Topic 8: Cancer genetics Flashcards
what are some important concepts from the pre-molecular era?
- Cancer is a disease of the cells
- Cancer involves changes in DNA
- Cancer cells have become immortalized
- roperties of cancer cells are transmitted from
parental to daughter cells - Carcinogens are physical and chemical agents
that cause mutations - Some viruses can cause cancer
what are emerging hallmarks of cancer?
deregulating cellular energetics and avoiding immune destruction
what are enabling characteritics in cancer?
genomic instability and mutation & tumor-prooting inflammation
what are the hallmarks and stress phenotypes of cancer cells?
top half = “hallmarks” relating to oncogenes and tumor supressors
bottom half = “stress” relating to non-oncogene factors
what are the enabling characteristics of cancer?
genome instability and mutation & tumor-promoting inflammation
what are the different hallmarks and stress phenotypes of cancer cells?
- hallmarks: angiogenesis, invasion/metastais, evading apoptosis, sustained growth signal, insensitive to anti-growth signal, immortal
- stresses: evading immunity, metabolic stress, proteolytic stress, mitotic stress, oxidative stress, DNA damage stress
what are different therapeutic strategies to target the hallmarks of cancer?
- EGFR inhibitors
- CDK inhibitors
- immune activating mAb
- telomerase inhibitors
- anti-inflammatory drugs
- inhibitors of HGF/c-Met (metastasis)
- inhibitors of VEGF (angiogenesis)
- PARP inhibitors
- pro-apoptotic mimetics
- aerobic glycolysis inhibitors
what are the classes of cancer susceptibility genes?
tumor supressor genes and oncogenes
how do we classify whether a gene is a tumor supressor or an oncogene vis genetic analysis?
The 20/20 rule of Vogelstein:
* oncogene: >20% of the recorded mutations in the gene
are at recurrent positions and are missense
* tumour supressor: >20% of the recorded mutations
in the gene are inactivating
what type of gene is DICER1 and why?
neither a tumour supressor or an oncogene since is has an unusual mutational profile – where it does not active or inhibit the gene, but instead leads to new functional protein (neomorphic functions)
how was the first oncogene found?
sarcomas from chicken were taken, ground up, and filtered. The filtrate was then injected into healthy chickens, which then developed sarcomas
what are two ways where retoviruses can leads to cancer? what are their differences?
- cause cellular transformation by inserting
themselves in the genome produce tumors after a long
latency period - carry a viral oncogene produce
tumors after a short-latency
how were oncogenes first detected in humans?
you can take human cancer cells and they will cause transformation
Ras id a crucial regulator of what processes?
- cell shape
- motility
- growth
what are the two states of Ras?
active: GTP bound
inactive: GDP bound
where is Ras usually mutated?
codon 12 is the most common, but can also be mutated in codon 13, 59, and 61
what lead to the introduction of the term proto-oncogene?
when we saw that ras must be mutated in order for it to be oncogenic
The HER2 Gene Is Amplified in 20-25% of what cancer?
breast cancer
what is the role of HER2?
it is Human Epidermal Growth Factor Receptor 2, so it participates in:
signalling pathways involved in cell
proliferation, differentiation, survival, angiogenesis and invasion
what is Trastuzumab and Pertuzumab?
antibodies against HER2
what causes the majority of f chronic myelogenous
leukemia (CML)?
Creation of the Philadelphia chromosome (combination of two genes from chromosomes 9 and 22), bcr-abl
why was a small-molecule inhibitor created for bcr-abl cancer instead of a mAb?
since Abl is a tyrosine kinase, it is a cytosolic protein, making it hard to target via mAbs.
what is Gleevec used for? how does it work?
a small molecule that targets bcr-abl, therfore treating CML:
designed to fit into the ATP binding pocket of the Bcr-Abl Tyrosine kinase, this competes with access to the active site
most cancers are caused by what?
sporadic mutations
what does hereditray cancer syndrome mean?
and how are these inherited?
An inherited disorder in which there is a higher-than-normal risk of developing cancer
most are autosomal dominant and a few are recessive
what characterizes/defines hereditary cancer syndromes?
what genetic phenomena affect these?
