Lecture 5: Mutation and Cancer Flashcards by Sarah King

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

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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)

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Can genetic mutations in somatic cells (cells other than sperm or egg cells) be passed on the next generation?

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What are the types of mutations at the chromosomal level?

Deletions
Duplications
Inversions
Translocations t[#,#]

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d9p

Acute Lymphoblastic Leukemia

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d13q14

Retinoblastoma

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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

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Philadelphia Chromosome-
t(9:22)

Chronic Myelogenous Leukemia(CML)

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most common variant: t(8;14)(q24;q32)

Burkitts Lymphoma

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______ encodes a cytoplasmic tyrosine kinase

C-abl

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____ promotes oligomerization

Bcr

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________ fusion promotes activation of abl by oligomerization induced autophosphorylation.

Bcr-abl

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Philadelphia chromosome –
translocation of chr ____ and ____

9, 22

-Translocation resulting in fusion of 2 genes with alters structure of normal c-abl protein

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Burkitts Lymphoma-most Common Variant
T….

(8;14)(q24;q32)

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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

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Associated with the Epstein-Barr Virus (EBV) in nearly 100% of cases in endemic form in central Africa.

Burkitts Lymphoma

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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

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Type of mutation at the DNA level.

transition (purine for purine, pyrimidine for pyrimidine)
transversion (purine for pyrimidine)

Base substitutions (Point Mutation)

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Mutation type at the DNA level leads to risk factor and/or risk marker in
disease

SNP

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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)

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Consequences Of Point Mutations

-Silent
-Missense*
-Nonsense-change to stop codon

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Examples of Missense point mutation

hemaglobinopathies (sickle cell, T for A; glutamic acid to
valine)

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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

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from stop codon to glutamine @ 142 (TAA to
CAA) in alpha-thalassemia

Constant Spring

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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

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.