cancer genetics Flashcards
familial cancer
inherited from family …
family has a predisposition through a germ line mutation
which increases the prob that further mutations will occur
sporadic cancers
new mutations arising in the somatic cells of the body
properties of cancer calls
autocrine stimulation: grow in the absence of growth factors
lack of gap junctions: lack of “communication”
resistance to cell death
rapid growth: presistent telomerase activity
angiogenesis: capilary growth
clonal
accumulation of successive mutations
cell proliferation rates
slow : bone nervous system
fast: RBC
age dependent proliferation: retinoblast
oncogenes
Genes that induce cell division . Gain of function
mutations
Mutations results in abnormal stimulation of cell division
and proliferation
They are dominant so single mutation i sufficient to cause change
tumor suppressor genes
–Genes that suppress cell division
Loss
of function mutations.
pro- and anti-apoptotic
A related category is genes that induce cell death through a
program called apoptosis.
Chromosomal translocations
cause mis-expression of
genes or create chimeric genes also cause cancer
MEN2
Multiple Endocrine Adenomatosis, Type 2
mutation in the RET( tyrosine kinase)
gain of function causes cancer of endocrine glands (thyroid and endocrine)
burkitt lymphoma
t(8;14) affects MYC casues more proliferation
Translocation of cmyc from chromosome 8 to chromosome 14, adjacent to the immunoglobulin heavy chain gene locus. Overexpression of cMyc.
Chronic Myelogenous Leukemia
(Philadelphia chromosome): t(9; 22) (q34; q11): BCR-ABL chimeric gene, has tyrosine kinase activity.
Acute Promyelocytic Leukemia
t(15;17)(q22;q11): PML-RARα chimera
characterized by a proliferation of malignant
promyelocytes in the bone marrow
PML–RAR has dual effects.
– It causes apoptosis resistance.
– it blocks the transcription of RAR target genes. PML–RAR
homodimers bind tightly to transcriptional corepressors, which
attract histone deacetylases (HDACs)
Follicular B-cell Lymphoma
Primary abnormality in B-cell lymphoma is over expression of the anti-apoptotic protein, Bcl-2, caused by a t(14,18)(q32q21) translocation.
Bcl-2 prevents release of cytochrome c, an essential component for apoptosis.
• Translocation brings Bcl-2 under the control of the
immunoglobulin heavy chain locus and the Bcl-2 locus.
telomerase as oncogene
telomerase is a reverse transcriptase responsible for lengthening telomeres
Telomerase activity dwindles with every cell cycle eventually causing cell death
telomerase expression reappears in cancer cells indefinitely
Two hit hypothesis
retinoblastoma as an
example: hereditary vs. sporadic forms: bilateral,
early onset for the former, unilateral, late onset for
the latter.
• Second hit is mostly a somatic mutation, mostly
caused by Loss of heterzygosity.
mechanisms of second mutation
can happen via
epigenetic silencing
mutations
somatic recombination
loss and duplication
chromosome loss
Cancers caused by Tumor Suppressor
Gene Mutations
familial polyposis coli,
breast cancer, hereditary non polyposis colon carcinoma
and Li-Fraumeni syndrome involve tumor suppressor
genes
Retinoblastoma
loss of function tumor suppressor gene
can cause other cancers with one additional mutation
RB1
p110 cell cycle regulation
gate keepers
directly regulate genes
eg p53 and retinolblastoma
caretakers
a defect in a caretaker is not likely to provide a selective advantage but rather leads to mutaitons of gatekeepers
Regulation of G1 to S
Progression by
Retinoblastoma Protein
pRB binds to transcription factors inhibiting from binding to DNA inhibing transcription from G1–>S
cyclin cdk phosphoralates pRB and frees up the transcription factors which activiates transcription
pRB mutated causes no supression of trancription factors to DNA
P53
gatekeeper
DNA binding protein important in cellular
response to DNA damage.
also triggers apotosis pathway if too much damage
Loss of p53 thereby allows cells with damaged
DNA to survive and divide
Mechanism of
G1 Arrest
Caused by DNA
Lesions
p53–> promoter –>activates WAF1—> produces p21(cdk inhibitor) —–> makes complex with cyc cdk and causes blockade transition from g1 ti S due to no phosphorylation of pRB
Apoptosis
A trigger sets off a series of events, including:
– cell shrinkage
– activation of endonucleases that chew up DNA
– mitochondrial damage that prevents energy generation
– activation of a class of proteases called caspases that
proteolytically cleave intracellular proteins required for
cellular function and infrastructure.
– The cells are engulfed by neighboring cells and
macrophages without generating an inflammatory
response.
Familial Breast Cancer: BRCA1 & BRCA2
BRCAmutations account for a majority of autosomal dominant familial
breast cancer Caretaker genes tummor suppressor genes take part in DNA repair
Hereditary non polyposis colon cancer
Inheritance:autosomal dominant. Group of 5 similar cancersyndromes, caused by one of 5 distinct DNA repair genes:
MLH1, MSH2, PMSL1, PMSL2, MSH6
Caretaker genes. Two hit hypothesis in play. Result is
genomic instability and mutations of other genes.
