Solid Tumors Flashcards
temozolomide adds ______ groups to the sixth position oxygen atoms of ____ to produce adduCts
methyl (methylguanine adducts)
guanine
O6-methylguanine-DNA methyltransferase (MGMT) restores methylguanine adducts by transferring the methyl group to a ________ residue of MGMT
cysteine
__________ of the MGMT promoter is the major mechanism of MGMT inactivation in glioblastomas and allows for temozolomide sensitivity
Hypermethylation (epigenetic silencing)
What are the four potential consequences of MGMT promoter hypermethylation?
- Temozolomide response
- Decreased ability to repair DNA
- Inactivation of MGMT
D. Overall survival benefit
Sodium bisulfite treatment cause a ___________ to become a ___________
cytosine, uracil
Partial MGMT promoter methylation in a tumor may be the result of these 3 things:
- Incomplete conversion
- Presence of nonneoplastic cells
- Tumor heterogeneity
Which DNA-based assessment does not rely on bisulfite conversion?
Quantitative MSP
Temozolomide most commonly causes a methyl adduct at the N7 position of __________, followed by the O3 position of _______ and O6 position of _______
N7 guanosine > O3 adenosine > O6 guanosine
Which DNA assessment/assay does not rely on bisulfite conversion?
MS-MLPA
Methylation-specific multiplex ligation-dependent probe amplification
The net effect of bisulfite conversion is the conversion of unmethylated ___________ to _________________
cytosine to uracil
_____________________ is the gold standard for the analysis of DNA methylation profiles
bisulfite sequencing - too expensive and complex for routine clinical application – methylation specific PCR is what is used
______________ is the only test that has repeatedly been shown to be of predictive or prognostic value in clinical trials with glioblastomas and temozolomide
MSP - methylation specific PCR
Glioblastoma often shows an EGFR variant III with deletion of exons _____ to _______
exons 2 - 7
CpG islands are short GC-rich DNA stretches of _________ to _______ bp in the _________ region of genes
300 to 3000 bp
promoter regions
MGMT is located on 10q26 and has a _____-less and ____-less promoter
TATA-less
CAT-less
Given 97 CpGs in the MGMT CpG island that stretches through the minimal promoter and the enhancer, the _________ seems to be more critical for MGMT gene expression and most methylation-specific tests are designed to interrogate this region
enhancer
Which diffuse glial tumor is characterized by IDH1 mutation and loss of chromosomal arms 1p and 19q?
Oligodendroglioma
What is the advantage of FISH over PCR for assessment of 1p19q?
It does not required a normal sample
What is the main role of testing for 1p19q loss?
1p/19q predicts response to adjuvant therapy
What does aneuploidy detected by FISH signify in brain biopsies/resections?
Neoplastic tissue
What tumor has the highest likelihood of having 1p19q loss?
Oligodendroglioma, WHO grade 2
Oligodendrogliomas _____ the der(1;19)(p10;q10) and _____ the der(1;19)(q10;p10) in the nucleus
lose der(1;19)(p10;q10)
maintain der(1;19)(q10;p10)