- genetic pleiotrophy
- variable expressivity
- variable penetrance
what is genetic pleiotrophy?
The phenomenon in which a single gene is responsible for a number of distinct and seemingly unrelated phenotypic effects
what is variable expressivity?
phenomenon of differing clinical features or phenotype among individuals carrying the same gene allele or genotype
what is variable penetrance?
Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype)
when do we suspect a hereditary cancer syndrome?
- early onset: < 50 yrs old
- rare cancer type
- multifocal disease
- multiple primary cnacers
- specific precursor lesions
- specific ethnicities
what do we define as “suspicious family history”?
- multiple affected family members on one side of the family
- multiple affected generation
- specfiic types of cancer clustered in the family
- cancers at an early age
what is the two-hit hypothesis?
According to the two-hit hypothesis:
First Hit: The first mutation or “hit” occurs in one of the alleles (copies) of a tumor suppressor gene. This mutation can be inherited or can happen sporadically.
Second Hit: For the tumor to actually form, a second mutation needs to happen in the remaining normal allele of the same tumor suppressor gene. This second hit leads to loss of function of the gene, which normally works to prevent uncontrolled cell division
what types of changes can contribute to the “second hit” in the two-hit hypothesis?
- Point Mutations: A change in a single nucleotide base pair in DNA can render the tumor suppressor gene non-functional.
- Small Deletions or Insertions: These changes can disrupt the gene’s coding sequence, leading to a loss of gene function.
- Loss of Heterozygosity (LOH): This occurs when the remaining normal allele is lost, leaving the cell with only the mutated, non-functional allele.
- Gene Methylation: The addition of methyl groups to the DNA can silence the gene, effectively turning it off.
- Chromosomal Rearrangements: Structural changes in chromosomes, such as translocations, inversions, or deletions, can inactivate the gene.
what is the founder effect?
The principle when a small sample of a larger
population establishes itself as a newly isolated
entity, its gene pool carries only a fraction of the
genetic diversity represented in the parental
population. The evolutionary fates of the parental
and derived populations are thus likely to be set
along different pathways because of the different
evolutionary pressures in the different areas
occupied by the two populations will be operating
on different gene pools
what is the relevance of the founder effect in cancer?
mutation that appears in the DNA of one or more
individuals which are founders of a distinct population and results in a medically-relevant phenotype, such as cancer, leading to higher levels of cancer in these populations
what is the Inuit founder mutation?
PMS2 mutation, leading to attenuated constitutional mismatch repair deficiency phenotype
which population has an increase prevalence of BRCA1/2 mutation?
ashkenazi jews
what cancer does BRCA1/2 mutations cause?
breast and ovarian
but can also cause prostate and pancreatic sometimes
what is one of the major goals of breast cancer genetics?
to prevent the occurrence of another, far more deadly cancer: high grade serous cancer of the fallopian tube, ovary, endometrium and peritoneum (HGSCp)
BARD1 is linked to what?
ovarian cancer
BRIP1 is linked to what?
HGSCp
and importantly NOT breast cancer
what 10 genes are associated to breast (and ovarian) cancer?
- ATM
- BARD1
- BRCA1
- BRCA2
- BRIP1
- CHEK2
- PALB2
- RAD51C
- RAD51D
- TP53
can be considered ‘the’ clinical panel for use in patients with breast or ovarian cancer
of the genes that are associated with breast cancer, what are they involved in?
DNA repair via homologous recombination
of double stranded break
Why do we care about DNA repair?
in the context of breast cancer?
- Perhaps the only molecular feature that is unequivocally shared by the two genes: could also be a link to TNBC that respond to DNA damaging drugs
- Detailed exploration of these functions has led to important new treatment initiatives
what is the role of BRCA in the DNA repair pathway?
what is the recombination repair pathway
- once there is a double stranded break, MRE11, RAD50, and NBN complex senses the break
- causes activation of ATM
- causes activation of CHK2
- then leads to recruitment of homology repair complex (BRCA1, BRCA2, BRIP1, BARD1, PALB2, RAD51)
what are different DNA repair mechanisms?
