Comprehensive genomics of cancer Flashcards
What four classes of genomic alterations are distinguished by comprehensive genomic profiling? Give one example for each
- base substitutions: BRAF p.V600E
- insertions and deletions: EGFR exon 19 deletion in lung cancer
- copy number alterations: Amplification of HER2 in breast cancer
- rearrangements: ALK gene fusion and ABL gene fusion
what are copy number alterations?
somatic changes to the chromosome structure that result in a gain or loss of copies of DNA sections
what are rearrangements?
either one fusion that preserves the proper complement of genetic information or complex, several fusions that disrupt the balance
Rearrangements occur via deletions, dublications, inversions and translocations
What are microsatellites and why are they instable?
microsatellites are repetitive, highly preserved DNA sequence that occur through out the genome
They are prone to DNA- mismatching errors that occur during DNA replication
which four genes are involved in mismatch repair? What happens if this system is inactivated?
- MLH1
- MSH2
- MSH6
- PMS2
–>inactivation leads to microsatellite instability
How can microsatellite instability be detected?
immunohistochemistry or PCR
what is the tumor mutational burden (TMB)
(kr!)
TMB = number of somatic, non-synomous, coding base mutations that occur in a defined region of tumor genome. This high number of mutations is able to generate several neoantigens that can potenitally elicit immune response against tumor
–> immune evasion
In which tumor is TMB observed?
PD-L1
which mutations were associated with resistance to immunotherapeutic drugs?
STK11
how can targetable gene fusions be experimentally identified?
-RT-PCR
-NGS
-multiplex digital color coded barcode technology
Which gene fusions make a patient eligable for tyrosine kinase inhibitor therapy?
gene fusions involving ALK or ROS1
What can help in assessing risk of malignancy? Name on example
identification of gene fusions
example: PAX8/PARG and RET/CCDC6 gene fusions are associated with thyroid cancer malignancies
What role do splice variants play in cancer therapy?
they have a predictive role. They also play a role in resistance
Which gene test must be performed for an informed treatment decision in non-small cell lung cancer?
-PD-L1
-EGFR
-ALK
-ROS1 fusion protein
-BRAF V600E
-KRAS
Which signaling pathways are turned on by ROS1 fusion proteins?
- PI3K –> AKT –> MTOR
- RAS –> RAF –> MEK –> ERK
- JAK –> STAT
describe the role of PD-L1 and what type of treatment can be used?
PD-L1 is a receptor expressed on tumor cells that can interact with PD1 receptors on T-cells
immunotherapy can be used
Which rare mutations show a high sensitivity to cabozatinib and Larptrectinib in lung cancer?
RET, NTRK, MET (exon 14 skipping)
Wich patients respond to afatinib treatment?
patients with NRG1 treatment
Name biomarkers for breast cancer?
-ER
-PR
-HER2
Name inhibitors that can be used to treat breast cancer
- PI3K inhibitor: alpesilib, fulvestrant
- PARP inhibitor
Name mutations found in metastatic breast cancer who have a good survival chance and their role
-PI3KCA mutations -> activation of PI3K/AKT/mTOR pathway -> cell survival and proliferation
-germline BRCA1/2 mutations: homologous recombination deficiency
-HER2 amplifications
-MSI, NTRK translocation
Match drug to cancer
1. alpesilib
2. fulvesant
3. cabozatinib
4. Larptrectinib
5. sunitinib and sorafenib
6. c-kit inhibitors
7. Larotrectinib and entrectinib
- breast cancer: PI3K inhibitor
- breast cancer: PI3K inhibitor
- lung cancer
- lung cancer
- gastrointestinal stromal tumors
- melanomas
- infantile fibrosarcoma
How can BRCA1/2 mutations be inhibited?
By inhibiting PARP enzymes because PARP is needed for DNA repair of singla strand breaks. No repair leads to cell death
Which mutation is found in half of all melanomas? What is the mechanism behind it?
BRAF mutations V600E and V600K
–> kinase activation ..> relief of intramolecular autoinhibitory interaction between the activation segment and the p-loop of the protein
Name mutations in melonoma
- BRAF mutation
- C-kit
Name mutations in gastrointestinal stromal tumors
- KIT
- PDGFRA
