Lecture 5: Mutation and Cancer Flashcards
Gene Mutations Classification:
- mutations are inherited from a parent and are present throughout a person’s life in virtually every cell in the body
Inherited (germ line)
-These mutations are also called germline mutations because they are present in the parent’s egg or sperm cells, which are also called germ cells
Gene Mutations Classification:
- mutations occur at some time during a person’s life
- present only in certain cells, not in every cell in the body.
- These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division.
Acquired (somatic/sporatic)
Can genetic mutations in somatic cells (cells other than sperm or egg cells) be passed on the next generation?
No
What are the types of mutations at the chromosomal level?
- Deletions
- Duplications
- Inversions
- Translocations t[#,#]
d9p
Acute Lymphoblastic Leukemia
d13q14
Retinoblastoma
Rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common malignant cancer of the eye in children.
Retinoblastoma
Philadelphia Chromosome-
t(9:22)
Chronic Myelogenous Leukemia(CML)
most common variant: t(8;14)(q24;q32)
Burkitts Lymphoma
______ encodes a cytoplasmic tyrosine kinase
C-abl
____ promotes oligomerization
Bcr
________ fusion promotes activation of abl by oligomerization induced autophosphorylation.
Bcr-abl
Philadelphia chromosome –
translocation of chr ____ and ____
9, 22
-Translocation resulting in fusion of 2 genes with alters structure of normal c-abl protein
Burkitts Lymphoma-most Common Variant
T….
(8;14)(q24;q32)
Burkitts Lymphoma-most Common Variant
T(8;14)(q24;q32):
____ is brought under the
transcriptional control of the IG enhancer elements leading to its constitutive transcriptional deregulation.
MYC
Associated with the Epstein-Barr Virus (EBV) in nearly 100% of cases in endemic form in central Africa.
Burkitts Lymphoma
Burkitts Lymphoma:
In the sporadic forms (occur in Western countries), EBV is present in approximately ___% of cases and in ____% of immunodeficiency associated cases
30, 40
Type of mutation at the DNA level.
- transition (purine for purine, pyrimidine for pyrimidine)
- transversion (purine for pyrimidine)
Base substitutions (Point Mutation)
Mutation type at the DNA level leads to risk factor and/or risk marker in
disease
SNP
Type of mutations at the DNA level
- Base substitutions (Point Mutation)
- Frame shift mutation
- Deletion
- Insertion
- SNP (when leads to risk factor and/or risk marker in
disease)
Consequences Of Point Mutations
-Silent
-Missense*
-Nonsense-change to stop codon
Examples of Missense point mutation
hemaglobinopathies (sickle cell, T for A; glutamic acid to
valine)
Examples of nonsens-change to stop codon mutations
- Alpha thalassemias
-decreased protein produced (alpha vs beta globin)
-Constant Spring: from stop codon to glutamine @ 142 (TAA to
CAA) in alpha-thalassemia
from stop codon to glutamine @ 142 (TAA to
CAA) in alpha-thalassemia
Constant Spring
Fragile X: FMR-1(fragile -X mental retardation protein:
Premutation alleles generally considered to be between ____ to ____ repeats in length.
55, 200
Fragile X: FMR-1(fragile -X mental retardation protein:
Excessive amplification of a base triplet normally repeated only a few to 50 times, most commonly in the _____________.
5’ untranslated region of FMR1
Fragile X: FMR-1(fragile -X mental retardation protein:
Fragile X: FMR-1(fragile -X mental retardation protein: > _____ repeats of CGG)
200
Huntingtons Disease
Caused by the length of a repeated section (____, codes for _____) of a gene exceeding a normal range.
CAG, Gin
Huntington’s Disease:
The HTT gene is located at ________.
4p16.3
> 40 trinucleotide repeats – full penetrance ie. the proportion of individuals carrying a particular variant of a gene (allele or genotype) that also expresses an associated trait (phenotype)
Huntington’s Disease
Epstein-Barr virus, one of the herpes viruses:
Burkitt’s Lymphoma-involves the fusion of
c-myc, IGH
Epstein-Barr virus:
Causes infectious mononucleosis and linked to what two cancers?
non-Hodgkin lymphomas and nasopharyngeal cancer.
The cancer is thought to be due to the pro-oncogenic effect of viral DNA
incorporated into host lymphocyte DNA
Human T-cell Leukemia (HTLV-1)
Long-standing infection with the hepatitis ___ or ____ viruses can lead to cancer of the liver
B, C
The Kaposi’s sarcoma-associated herpesvirus (KSHV), is associated with
non-Hodgkin lymphoma
Early genes of HPV:
E6 —>
transforming protein; causes p53 degradation
Early genes of HPV:
E7 —->
transforming protein; interferes with Rb binding
HPV:
E___ being largely responsible for driving cell proliferation and E__ for enhancing cell survival
7, 6
HPV: the combination of E6 and E& is a very potent inducer of…
keratinocyte immortalization
Cancer:
a gene which in certain circumstances can transform a cell into a tumor cell.
Usually a gain of _______
Oncogenes
usually a gain of function and dominant
Cancer:
genes normally arrest cell
division.
Usually a loss of
Tumor suppressors
usually a loss of
function and recessive
Proto-oncogenes and oncogenes have italicized three letter designations, such as ____.
ras
An oncogene that occurs within a virus has the prefix “__”
* An oncogene that occurs within a cell has the prefix “__”
“v” v-ras
“c” c-ras
-Proto-oncogenes and oncogenes have italicized three letter designations, such as ras.
