Pharmacogenomics Flashcards
Who is the father of medicine?
Hippocrates
-it is more important to know what sort of person has a disease than to know what sort of disease a person has
What is the triangle for optimization of disease?
disease
human body
drug
What are diseases partially the result of?
gene expressions and regulations
What does genomics help provide a better understanding of?
development and progression of diseases such as cancer and CV disease
also ensures patient safety by providing info on drug metabolism and DDI
What is the goal of pharmacogenomics?
achieve the 4 right
-right person
-right drug
-right time
-right dose
How many cells are in the human body?
30-40 trillion
How many different types of cells does the human body have?
over 200 different types such as neurons, epithelial cells and RBCs
How many human cells die each day?
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”
What are the cell cycle phases?
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
When are the checkpoints in the cell cycle?
one in G1 and one in G2 and apoptosis starts if anything goes wrong
-G1: DNA synthesis
-G2: preparation for mitosis
What is the restriction point?
cell commits to the cycle for division
-occurs in G1
Describe mitosis.
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
How many chromosomes in a human?
23 pairs
What makes up a chromosome?
complex of a DNA molecule and proteins
What is the composition of a DNA molecule?
linear double stranded (50-250 million base pairs)
What is the composition of an average chromosome?
2500-5000 genes within 130 million base pairs
What is the composition of a microband?
3-5 million base pairs and 60-120 genes
What percentage of human chromosomes code for genes?
10%
rest play a regulating role
What is a gene?
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)
What is the size of a gene?
small (1.5kb) to large (2000kb)
What is the size of mature mRNA?
1/10 of the gene size (RNA splicing)
What is RNA splicing?
precursors mRNA –> mRNA
What are the four types of nucleotides and their pairs in DNA? What about RNA?
DNA:
-nucleotides: ATGC
-pairs: AT, GC
RNA:
-nucleotides: AUGC
-pairs: AU, GC
What is gene expression?
gene –> mRNA –> protein
Differentiate transcription and translation.
transcription: gene –> mRNA
translation: mRNA –> protein
How many genes are expressed in a typical human cell?
~15,000 genes
-expression varies from one cell to another
What can be found in eukaryotic genes?
exons and introns
What is involved in many diseases?
gene malfunction
What are promoters?
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
Where are promoters found?
upstream of genes
RNA polymerase binding site
What can repress gene transcription?
promoter methylation
What is the goal of the Human Genome Project?
complete DNA sequence of human
-most complex and largest genome (up to now)
Differentiate the nuclear DNA genome and the mitochondrial DNA genome.
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
What is ENCODE?
encyclopedia of DNA elements
annotation of functional elements encoded in human genome
What are gene switches?
non-gene parts of DNA contributing to human diseases such as:
-MS
-lupus
-RA
-Crohns
What is genomics?
an interdisciplinary study of human genome
-structure
-function
-mapping and annotation
-regulation
-evolution
understand disease development - interaction between genome and environment
What are the types of genomic studies?
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
What are the four essential parts of genomic studies?
genetic variations
gene expressions
gene regulations
gene correlations
What are the types of genetic variations?
single nucleotide polymorphisms
copy number variations
insertions and deletions
large scale variations
structural variations
What is the most common type of genetic variation?
single nucleotide polymorphisms
What is a SNP?
small stretches of DNA that differ in only one base
-serve to distinguish individual genetic material
-millions of SNPs have been discovered
What is the frequency at which SNPs occur?
1 in 1,000 bases to 1 in 100-300 bases
SNPs comprise what percentage of known polymorphisms?
80%
How many coding SNPs per each gene?
each gene has 5 coding SNPs
True or false: there is no relationship between SNPs and drug response
false
there is a relationship between SNPs and drug response
What is the impact of a SNP on the following:
-non coding region
-regulatory region
-coding region
non-coding: no effect
regulatory: change expression level
coding: change protein structure
Differentiate coding SNPs and non-coding SNPs.
coding: SNPs that have phenotypic effects
non-coding: SNPs that have no phenotypic effects
What percentage of human SNPs impact protein function?
< 1%
What are copy number variations?
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
What are the mechanisms that produce CNVs?
recombination-based and replication-based mechanisms
What is the predominant mechanism for genome evolution?
gene duplication and exon shuffling
What are some diseases associated with CNVs?
cancer
autism
lupus
autoimmune disorders
stroke
What are INDELs?
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
What are the categories of INDELs?
