79. Pharmacogenomics

Question 1

What are the different nucleotide bases in DNA vs RNA?

Answer 1

2 purines (adenine and guanine) and 2 pyrimidines (thymine and cytosine)
In RNA, uracil is present instead of thymine

Question 2

How many pairs of chromosomes do human cells contain?

Answer 2

23 pairs

Question 3

Alleles are either wild-type or variants. ____ is usually the most commonly occurring allele

Answer 3

Wild-type

Question 4

Homozygous vs heterozygous genotypes

Answer 4

2 identical alleles = homozygous genotype (e.g. CYP2C19 * 1 / * 1)
2 different alleles = heterozygous genotype (CYP2C19 * 1 / * 3)

Question 5

Genotype vs phenotype

Answer 5

Genotype = set of unique genes that determine a specific trait
Phenotype = observable trait of the genotype (ex. hair color, sickle cell disease, etc.)

Question 6

What is single nucleotide polymorphism (SNP)?

Answer 6

A change in a single nucleotide in a genetic sequence (e.g. C replaced with G)
Most common genetic alteration in DNA, can be harmless or cause disease
Responsible for majority of individual variability in response to a drug

Question 7

____ is an inherited variation in the DNA sequence such as SNP or SV

Answer 7

Polymorphism

Question 8

Test/Reason for testing/Action: Abacavir and combo drugs (Triumeq, Epzicom)

Answer 8

HLA-B*5701
Increased risk for hypersensitivity reaction (fatal), test prior to starting
If positive, do NOT use

Question 9

Test/Reason for testing/Action: Allopurinol (Zyloprim, Aloprim)

Answer 9

HLA-B*5801
Increased risk for SJS, consider testing high-risk individuals (Korean pts with renal impairment or those with Han Chinese or Thai ancestry)
d/c at first sign of an allergic reaction
If positive, do NOT use

Question 10

Test/Reason for testing/Action: Carbamazepine (Tegretol), Oxcarbazepine (Trileptal), Phenytoin (Dilantin), Fosphenytoin (Cerebyx)

Answer 10

HLA-B*1502
Increaesd risk of SJS and TEN
Test all Asian patients before starting carbamazepine; testing suggested for oxcarbamazepine and optional for phenytoin/fosphenytoin
If positive, do NOT use (unless benefit clearly outweighs risk)

Question 11

Test/Reason for testing/Action: Clopidogrel (Plavix)

Answer 11

CYP2C19
Clopidogrel is prodrug
Allele *1 is fully functional but patients with *2 and *3 are poor metabolizers and increased CV events
If patient has CYP2C19 *2 or *3, consider alternative treatment

Question 12

Test/Reason for testing/Action: Codeine

Answer 12

CYP2D6
Codeine is prodrug
Ultra-rapid metabolizers at increased risk of opioid overdose, CNS effects, respiratory depression (infant deaths occurred when nursing mothers who were ultra-rapid metabolizers took codeine, passed via breast milk)
If patient is CYP2D6 ultra-rapid metabolizer, do NOT use

Question 13

Test/Reason for testing/Action: Warfarin (Coumadin, Jantoven)

Answer 13

CYP2C9*2 and *3, VKORC1
Increased bleeding risk with those alleles, CYP2C9 *2 and *3, VKORC1 G > A variant
If these allele variations are known to be present, start at LOWER dose

Question 14

Test/Reason for testing/Action: Trastuzumab (Herceptin) and other HER2i

Answer 14

HER2 gene expression
These drugs require overexpression of HER2 for efficacy
If tumor is HER2 negative, drug is NOT effective

Question 15

Test/Reason for testing/Action: Cetuximab (Erbitux) and other EGFRi

Answer 15

KRAS mutation
Only patients who are KRAS mutation-NEGATIVE (wild-type) should receive this drug
If positive for KRAS mutation, do NOT use

Question 16

Test/Reason for testing/Action: Azathioprine (Azasan, Imuran)

Answer 16

Thiopurine methyltransferase (TPMT)
Low/absent TPMT activity increases risk of severe life threatening myelosuppression (decrease WBC, RBC, and platelets)
If TPMT activity is low/present, start at very low dose or use alternative treatment

Question 17

Test/Reason for testing/Action: Capecitabine (Xeloda), Fluorouracil

Answer 17

DPD deficiency
DPD deficiency increases risk of severe toxicity (diarrhea, neutropenia, neurotoxicity)
If DPD deficiency, do NOT use

Question 18

HLA-B positive test predicts ___

Answer 18

Increased risk of hypersensitivity

Question 19

KRAS mutation test predicts ____

Answer 19

poor response

Question 20

HER2 expression test predicts ___

Answer 20

poor response

Question 21

Which drugs is testing required or strongly recommended?

Answer 21

Abacavir and combo meds
Azathioprine
Carbamazepine
Cetuximab and other EGFRi
Trastuzumab and other HER2 inhibitors