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PHAR225 > Pharmacogenomics > Flashcards

Pharmacogenomics Flashcards

1
Q

Who is the father of medicine?

A

Hippocrates
-it is more important to know what sort of person has a disease than to know what sort of disease a person has

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1
Q

What is the triangle for optimization of disease?

A

disease
human body
drug

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2
Q

What are diseases partially the result of?

A

gene expressions and regulations

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3
Q

What does genomics help provide a better understanding of?

A

development and progression of diseases such as cancer and CV disease
also ensures patient safety by providing info on drug metabolism and DDI

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4
Q

What is the goal of pharmacogenomics?

A

achieve the 4 right
-right person
-right drug
-right time
-right dose

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5
Q

How many cells are in the human body?

A

30-40 trillion

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6
Q

How many different types of cells does the human body have?

A

over 200 different types such as neurons, epithelial cells and RBCs

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7
Q

How many human cells die each day?

A

as many as 100 billion cells die each day and replaced by new cells
-new cells are made by cell division
-each cell division process is called a “cell cycle”

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8
Q

What are the cell cycle phases?

A

G1: cell grows and prepares for DNA replication
S: DNA replication
G2: cell continues to grow and prepares for mitosis
M: cell stops growth and starts division
G0: cell has left the cell cycle and stopped dividing

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9
Q

When are the checkpoints in the cell cycle?

A

one in G1 and one in G2 and apoptosis starts if anything goes wrong
-G1: DNA synthesis
-G2: preparation for mitosis

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10
Q

What is the restriction point?

A

cell commits to the cycle for division
-occurs in G1

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11
Q

Describe mitosis.

A

M phase:
-prophase: condensation of chromatin and disappearance of nucleus
-metaphase: chromosomes align on the metaphase plate
-anaphase: chromosomes split and move to the opposite pole of the cell
-telophase & cytokinesis: spindle disappears, nucleus reforms and mother cell divides
anaphase checkpoint

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12
Q

How many chromosomes in a human?

A

23 pairs

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13
Q

What makes up a chromosome?

A

complex of a DNA molecule and proteins

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14
Q

What is the composition of a DNA molecule?

A

linear double stranded (50-250 million base pairs)

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15
Q

What is the composition of an average chromosome?

A

2500-5000 genes within 130 million base pairs

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16
Q

What is the composition of a microband?

A

3-5 million base pairs and 60-120 genes

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17
Q

What percentage of human chromosomes code for genes?

A

10%
rest play a regulating role

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18
Q

What is a gene?

A

a portion of chromosomal DNA sequence required for the production of a polypeptide (protein) or a functional RNA molecule
-includes the coding sequence and adjacent sequences required for regulation of expression (such as promoters)

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19
Q

What is the size of a gene?

A

small (1.5kb) to large (2000kb)

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20
Q

What is the size of mature mRNA?

A

1/10 of the gene size (RNA splicing)

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21
Q

What is RNA splicing?

A

precursors mRNA –> mRNA

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22
Q

What are the four types of nucleotides and their pairs in DNA? What about RNA?

A

DNA:
-nucleotides: ATGC
-pairs: AT, GC
RNA:
-nucleotides: AUGC
-pairs: AU, GC

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23
Q

What is gene expression?

A

gene –> mRNA –> protein

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24
Q

Differentiate transcription and translation.

A

transcription: gene –> mRNA
translation: mRNA –> protein

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25
Q

How many genes are expressed in a typical human cell?

A

~15,000 genes
-expression varies from one cell to another

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26
Q

What can be found in eukaryotic genes?

A

exons and introns

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27
Q

What is involved in many diseases?

A

gene malfunction

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28
Q

What are promoters?

A

DNA sequences that “promote” gene expression
required for DNA transcription (mRNA synthesis)
direct the exact place to initiate DNA transcription
determine when and how a gene is transcribed

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29
Q

Where are promoters found?

A

upstream of genes
RNA polymerase binding site

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30
Q

What can repress gene transcription?

A

promoter methylation

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31
Q

What is the goal of the Human Genome Project?