- base excision repair
- nucleotide excision repair
- homologous recomination repair
what does the cancer signature profile allow us to do?
what is the point?
Understanding the underlying mechanism allows us to specifically target therapy the defect
what is the role of PARP?
DNA Repair (base exision repair): PARP enzymes, particularly PARP1, are involved in the repair of single-strand breaks in DNA. When DNA damage occurs, PARP1 detects the break and signals other proteins to come and repair it. This process is essential for preventing mutations that could lead to cancer
how can PARP inhibitors be used?
act as synthetic lethality therapeutic: normal cells will be viable since they have a working homolous repair system, which can take over if there is DNA damage, but since BRCA-deficient cells dont have a working homolous repair system, inhibiting base excision repair leads to cnacer cell death.
olaparib
how well did olaparib work? how does it compare to other targeted therapies?
it was generally better than standard therapy, but only had a ~52% disease control rate, which is much less than other targeted therapies (e.g. imatinib) which have between 80-90% disease control rate
what are issues that arose with Olaparib?
Restoration of Homologous Recombination Repair(HRR): Tumor cells can acquire secondary mutations that restore the function of BRCA1 or BRCA2 genes, which are crucial for HRR. This restoration allows the cells to repair DNA damage more effectively, reducing the efficacy of PARP inhibitors
how does knowing that a person has a BRCA1/2 mutation affect the next steps to take?
treatment and further testing
- Affects treatment options: Surgery (Lumpectomy vs. mastectomy vs. bilateral mastectomy) & Chemotherapy (PARP inhibitors?)
- Can estimate future cancer risk: Surveillance options (Frequency, type of imaging) & Additional surgical options?
- can help additional family members
other than BRCA1/2, what would be plausible treatment targets?
PALB2 and RAD51D
what gene causes Familial Adenomatous polyposis?
APC
what type of inheritence is seen in Familial Adenomatous polyposis?
and what is the cancer risk?
autosomal dominant, 98% by age 50 if untreated
what are clinical features of Familial Adenomatous polyposis and what are other associated tumour?
- > 100 adenomatous polyps on endoscopy
- other cancers: thyroid, stomach, osteoma, brain
what gene causes MUTYH-associated Polyposis and what is the inheritence pattern?
MUTYH and autosomal recessive
what is the role of MUTYH?
plays a crucial role in the base excision repair (BER) pathway
what type of gene is APC?
is a tumor supressor gene (controls cell growth)
what are clinical features of MUTYH-associated Polyposis and what are other associated tumour?
- 10->100 adenomatous polyps by age 50
- other cancers: duodenal, thyroid, ovary, bladder, breast, skin, endometrial
what gene causes lynch syndrome?
PMS2, MSH2, MSH6, MLH1
what is the inheritence pattern of lynch syndrome and what is the cancer risk?
- autosomal dominant
- 52-82% by age 44-61
what type of genes are affected in lynch syndrome? how do they work?
in genes part of the complex responsible for mismatch repair, which work by finding the error and cutting it out, allowing it to be replaced by another complex.
it can also be caused by a mutation in EPCAM which leads to epigenetic inactivation of MSH2
how does deficient mismatch repair lead to cancer?
leads to microsatellite instability, leading to insertions or delection of small repeats, leading to even more issues/mutations
what type of therapy was thought to maybe work well againt tumours with errors in mismatch reapir genes?
immunotherapy
how does immunotherapy work?
PD-1 (Programmed Death-1): A protein on T cells that, when bound to its ligand PD-L1 (Programmed Death-Ligand 1) on cancer cells, sends an “off” signal to the T cells. Inhibitors of PD-1 or PD-L1 can prevent this interaction, boosting the immune response against cancer cells
what causes constitutional mismacth reapir deficiency (CMMRD) and what is its inheritenec pattern?
- homozygous or compound heterozygous mutations in mismatch repair genes (PMS2, MSH2, MSH6 and MLH1)
- An autosomal recessive cancer predisposition syndrome
such as what is seen in the inuit founder mutation
what are clinical features of CMMRD?
- Cutaneous features such as café-au-lait macules
- Predisposition to a variety of tumour types at a young age
