Cancer and Genetics I Flashcards
describe hemochromatosis and genetic testing for it
PCR –> restriction endonucleases on the HFE gene
- hemochromatosis (type I) –> mutation in HFE gene
- C282Y = 90%, H63D = 1%
- defective function of this gene leads to excessive iron absorption and deposition
- chronic fatigue, arthritis, heart disease, cirrhosis, diabetes
- frequency = 1/200 in North America
- other types:
- type 2a: hemojuvelin mutation
- type 2b: hepcidin mutation
- type 3: transferrin receptor 2 mutation
describe Factor V Leiden
- mutation changes factor V protein making it resistant to inactivation by protein C – thrombophilia and venous thromboembolism
- heterozygous and homozygous mutation increases risk of thromboembolism, further aggravated by oral contraceptive, pregnancy, surgery
describe genetic testing for Factor V Leiden
PCR –> restriction endonucleases
describe tumor susceptibility based on gene mutations
- BRCA1/2: breast and ovarian cancer
- RET: MEN syndrome
- P53: Li Fraumeni syndrome
- APC: adenomatous polyposis
HNPCC is characterized by…
- younger age at diagnosis
- synchronous and metachronous tumors in the right colon
- also tumors in endometrium, ovary, stomach, small bowel, ureter and kidney
- HNPCC related tumors in 1st degree relative
describe microsatellite instability (MSI)
defects in Lynch syndrome (HNPCC)
- microsatellite
- short repetitive DNA segments in non-coding region
- MSI = change in length of microsatellite due to insertion/deletion
- failure of error correction by mismatch repair (MMR) system during DNA replication –> MSI
describe testing for HNPCC
- protein level: immunocytochemistry in the tissues using antibody
- if the genes are mutated or methylated, their protein products will be absent in the tumor
describe testing for microsatellite instability (MSI)
- confirmation by sequencing
- however before sequencing:
- testing for BRAF V600E gene mutation is done
- BRAF V600E mutation is NOT present in patients with germline mutation and is associated with promoter methylation of MLH1
describe gene rearrangement testing
- paraffin embedded tissues were subjected to DNA extraction and IGH gene rearrangement tests
- the products are analyzed on polyacrylamide gel
- monoclonal type of IGH gene rearrangement
describe tests for prediction of malignancies
BRCA1/BRCA2
describe tests for prognosis of malignancy
NMYC, HER2/NEU, LOH, MSI
describe tests for diagnosis of metastasis/tumor characterization
specific mRNA detection: PSA, tyrosinase, cytokeratin
describe synovial sarcoma and genetic testing for it
RNA extracted from tissue, RT-PCR for the mRNA was performed (RNA –> DNA first via RT)
- tumors of adolescents and young adults
- 2 histologic types:
- biphasic: epithelial and mesenchymal cells
- monophasic: predominantly spindle cells
- t(X:18)
describe HER2 (neu) and genetic testing for it
- 25% breast cancer: amplification of the human epidermal growth factor receptor 2 (HER2) gene
- HER2 overexpression correlates with:
- aggressive features
- shortened disease-free survival
- Herceptin (antibody against Her2 protein) treatment
describe K-RAS (and genetic testing) and anti-EGFR treatment
detection: sequencing, scorpion reaction (PCR variation)
describe BRAF in melanoma and how to test for it
- 40-60% of melanomas contains BRAF mutation >> MAP kinase activation
- majority results in substitution of glutamic acid for valine at amino acid 600 (V600E)
- mutation = aggressive behavior
- test by RT-PCR/sequencing
- targeted therapy
describe treatment of non-small cell lung cancer (NSCLC)
- mutations in EGFR, KRAS and anaplastic lymphoma kinase (ALK) are mutually exclusive
- EGFR tyrosine kinase inhibitors (TKIs) are effective in tumors with:
- mutations within the EGFR
- RAS mutations are resistant to TKI
- patients with ALK mutation are not treated by EGFR-targeting TKIs but with ALK inhibitor instead
describe the treatment breakdown of NSCLC
describe testing for CML
cytogenetic analyses done by double fusion FISH (D-FISH)
testing may also be performed by RT-PCR
describe CML and a potential treatment for it
- incidence of CML is 1-2 per 100,000
- CML caused by t(9,22)
- the product of this fusion gene is BCR-ABL tyrosine kinase
-
Gleevec is an inhibitor of BCR-ABL kinase
- an effective therapy for CML
- Gleevec is also used in the treatment of GI stromal tumors
describe transplantation testing
- tissue antigen matching
- engraftment
- similar tests as identity testing
- X chromosome probes
describe diagnosis and treatment of acute lymphoblastic leukemia (ALL)
- TPMT - SNP analysis was performed before maintenance on oral mercaptopurine
- a SNP in TPMT leads to increased blood levels of 6-mercaptopurine and toxicity, therefore need to administer lower dose
____ are major factors influencing drug response
SNPs are major factors influencing drug response