A

complete DNA sequence of human
-most complex and largest genome (up to now)

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32
Q

Differentiate the nuclear DNA genome and the mitochondrial DNA genome.

A

nuclear DNA genome:
-22 pairs of autosomes and 2 sex chromosomes
-3 billion base pairs
-19,000 genes
mitochondrial DNA genome:
-17 thousand base pairs
-38 genes

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33
Q

What is ENCODE?

A

encyclopedia of DNA elements
annotation of functional elements encoded in human genome

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34
Q

What are gene switches?

A

non-gene parts of DNA contributing to human diseases such as:
-MS
-lupus
-RA
-Crohns

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35
Q

What is genomics?

A

an interdisciplinary study of human genome
-structure
-function
-mapping and annotation
-regulation
-evolution
understand disease development - interaction between genome and environment

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36
Q

What are the types of genomic studies?

A

structural genomics:
-structure of proteins encoded by the whole genome
functional genomics:
-regulation of different biological functions regulated by the genome
comparative genomics:
-genomic variances between different species
genetic mosaicism:
-DNA mutations in the genome and underlying mechanisms
genome-wide association:
-genetic markers and association with phenotypes

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37
Q

What are the four essential parts of genomic studies?

A

genetic variations
gene expressions
gene regulations
gene correlations

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38
Q

What are the types of genetic variations?

A

single nucleotide polymorphisms
copy number variations
insertions and deletions
large scale variations
structural variations

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39
Q

What is the most common type of genetic variation?

A

single nucleotide polymorphisms

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40
Q

What is a SNP?

A

small stretches of DNA that differ in only one base
-serve to distinguish individual genetic material
-millions of SNPs have been discovered

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41
Q

What is the frequency at which SNPs occur?

A

1 in 1,000 bases to 1 in 100-300 bases

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42
Q

SNPs comprise what percentage of known polymorphisms?

A

80%

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43
Q

How many coding SNPs per each gene?

A

each gene has 5 coding SNPs

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44
Q

True or false: there is no relationship between SNPs and drug response

A

false
there is a relationship between SNPs and drug response

45
Q

What is the impact of a SNP on the following:
-non coding region
-regulatory region
-coding region

A

non-coding: no effect
regulatory: change expression level
coding: change protein structure

46
Q

Differentiate coding SNPs and non-coding SNPs.

A

coding: SNPs that have phenotypic effects
non-coding: SNPs that have no phenotypic effects

47
Q

What percentage of human SNPs impact protein function?

A

< 1%

48
Q

What are copy number variations?

A

variation among people in the number of copies for a particular gene or DNA sequence
-a source of genetic diversity
-higher de novo locus-specific mutation rate than for SNPs

49
Q

What are the mechanisms that produce CNVs?

A

recombination-based and replication-based mechanisms

50
Q

What is the predominant mechanism for genome evolution?

A

gene duplication and exon shuffling

51
Q

What are some diseases associated with CNVs?

A

cancer
autism
lupus
autoimmune disorders
stroke

52
Q

What are INDELs?

A

insertions and deletions of small pieces of DNA
-alternative form of natural genetic variation
-likely to have a major impact on humans, including health and susceptibility to diseases

53
Q

What are the categories of INDELs?

A

insertions or deletions of single base pairs
expansions by only one base pair (monomeric expansion)
multi-base pair expansions of 2-15 repeats
transposon insertions (insertions of mobile elements)
random DNA sequence insertions or deletions

54
Q

What are some diseases associated with INDELs?

A

cystic fibrosis
-three base pair deletion in CFTR gene
Huntingtons disease
-triplet repeat expansion
breast cancer
-deletion of BRCA2 gene

55
Q

What is a large scale variation?

A

large portions of DNA repeated or missing for no known reasons in healthy persons
-associated with CNV of many genes
-may underlie disease susceptibility

56
Q

What are structural variations?

A

kilobase to megabase sized deletions, duplications, insertions, inversions and complex combination of rearrangements
-genome structural changes are involved
-extremely common in human populations

57
Q

What is a hot spot?

A

regions with a lot of variation and often associated with genetic disorders and diseases
-ex: short arm of chromosome 1

58
Q

What is the Philadelphia chromosome?

