), and problems in DNA repair
(hereditary non-polyposis colon cancer)
 Note: Refer to the table on page 10 of lecture for a good comparison of
oncogenic and tumor suppressor tumorigenic characteristics
4.
Genetic instability origin and contribution to oncogenesis: genetic instability
originates from mutations that allow the cell to divide when the chromosome is
altered. This allows cells to survive for more generations because normally, cells
will age and incur chromosomal damage before apoptosis. In cancer, when this
occurs, the cells block apoptosis and continue to divide, making the cells capable
of infinite cell divisions and tumorigenesis.
 Note: the notes reference two major causes of genetic instability:
o p53: a cell cycle checkpoint that arrests the cell cycle when DNA
damage is detected. In the absence of p53, the cell can proliferate
with DNA damage, leading to genetic instability
o Telomerase: if a cell line is proliferating rapidly, the telomeres of
the cell shorten, and the cell will ultimately have severe DNA
damage due to chromosomal joining during mitosis and subsequent
breakage of chromosomes during anaphase. Telomerase activation
protects against this by adding base pairs back to telomers after
cellular division, thus protecting cancerous cells from severe DNA
damage that would ultimately result in cell death.
C.
Molecular Oncology:
1.
Multi-step carcinogenesis: since cancer is not often caused by a single mutation
in a proto-oncogene or tumor suppressor gene, carcinogenesis must be described
on a wide spectrum ranging from relatively benign hyperplasia to severe
carcinoma. The “steps” between hyperplasia and carcinoma represent the multistep process of carcinogenesis
Implications for prevention/treatment: since advanced malignancies are
difficult to treat, it is important to treat cancer early, and with preventative agents
in at-risk populations.
2.
Molecular complexity of pathogenesis and therapeutic hindrance: since
advanced malignancies have a host of cells with different mutations, often one
type of therapy proves unsuccessful, leaving behind malignant cells not targeted
by the therapy. Also, in advanced malignancies, cells may no longer require
initiation of genetic defects, and targeting cancerous cells in this manner may be
rendered ineffective.
3.
Clinical application of molecular genetics for diagnosis/staging of cancer:
PCR assays screening for tumor-specific genetic alterations has allowed for
earlier, more accurate diagnoses while detecting smaller amounts of cancerous
cells.
4.
Cancer treatment development for tumor-specific genetic alterations:
knowledge of a tumor-specific genetic alteration can alter therapy based on the
specific genetic alteration. Procedures that utilize this knowledge include
manufacturing of antibodies specific for a tumor-specific antigen, molecularly
targeted drugs that affect tumor-specific molecules, and gene therapy that inserts a
specific, normal gene in place of a tumor-specific mutated gene.