Germline Mutations Flashcards
Cancer malignancy arise from
-transformation of genetic material from a normal cell
Germline PG marker drugs
-mercaptopurine
-irinotecan
Mecaptopurine
-inhibits purine nucleotide synthesis involved in DNA replication
-pediatric cancer and ADL
-TPMT and NUDT15 genes
-myelosuppresion
Irinotecan
-inhibits topoisomerase I involved in DNA replication and transcription
-colorectal and lung cancer
-UGT1A1
-neutropenia, diarrhea
Acute Lymphoblastic Leukemia (ALL)
-cancer of blood and bone marrow
-most common childhood malignancy
-survival rate 90%
-inc production of lymphoblasts, B, or T lymphocytes
-dec granulocytes, RBCs, platelet production (infection, anemia, bleeding)
-spreads to the CNS
ALL treatment
-maintenance chemo up to 2 years
-oral 6-mercaptopurine 50mg
TPMT
-metabolized mercaptopurine?
-cytotoxic nucleotides accumulate in absence of TPMT
-something about NDT15
-low TPMT or low NUDT15 activity = elevated concentration of mercaptopurine metabolites
=hematological toxicity = myelosuppression (reduced RBCs, WBCs, platelets)
TMPT drug labeling
-TMPT*2, *3A, *3C account for 95% of reduced function
-Wt/Wt homo is normal activity
-Wt/Mu is intermediate
-Mu/Mu is low/no activity
Pt with inherited little/no TMPT activity:
-inc risk of severe toxicity from conventional doses of mercaptopurine
-require dose reduction
-optimal starting dose for homozyg not established
guidelines?
slide 9
TPMT genotype testing
-done in clinic
-assessed prior to 6-MP admin in pediatric ALL
-reduced doses in homozyg has been successful
Patients can get myelosuppression with normal TMPT function
-additional pathways may also be polymorphic
-CBC tests monitored during 6-MP therapy regardless of genotype
Irinotecan
-topisomerase I
= cuts DNA to allow replication and repair
-inhbibted by irinotecan = cell apoptosis
-metastatic colorectal cancer in combo w others
-SN-38 active metabolite (1000x more potent)
-inactivated by UGT1A1/6/9
UGT1A1
-more than 30 variants
-UGT1A1*28 most studied
-reduced function dec SN-38 metabolism
-inc risk for neutropenia and severe diarrhea
Dosage in pt homo for UGT1A1*28 allele
-reduce starting dose by at least one level
-precise dose reduction not known
SN-38 toxicity risks
-age >65 (monitor/reduce dose)
-pelvic/ab radiotherapy
-poor performance status
-inc bilirubin concentration
-UGT1A1 genotype
-likely SN-38 exposure
TMPT/NUDT15 genotyping summary
-do before mercaptopurine initiation (aka Azathioprine) for immunosuppresion
-reduced function alleles = reduce dose
UGT1A1 genotyping summary
-less common for irinotecan
-predictive for toxicity but benefit higher dose often outweights risk
-important to consider other predictive clinical markers for toxicity when choosing dose