A

balanced translocation of chromosome 9 and 22
create BCR-ABL fusion gene
lead to ALL and CML

59
Q

Differentiate genetics and genomics.

A

genetics:
-study of heredity
-specific gene
-function and composition of a single gene
genomics:
-study of entirety
-entire genome
-address all genes and their relationships

60
Q

Differentiate pharmacogenomics and pharmacogenetics.

A

pharmacogenomics:
-development of drug therapies to compensate for genetic differences in patients
pharmacogenetics:
-study the genetic basis for variability in drug response

61
Q

What is the use of pharmacogenomics?

A

determining appropriate dosing
avoiding unnecessary toxic treatments
ensure maximal efficacy
reducing adverse side effects
developing novel treatments
explaining variable response to drugs

62
Q

What might pharmacogenomic biomarkers describe?

A

drug exposure
drug dosing
clinical outcomes
adverse effects
drug target
MOA

63
Q

What is personalized medicine?

A

right drug, right patient, right dose

64
Q

What is P4 medicine?

A

predictive
preventive
participatory
personalized

65
Q

What are the two methods to do DNA sequencing?

A

whole genome sequencing (WGS)
-cost: $1,000-3,000
whole genome exon sequencing (WGES)
-cost: $1,000-2,000

66
Q

What is a biochip?

A

an array of selected biomolecules immobilized on a surface

67
Q

What is a microarray?

A

a rapid method of sequencing and analyzing genes

68
Q

What are some biochip technologies?

A

PCR on a chip
gene profiling array
Arrayit H25K
AmpliChip

69
Q

What is Duchenne muscular dystrophy?

A

caused by mutations in the dystrophin gene
-happens in 1 in 3,500 male births (X-chromosome linked)
-muscle weakness, scar tissue formation, inflammation
-prevalently characterized by large deletions and single point mutations

70
Q

What is the largest known human gene?

A

dystrophin gene (DMD)
-spanning approximately 2.5 MB on the X-chromosome
-79 exons

71
Q

What is the MOA of eteplirsen (Exondys 51) ?

A

exon skipping therapy
-causes excision of exon 51 during pre-mRNA splicing
-the shortened dystrophin has ~50% normal function

72
Q

What is the use of eteplirsen?

A

treat, not cure, of some types of DMD

73
Q

What is the first FDA-approved cancer drug targeted to genetic mutation, not cancer type?

A

larotrectinib (Vitrakvi)

74
Q

What is the use of larotrectinib?

A

adults and children with solid tumors that test positive for NTRK gene fusions without a known acquired resistance mutation
-known acquired resistance mutations: G623R, G696A, F617L

75
Q

What is SNP genotyping?

A

high resolution genome-wide association of SNPs to risk profiles of common diseases

76
Q

What are the association studies with SNP genotyping?

A

SNPs and disease susceptibility
SNPs and drug response
SNPs and treatment outcomes

77
Q

Which drug causes more emergency department visits among the elderly than any other drug?

A

warfarin

78
Q

How is warfarin metabolized?

A

CYP 2C9
-2C91: wild type
-2C92: slow metabolizer
-2C9*3: slow metabolizer
people with these 2C9 variants need lower warfarin doses

79
Q

How are CNVs detected?

A

high-throughput scanning technologies such as comparative genomic hybridization (CGH) and high-density SNP microarrays

80
Q

What is gene expression profiling?

A

measurement of the expression and activity of thousands of genes at once
-get a global picture of cellular function

81
Q

What is the use of gene expression profiling?

A

identify association of gene expression profiles with disease susceptibility and development, drug metabolism and AE
identify drug design targets and predict drug responses

82
Q

What are pharmacogenomic biomarkers?

A

demonstrate inter-individual genetic differences on the PK, PD, efficacy, and safety of drug treatments

83
Q

What is the use of imatinib?

A

chronic myelogenous leukemia (CML)
acute lymphocytic leukemia (ALL)

84
Q

What is the MOA of imatinib?

A

inhibit BCR-ABL tyrosine kinase
-inhibit proliferation and induce apoptosis in BCR-ABL + cells

85
Q

What are the considerations in the treatment plan of breast cancer?

