Elements of genetics Final exam

When does cancer begin?

begins at the first cell that has lost the ability to function normally

benign

a population of cancer cells that are constrained to the tissue of orign

malignant

a population of cancer cells that have spread to other tissues and/or organs

metastatic

a population of cancers cells that have travelled through the blood or lymph system and have formed in other distant organ systems

cancer

uncontrolled cell division

How is cancer classified?

classified by the original cancerous cell and its organ of origin

Apoptosis

programmed cell death

Proto-oncogenes

code for proteins that stimulate normal cell growth and division, kills cells before they enter the cell cycle

tumor suppressors

regulate mitosis by pausing the cell cycle

oncogenes

proto-oncogenes that have a GOF mutation causing the cell growth pathway to be permanently ON

LOF mutation in tumor suppressors

causes uncontrolled cell division, mush have 2 LOF alleles for cancer to be present

Three types of mutation that turn proto-oncogenes to oncogenes

1. Missense mutation

2. Gene amplification

3.Chromisonal translocation

ras proto-oncogene

an active ras enzyme promotes cell division by binding to GTP, an inactive ras enzyme is resting by binding to GDP, a missense mutation can cause ras to be permanently ON

chromosomal translocation

When part of one chromosome breaks off and attaches to another non homologous, chromosome. For cancer, a super enhancer binds to a non homologous chromosome causing on oncogene

Philadelphia chromosome

the protooncogene abl (on chromosome 9) translocates to chromosome 22 and attaches to the super enhancer ber which causes cancer

what cancer does the Philadelphia chromosome cause?

chronic myelogenous leukemia (CML)

Familial cancers are usually caused by tumor suppressors or oncogenes?

tumor suppressors

retino blastoma

a tumor suppressor (LOF) that causes eye cancer, young children can get eye cancer because retinoblastoma is often familial, works with E2F

E2F

a proto-oncogene that promotes cell division, is controlled by retinoblastoma

2 hit model

for tumor suppressors to cause cancer there must be 2 LOF alleles present in the genome. One LOF could be familial (germline cells) and one sporadic (somatic cells) or both could be sporadic

BRCA1

a tumor suppressor important for DNA repair, is on a mutation hotspot

What cancer is associated with E2F?

eye cancer (retinoblastoma)

What cancer is BRCA1 associated with?

breast and ovarian cancer

What was the 1st tumor suppressor gene to be discovered?

retino blastoma

What was the second tumor suppressor gene to be discovered?

p53

p53

a tumor suppressor that determines if a cell has incurred DNA damage, is a pleiotropic master regulator thus controls many other genetic codes

which tumor suppressor is responsible for over 70% of all human cancers?

p53

Environmental mutagens can cause what in p53?

double stranded breaks

Three things that p53 transcription factor does?

Activate genes that...

1. promote DNA repair (BRCA1)

2. arrest cell division (ras or E2F)

3. promote apoptosis (caspase-10)

Three things that happen in apoptosis?

1. cell shrinkage

2. chromatin condensation

3. DNA degradation

What is apoptosis facilitated by?

by genes or protease known as caspases or cell executors

caspase-10

a tumor suppressor that promotes apoptosis, has p53 binding sites

Three ways tumor suppressor genes can be lost?

1. any classical LOF mutation (i.e. nonsense or CRE 5'UTR=3'UTR)

2. DNA methylation (inhibits transcription)

3. aneuploidy (chromosome loss)

what is the second most common cancer in the US?

colorectal cancer

What tumor suppressor is correlated with colorectal cancer?

APC

True or false, the order in which mutations occur in cancer is fixed?

False, any mutation can happen at any stage and no two cancer cells will be identical

proto-oncogenes we need to know

1. ras

2. abl

3. EGFR (EGF receptor)

4. E2F

tumor suppressors we need to know

1. p53

2. retinoblastoma

3. caspase-10

4. BRCA1

5. APC

What epigenetic modifications can lead to cancer?

DNA METHYLATION, histone modifications, chromatin remolding

What environmental agents lead to cancer?

1. polycyclic aromatic hydrocarbons

2. benzene

3. endocrine disruptors

4. cadmium

5. nickel

6. arsenic

What cancers are associated with polycyclic aromatic hydrocarbons?

lung, breast, stomach, and skin cancers

What cancers are associated with benzene?

leukemia, lymphoma, and multiple myeloma

What cancers are associated with endocrine disruptors?

breast, prostate, and thyroid cancers

What cancers are associated with cadmium?

lung and breast cancers

What cancers are associated with nickel?

lung and nasal cancers

What cancers are associated with arsenic?

skin, bladder, kidney, and liver cancers

demethylation occurs in which type of gene?

proto-oncogenes, becomes an oncogene

methylation occurs in which type of gene?

tumor suppressors, becomes LOF

How can hox genes cause cancer?

hox genes are only met to be ON during embryonic life thus if they are demethylated later on in life then they cause GOF mutations thus leading to cancer, associated with many cancers

CpG islands

section of DNA that contains many cytosine and guanine nucleotides, the region on DNA that becomes methylated/demethylated

euchromatin

unmethylated, transcription is ON

heterochromatin

methylated, transcription is OFF

How to scientists find the function of a genomic locus?

