HRR: cancer genetics and genomics I Flashcards
What are the 4 functional classes of genes to which mutation can cause malignant transformation
- proto-oncogenes
- tumor suppressor genes
- DNA repair genes
- apoptosis genes
what are somatic mutations
Non-heritable mutations that do not pass down; could be from smoking or sun damage
what are germline mutations
These are heritable, as they occur in the germline. This also means all cells will be impacted.
What is a gain of function mutation
This is usually found in proto-oncogenes, and only one copy needs to be mutated. The mutation confers enhanced or new activity of a protein.
What is a loss of function mutation
This is usually found in tumor suppressor genes, and a defect in both copies is needed. The mutation results in reduced or abolished protein function
What are passenger mutations
Mutations found in the tumor that don’t really play a role
What are driver mutations
Occur in cancer-related genes and are presumed to be involved in the development or progression of the cancer
Describe proto-oncogenes
These promote survival and growth of cells. When they have a gain of function mutation, they are driver-mutations and are activated oncogenes. These are often dominant and only require one mutation.
Ras and BRAF are examples of…
proto-oncogenes
The most common mutations in
proto-oncogenes are…
constitutive action; this means the proto-oncogene becomes an oncogene that proliferates and behaves independant of regular stimuli and signalling
Define tumor suppressor gene
they inhibit cellular proliferation in response to stimuli such as damage. When activated via a loss-of-function mutation, they can lead to cancer. These are often recessive and require issues in both alleles.
Describe the CDKN2A gene
It encodes two tumor suppressor genes: p14 and p16.
Describe the action of p14
P14 activates the p53 pathway, leading to cell cycle arrest in damaged cells
Describe the action of p16
it inhibits CDK4 and CDK6, preventing phosphorylation of Rb. when Rb is phosphorylated, it releases from E2F, which translocates to the nucleus and promotes transcription and thus movement from G1 to S. p16 inhibits this movement.
What is the “guardian of the genome”
p53
What does the TP53 gene encode
P53, a really important tumor suppressor gene
Mutations and epigenetic changes accumulate in cell lineages via…
Clonal selection and expansion
What is tumor growth dependent on
Their ability to develop blood supply to continue to feed the growing population of cells
Describe exon 14 skipping
Alternative splicing results in the exclusion of exon 14 out of the MET gene. This leads to impaired receptor degradation/accumulation of MET and increases downstream signaling. This will lead to oncogenic transformation, often seen in lung cancer
Describe the Philadelphia chromosome
A fusion gene resulting from translocation between chromosomes 9 and 22 that encodes BCR-ABL1 fusions. BCR-ABL1 is a tyrosine kinase, and this mutation causes enhanced activation of the kinase and increased downstrea signalling. This is often seen in CML.
Describe MYC
A proto-oncogene that gets translocated upstream of immunoglobulin heavy chain locus. This results in strong constitutive promotion and drives MYC expression. MYC encodes a protein involved in many processes, and ultimately leads to increased proliferation. This is often seen in Burkitt lymphoma
Describe the rationale behind targeted therapies
It is thought that some tumors rely on a single dominant oncogene for growth and survival, known as oncogene addiction. The thought is that if we can target the specific oncogene, the tumor will shrink. However, this does not hold up in all cancers.
The most inherited variants that contribute to familial syndromes are __ genes
tumor suppressor
What are denovo mutations
New mutations occurring during the formation of germ cells. This results in unaffected siblings and an absence of mutation in maternal tissues. You would not see a family history.
What is the two-hit hypothesis
Cancer requires two genetic events to initiate oncogenic transformation. The inherited mutation is the first event, and the second event often occurs early in life.
Describe loss of heterozygosity in terms of oncogenic transformation
After inherited mutation, an issue forming a defective copy of the second (non-mutated) allele at some point after birth is necessary for tumor development.
Name the ways we can develop loss of heterozygosity
Chromosome loss, deletion, unbalanced translocation, loss and replication, mitotic recombination, point mutation, methylation
What is the typical age of onset for familial cancers
early age of onset
What pattern is seen in paired organs in familial cancer
Bilateral distribution
What is the typical inheritance pattern seen in familial cancer syndromes
Autosomal dominant
What distribution among the family is used to classify familial cancers
Same cancer in two or more close relatives on the same side of the family
If an individual gets two rare cancers back to back, what does this mean
They likely have a familial cancer syndrome
Evidence of autosomal dominant transmission of a cancer indicates what?
familial cancer syndromes