A protein that a c-proto-oncogene or c-oncogene encodes has the same
three letter designation as the v-proto-oncogene or v-oncogene.
However, the term is not ________, and the first letter is capitalized. Ras
italicized
Dominantly acting gene involved in up-regulated cell growth and
proliferation responsible for tumor development
Derived from normal cellular genes (by viral enhancement, mutation,
inappropriate overexpression) that function in cell growth and division
Oncogenes
Human Oncogenes:
sis function?
growth factor, platelet-derived growth factor
(breast cancer)
Human Oncogenes:
Her-2/neu (receptors) function?
protein kinase
(breast cancer)
Human Oncogenes:
abl (intracellular signaling) function?
tyrosine kinase
(chronic myeloid leukemia)
Human Oncogenes:
N-ras (intracellular signaling) function?
signal transduction
(many cancers)
Human Oncogenes:
c-myc (nuclear protein) function?
nuclear protein, initiate cell cycle
(leukemia, Burkitt’s lymphoma)
Locations of proto-oncogenes?
can be present in any chromosomes
Code for proteins that regulate cell-cycle progression, and hold cells in quiescence or induce apoptosis if conditions are unfavorable for cell cycle progression
Tumor Suppresser Genes (Anti-oncogenes)
mutation in P__ alteration is associated with almost all cancers
53
Two tumor suppressor genes?
-Retinoblastoma (Rb)
-p53
Knudson hypothesis is also know as….
two-hit hypothesis or multiple-hit hypothesis
cancer is the result of accumulated mutations to a cell’s DNA
Knudson Hypothesis
Knudson’s hypothesis refers specifically to the _______________ of tumor
suppressor genes. A mutation in both alleles is required, as a single
functional TSG is usually sufficient.
heterozygosity
Carcinogenesis (the development of cancer) depended both on…
the activation of proto-oncogenes (genes that stimulate cell proliferation)
and on the deactivation of tumor suppressor genes (TSG), which are genes that keep proliferation in check
Retinoblastoma (Rb) –> deletion in…
long arm (q) of chromosome
13 (d13q14)
Retinoblastoma (Rb):
is a tumor suppresser that controls the cell cycle
Retinoblastoma protein (RB)
Retinoblastoma is inherited how?
autosomal recessive inheritance
What are the two forms of Retinoblastoma?
Inherited form:
* one chromosome has deletion
* second copy lost by somatic mutation
Sporadic form: both copies lost by individual somatic mutations
Normal Functions Of TP53 Protein…
G1 growth arrest
Induces apoptosis following DNA damage
Inhibits tumor cell growth
Inhibits S phase
Represses transcription factors for growth and
replication
Cancer may involve deletion, mutation, or functional
Cancer causes:
Point mutation within the proto-oncogene (RAS-____)
GTP
Cancer causes:
Genetic rearrangements
within the coding sequence of the proto-oncogene (c-____ in CML)
Genetic rearrangements outside the coding sequence of the protooncogene
(c-____ Burkitt’s Lymphoma)
abl/bc
abl/bc
Cancer causes:
Amplification and/or over expression of the proto-oncogene
insertion of a strong viral ________
gene copy number variation
promotor
Mutations outside of the structural gene may cause over expression
(high enhancer binding, decreased repressor binding)
Epigenetic overexpression of genes
Other Causes Of Cancer:
The formation of new blood vessels
. Tumors need blood vessels to grow and spread.
The physiological process through which new blood vessels form from pre-existing vessels.
Different from vasculogenesis, which is the de novo formation of endothelial cells from
mesoderm cell precursors
Angiogenesis
-VEGF, VEGF-R, angiopoietin-2, Tie1, Tie2 etc
TSP-1, TSP-2 and
Angiostatin
Angiogenesis inhibitors for cell migration, proliferation, adhesion
*BRCA1, BRCA2
Breast and ovarian cancer
*bcr-abl
chronic myelogenous leukemia
*bcl-2
B-cell lymphoma
*HER2/neu (erbB-2)
breast cancer, ovarian cancer, others
*N-mye
Neuroblastoma
*EWS
Ewing tumor
*C-myc
Burkitt lymphoma, others
*p53
Brain tumors, skin cancers, lung cancer, head and neck cancers, others
*MLH!, MSH2
colorectal cancers
*APCC
colorectal cancers
*RBI
Retinoblastoma (many different cancers)
*P53
Li-Fraumeni Syndrome (sacromas, brain tumors, leukemia)
-many different cancers
*INK4a
Melanoma (many different cancers)
*APC
Colorectal cancer (due to familial polyposis)
-most colorectal cancers
*MLH1, MSH2, or MSH6
Colorectal cancer (without polyposis)
-colorectal, gastric, endometrial cancers
*BRCA1, BRCA2
Breast and/or ovarian
(only rare ovarian cancers)
*WTI
Wilms Tumor
*NF1, NF2
Nerve tumors, including brain
-small numbers of colon cancers, melanomas, neuroblastomas)
*VHL
Kidney cancer
-certain types of kidney cancers)
For the most part, cancer arises from a single cell, that is, cancer is a _________ disease. The average human being contains about 1014
cells (i.e., 100,000,000,000,000 cells), any one of which could, in
principle, become a cancer cell, if it acquired the right sort of mutations while it still had the potential to proliferate.
clonal
Therefore, the cancer cell arises and progresses once out of a
possible 10 14 cellular targets. That only happens in 1 in 3 people.
Even then it usually takes 60 or 70 years to occur.