1. they "knock out" a single genomic locus in the genome and observe the phenotypic effect, this is a LOF method

2. they use dominate negative receptor mutation to create competition, this is GOF

Three things that happen in a KO experiment?

1. the phenotype changes or disappears

2. it's embryonic lethal

3. there is no effect due to paralogs

dominate negative receptor mutation

a genomic locus is changed to have partial function yet over expression, this creates competition for resources thus the locus being studied is not expressed (GOF)

what does the Cas enzyme do in bacteria?

helps RNA snip specific pathogens out of the DNA

How do humans use CRISPE/Cas 9 DNA editing?

use this enzyme to snip out specific portions of DNA to create LOF/GOF mutations or restore the wildtype (normal) DNA sequence

Which nucleotides does the Cas9 RNA complex recognize?

PAM= 5'NGG, where N is any nucleotide (A,C,G,T)

What does PAM stand for?

protospacer adjacent motif (NGG)

How can immunology help treat cancer?

it uses T cells mortified with CRISPR to seek out cells with the NY-ESO-1 marker and kills the effected cells

B lymphocytes

secrete antibodies when paired with a microbe

helper T lymphocytes

initiate immune response by activating macrophages and B lymphocytes

cytotoxic (killer) T lymphocytes

kill antigens or effect cells

How are T cell modified with CRISPR?

CRISPR adds a NY-ESO-1 receptor to killer T cells

Why do PDC1, TRAC, and TRBC have to be delated for immunotherapy to work?

they interfere with the NY-ESO-1 receptor on the killer T cells limiting cancer killing abilities

What must cancer cells have to be treated with immunotherapy?

an NY-ESO-1 marker

Why don't elephants get cancer?

they have extra paralogs of p53

What does SNP mean?

single nucleotide polymorphism

What is an SNP (single nucleotide polymorphism)?

Are the most common type of genetic variation among people. Represents a variance in a single nucleotide

Why do oncogenes rarely cause familial forms of cancer?

oncogenes are GOF thus only one affected allele is needed to cause cancer which is likely lethal at a very early stage in life

What is loss of heterozygosity (LOH)?

the genome goes from having one functional allele and one non functional allele to have no functional alleles

In familial cancers which kind of cell does the first hit occur in?

germline cells

Peto's Paradox

No correlation between body size and cancer between species

What do scientist need to know in order to preform CRISPR editing?

the DNA sequence

missense (nonsynonymous) mutation

A point mutation (nucleotide substitution) that causes an amino acid replacement (GOF or LOF)

Silent (synonymous) mutation

a point mutation that does not change the amino acid produced, has no effect

nonsense mutation

A point mutation that changes an amino acid codon to one of the three stop codons, resulting in a shorter and usually nonfunctional protein (LOF)

deletion mutation

a frameshift mutation in which one or more pairs of nucleotides are removed from a gene (LOF)

insertion mutation

a frameshift mutation in which one or more nucleotides are added to a gene (LOF)

duplication and expanding mutations

a frameshift mutation that causes one base pair or codon to multiply in the genome (GOF or LOF)

promoter mutation

a mutation in the CRE that increases or decreases the rate of transcription (GOF or LOF)

Regulatory element/operator site mutation

mutation in the CRE that disrupts the ability of the gene to be properly regulated (LOF)

5'UTR/3'UTR mutation

a CRE mutation that alters the ability of mRNA to be translated, many alter mRNA stability (LOF)

splice recognition sequence mutation

a CRE mutation that alters the ability of pre-mRNA to be properly splice (usually LOF)

Consider the following DNA sequence, which codes the first portion of a long protein beginning at the ATG (AUG in mRNA) start codon.

5' ATG CCC CGC AGT AGG GGG TGG AGA 3'

Which of the mutated sequences listed is most likely to be a deleterious mutation?

1. 5' ATG CCC CGC AGT AGG GAG TGG AGA3'

2. 5' ATG CCG CGC AGT AGG GGG TGG AGA3'

3. 5' ATG CCC CGC AGT AGG GGG TGA AGA3'

3. 5' ATG CCC CGC AGT AGG GGG TGA AGA3'

Which of the following is not an example of a cause of a spontaneous mutation?