A

stage
menopausal status
hormone receptor status
HER2 status
risk factors of recurrence
overall health condition
other breast cancer biomarkers

86
Q

What is the treatment of stage 1 breast cancer?

A

surgery (primary)
radiation therapy
hormonal therapy
chemotherapy (usually not offered)
target therapy (HER2+ and high risk of recurrence)

87
Q

What is the treatment of stage 2 breast cancer?

A

surgery (standard)
radiation therapy (including lymph nodes)
chemotherapy (adjuvant and neoadjuvant)
hormonal therapy
targeted therapy (HER2+ and high risk of recurrence)

88
Q

What is the treatment of stage 3 breast cancer?

A

chemotherapy (adjuvant and neoadjuvant)
targeted therapy (HER2+, ER+ or BRCA mutations)
surgery (before or after chemotherapy)
radiation therapy (after breast-conserving surgery)
hormonal therapy

89
Q

What is breast-conserving surgery?

A

removing cancer while leaving as much normal breast as possible
-lumpectomy or partial mastectomy

90
Q

What is the treatment of stage 4 breast cancer?

A

hormonal therapy
chemotherapy (reducing cancer growth within pts lvl of AE tolerance)
-monotherapy: common, fewer AE
-combination therapy: used if tolerable
targeted therapy

91
Q

What are the three surface receptors used to classify breast cancer?

A

estrogen receptor (ER)
progesterone receptor (PR)
human epidermal growth factor receptor 2 (HER2)

92
Q

What is luminal A breast cancer?

A

ER+ and/or PR+, HER2-

93
Q

What is luminal B breast cancer?

A

ER+ and/or PR+, HER2+

94
Q

What is HER2 breast cancer?

A

ER-, PR-, HER2+

95
Q

What is triple negative breast cancer?

A

ER-, PR-, HER2-

96
Q

What is normal-like breast cancer?

A

similar to luminal A

97
Q

What was the first CDK4/6 inhibitor?

A

palbociclib

98
Q

What is the MOA of palbociclib?

A

inhibit cyclin-dependent kinases CDK4 and CDK6
-block the phosphorylation of Rb
-prevent cancer cells to pass the R point
-arrest cancer cells in G1 phase

99
Q

What is the use of palbociclib?

A

in combination with an aromatase inhibitor or fulvestrant to treat HR+, HER2- advanced or metastatic breast cancer

100
Q

What is trastuzumab approved for?

A

HER2 subtype breast cancer

101
Q

What is the MOA of trastuzumab?

A

monoclonal antibody targeting HER2/neu/Erbb2 protein
-bind to subdomain IV of HER2 protein

102
Q

What is the MOA of pertuzumab?

A

monoclonal antibody binds to subdomain II of HER2 protein
block homodimerzation of HER2 and heterodimerization of HER2-HER3
inhibit HER2-signaling pathway and decrease cell growth

103
Q

What is a combination therapy for metastatic and recurrent HER2+ breast cancer?

A

trastuzumab + pertuzumab + docetaxel

104
Q

What is T-DM1?

A

conjugate of trastuzumab and emtansine

105
Q

What is emtansine?

A

potent cytotoxic agent, cleaved from T-DM1 and released inside breast cancer cells

106
Q

What is the use of T-DM1?

A

HER2+ metastatic breast cancer and early-stage HER2+ breast cancer after surgery

107
Q

What is the MOA of lapatinib?

A

dual tyrosine kinase inhibitor that can reversibly bind to the ATP binding pockets of both EGFR and HER2

108
Q

What are some combination therapies with lapatinib?

A

with capecitabine for advanced and metastatic HER2+ breast cancer
with letrozole for hormone receptor + metastatic breast cancer that overexpress HER2

109
Q

What is the MOA of gefitinib?

A

inhibitor of EGFR
-signaling via EGF-EGFR promotes DNA synthesis, proliferation, migration and survival

110
Q

What is the MOA of cetuximab?

A

monoclonal antibody against EGFR

111
Q

What is the use of cetuximab?

A

head and neck cancer and colorectal cancer

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