Tumor suppressor and oncogene

How would you describe this R248W mutant variant compared to wt p53? 1 nucleotide change results in 1 amino acid change 3 nucleotide changes result in 1 amino acid change 3 nucleotide changes result in 3 amino acid changes 1 nucleotide change results in 3 amino acid changes

1 nucleotide change results in 1 amino acid change

How many allele hits do you think are required to block the function of p53 in a single cell, predisposing the cell to the development of cancer?

2

Sequence variant

A different version of a gene sequence from that of the most common consensus sequence for the species. There is some change/alteration in the nucleotide sequence compared to other nucleotide sequences obtained for that gene.

Variant of unknown significance

A functional effect of the sequence variant is not known.

How does P53 work?

A gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppression. It is very important for cells in multicellular organisms to suppress cancer. P53 has been described as "the guardian of the genome", referring to its role in conserving stability by preventing genome mutation

Oncology pharmacy fellow

A graduate with an advanced pharmacy degree (e.g. PharmD) pursuing additional training in therapeutic (drug) decisions and clinical outcomes of cancer patients. This training can involve treating patients, research, and teaching.

Pathogenic variant

A sequence variant that has been shown to be associated with disease

How/why might the R248W variant lose normal p53 function? This DNA binding domain point mutation may... A. Inhibit interaction of the mutant p53 protein with DNA target gene sequences B. Block the ability of the protein to properly fold into its normal 3-D confirmation C. Lead to increased protein degradation D. Alter structure in another domain to inhibit protein-protein interactions

A. Inhibit interaction of the mutant p53 protein with DNA target gene sequences While all of these are possibilities resulting in loss of function due to a point mutation, research on the R248W variant suggests the protein is stable and able to tetramerize, but loses DNA binding activity with p53 consensus sequences in the promoter region of p53 target genes

For severe cell stress signals, what does p53 do?

Apoptosis Cell senescence

While the R248W p53 mutant loses normal tumor suppressor function, how could the mutant also gain function in an oncogenic manner??

Binding to new target genes could also result in new or inhibited protein-protein interactions In this way, some p53 mutations can make p53 behave like an oncogene in addition to a tumor suppressor!

Describe the genetic basis of cancer

Cancer is a genetic disease at the cellular level Resulting from an accumulation of multiple hits (mutations) over time Mutations conferring tumor-promoting function are selected for as the cancer evolves

Central Dogma

DNA -> RNA -> Protein

Of all the domains of p53, which is more likely to have mutations that cause cancer?

DNA binding core domain

What are the emerging hallmarks of cancer cells?

Deregulating cellular energetics Avoiding immune destruction

FoundationOne genomic test

Example of a test that can be ordered by a doctor to identify genetic mutations from a cancer patient's tumor cells. This information is obtained by sequencing the cancer cell DNA (through use of next-generation sequencing technologies).

What are the enabling characteristics of cancer cells?

Genome instability and mutation Tumor promoting inflammation

What are the analysis steps in determining where the cancer originates?

Identify the mutation location and type (how is the sequence different from the wildtype sequence) Basic Local Alignment Search Tool: BLAST (select Nucleotide Blast) Determine if the DNA mutation alters the protein sequence ExPASy Translate Tool: Translate If the protein sequence is altered, compare the mutant and wildtype protein sequences Basic Local Alignment Search Tool: BLAST (select Protein Blast)

Analysis steps for mutant protein identification

Identify the mutation location and type (how is the sequence different from the wildtype sequence) Basic Local Alignment Search Tool: BLAST (select Nucleotide Blast) Determine if the DNA mutation alters the protein sequence ExPASy Translate Tool: Translate If the protein sequence is altered, compare the mutant and wildtype protein sequences Basic Local Alignment Search Tool: BLAST (select Protein Blast)

What does the sequencing of a cancer patient's DNA reveal?

It may show that mutations that may be driving cancer development/progression

Clinical therapeutics

Medical treatment given to patients

Which of the following describes a tumor suppressor gene mutation that would be consistent with increased risk of developing cancer? Mutation resulting in gain of function of the gene Mutation resulting in loss of function of the gene Mutation resulting in over-expression of the gene Mutation resulting in activation of the gene when it is not normally expressed

Mutation resulting in loss of function of the gene

What are the Cancer-relevant gene types?

Oncogene Tumor Suppressor

For mild stress signals in the cell, what does p53 do?

Provide antioxidant functions Cell cycle arrests DNA repair

Hallmarks of cancer cells

Sustaining proliferative signaling Evade growth suppressors Activating invasion and metastasis Enabling replicative immortality Resisting cell death Induce angiogenesis

Pharmacogenomics

This allows use of genetic information from the patient to guide treatment. However, here we will be examining genetic information specifically from the cancer patient's tumor cells.

Oncogene

This is a gain of function mutation. A singular cell mutation event can cause creates an oncogene in a normal cell. Activation of the mutation enables the oncogene to promote cell transformation.

Tumor suppressor gene

This is a loss of function mutation The mutation event inactivates the tumor suppressor gene. You need both alleles to be mutated in order to see cancer. The 2nd mutation event inactivates the second gene copy. 2 inactivating mutations functionally eliminates the tumor suppressor gene and promotes cell transformation

What is the function of ExPASy

Translate tool to get protein sequence. This will provide you with an amino acid sequence. You can take the amino acid sequence and compare it to another amino acid sequence in blast.

If we know the DNA sequence, then we know the protein sequence. T or F?

True

Personalized Medicine (aka Precision Medicine)

Use of genetic information from the patient to guide treatment decisions.

Which variant do you think is most likely to exhibit loss of function? A point mutation, deletion or a frameshift mutation that introduces a premature stop codon

frameshift mutation that introduces a premature stop codon

What is the form of p53?

p53 forms and functions as a homotetramer: A dimer of dimers