1. tautomeric shifts

2. UV light

3. DNA replication errors

4. transposable elements

5. aberrant recombination

2. UV light

Beechdrops is a parasitic plant that cannot perform photosynthesis but relies on its host the Beech tree. However, beechdrops still retains many if not all of the genes for photosynthesis. Snapdragons and gladiolas are common garden flowers that rely on their ability to perform photosynthesis. If you were to compare the gene sequences for these three plants for ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) a protein necessary for photosynthesis what would you predict?

1. The differences between gladiolas and snapdragons would most likely be in the second nucleotide of codons while beechdrops would have a higher number of mutations in the third nucleotide of the different codons

2. The differences between gladiolas and snapdragons would most likely be missense mutations while those in beechdrops may be silent or missense

3. The differences between gladiolas and snapdragons would most likely be silent mutations while those in beechdrops may be silent or missense

4. Since these three plants are not highly related the sequences for RuBisCO would be very different between them

3. The differences between gladiolas and snapdragons would most likely be silent mutations while those in beechdrops may be silent or missense

For this question, match the types of mutation with the correct definition.

____ Changes a single amino acid in the protein

____ Converts an amino-acid codon to a termination codon

____ Involves the addition or deletion of nucleotides

____ When a change in a single amino acid does not have a noticeable effect on the protein

____ Does not involve a change in the amino acid structure of the protein

Missense - Changes a single amino acid in the protein

Nonsense - Converts an amino-acid codon to a termination codon

Frameshift - Involves the addition or deletion of nucleotides

Neutral - When a change in a single amino acid does not have a noticeable effect on the protein

Silent - Does not involve a change in the amino acid structure of the protein

The term that indicates that cancer has begun to migrate to other parts of the body is _________blank.

1. malignant

2. clonal

3. metastatic

4. invasive

5. benign

1. metastatic

Epigenetics may play a role in cancer by

1. directly inducing inversion mutations.

2. causing a change in gene expression patterns.

3. causing translocations.

4. directly resulting in gene deletions.

causing a change in gene expression patterns.

The general function of the p53 protein could be described as

1. a negative regulator of cell division.

2. maintaining genome integrity.

3. a positive regulator of cell division.

1. maintaining genome integrity.

What kind of mutation would be expected both within oncogenes and tumor suppressor genes that would result in gain-of-function or loss-of-function, respectively?

1. Silent

2. Neutral

3. Amplifications

4. Missense

Missense

A gene that promotes the development of cancer when it sustains a gain-of-function mutation is called a

1. caretaker gene.

2. proto-oncogene

3. housekeeping gene.

4. tumor suppressor gene.

1. proto-oncogene

What are the general ways that tumor suppressors and oncogenes act?

1. Tumor suppressors inhibit the cell cycle and oncogenes stimulate the cell cycle.

2. Oncogenes inhibit the cell cycle and tumor suppressors stimulate the cell cycle.

3. Both tumor suppressors and oncogenes stimulate the cell cycle.

4. Both tumor suppressors and oncogenes inhibit the cell cycle.

1. Tumor suppressors inhibit the cell cycle and oncogenes stimulate the cell cycle.

Complete each sentence with the appropriate term

If both alleles of a gene from a tumor cell have nonsense mutations that occur very soon after the initiation codon then this gene is probably an example of a(n) ____ gene.

tumor-suppressor

Complete each sentence with the appropriate term

One of the differences between oncogenes and tumor-suppressor genes is that for oncogenes to play a role in tumor development ____ allele has to be mutated while with tumor-suppressors ___ alleles have to be silenced or mutated.

one; both

Complete each sentence with the appropriate term

The src gene, isolated from _____ , was the first example of a(n) ____

RSV; oncogene

A loss-of-function mutation in what type of gene can lead to cancer?

Multiple Choice

1. Oncogene

2. Landscaper

3. Tumor suppressor

4. Growth factor

1. Tumor suppressor

A _________blank is a normal cellular gene that through a _________blank mutation becomes an oncogene.

Multiple Choice

1. tumor-suppressor gene; loss-of-function

2. proto-oncogene; loss-of-function

3. tumor-suppressor gene; gain-of-function

4. proto-oncogene; gain-of-function

1. proto-oncogene; gain-of-function

What are the common types of mutations that occur to convert proto-oncogenes to oncogenes?

Check All That Apply

1. Missense

2. Amplifications

3. Nonsense

4. Silent

5. Hypermethylation of promoter sequences

1. Missense

2. Amplifications