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
What are some diseases associated with INDELs?
cystic fibrosis
-three base pair deletion in CFTR gene
Huntingtons disease
-triplet repeat expansion
breast cancer
-deletion of BRCA2 gene
What is a large scale variation?
large portions of DNA repeated or missing for no known reasons in healthy persons
-associated with CNV of many genes
-may underlie disease susceptibility
What are structural variations?
kilobase to megabase sized deletions, duplications, insertions, inversions and complex combination of rearrangements
-genome structural changes are involved
-extremely common in human populations
What is a hot spot?
regions with a lot of variation and often associated with genetic disorders and diseases
-ex: short arm of chromosome 1
What is the Philadelphia chromosome?
balanced translocation of chromosome 9 and 22
create BCR-ABL fusion gene
lead to ALL and CML
Differentiate genetics and genomics.
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
Differentiate pharmacogenomics and pharmacogenetics.
pharmacogenomics:
-development of drug therapies to compensate for genetic differences in patients
pharmacogenetics:
-study the genetic basis for variability in drug response
What is the use of pharmacogenomics?
determining appropriate dosing
avoiding unnecessary toxic treatments
ensure maximal efficacy
reducing adverse side effects
developing novel treatments
explaining variable response to drugs
What might pharmacogenomic biomarkers describe?
drug exposure
drug dosing
clinical outcomes
adverse effects
drug target
MOA
What is personalized medicine?
right drug, right patient, right dose
What is P4 medicine?
predictive
preventive
participatory
personalized
What are the two methods to do DNA sequencing?
whole genome sequencing (WGS)
-cost: $1,000-3,000
whole genome exon sequencing (WGES)
-cost: $1,000-2,000
What is a biochip?
an array of selected biomolecules immobilized on a surface
What is a microarray?
a rapid method of sequencing and analyzing genes
What are some biochip technologies?
PCR on a chip
gene profiling array
Arrayit H25K
AmpliChip
What is Duchenne muscular dystrophy?
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
What is the largest known human gene?
dystrophin gene (DMD)
-spanning approximately 2.5 MB on the X-chromosome
-79 exons
What is the MOA of eteplirsen (Exondys 51) ?
exon skipping therapy
-causes excision of exon 51 during pre-mRNA splicing
-the shortened dystrophin has ~50% normal function
What is the use of eteplirsen?
treat, not cure, of some types of DMD
What is the first FDA-approved cancer drug targeted to genetic mutation, not cancer type?
larotrectinib (Vitrakvi)
What is the use of larotrectinib?
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
What is SNP genotyping?
high resolution genome-wide association of SNPs to risk profiles of common diseases
What are the association studies with SNP genotyping?
SNPs and disease susceptibility
SNPs and drug response
SNPs and treatment outcomes
Which drug causes more emergency department visits among the elderly than any other drug?
warfarin
How is warfarin metabolized?
CYP 2C9
-2C91: wild type
-2C92: slow metabolizer
-2C9*3: slow metabolizer
people with these 2C9 variants need lower warfarin doses
How are CNVs detected?
high-throughput scanning technologies such as comparative genomic hybridization (CGH) and high-density SNP microarrays
What is gene expression profiling?
measurement of the expression and activity of thousands of genes at once
-get a global picture of cellular function
What is the use of gene expression profiling?
identify association of gene expression profiles with disease susceptibility and development, drug metabolism and AE
identify drug design targets and predict drug responses
What are pharmacogenomic biomarkers?
demonstrate inter-individual genetic differences on the PK, PD, efficacy, and safety of drug treatments
What is the use of imatinib?
chronic myelogenous leukemia (CML)
acute lymphocytic leukemia (ALL)
What is the MOA of imatinib?
inhibit BCR-ABL tyrosine kinase
-inhibit proliferation and induce apoptosis in BCR-ABL + cells
What are the considerations in the treatment plan of breast cancer?
stage
menopausal status
hormone receptor status
HER2 status
risk factors of recurrence
overall health condition
other breast cancer biomarkers
What is the treatment of stage 1 breast cancer?
surgery (primary)
radiation therapy
hormonal therapy
chemotherapy (usually not offered)
target therapy (HER2+ and high risk of recurrence)
What is the treatment of stage 2 breast cancer?
surgery (standard)
radiation therapy (including lymph nodes)
chemotherapy (adjuvant and neoadjuvant)
hormonal therapy
targeted therapy (HER2+ and high risk of recurrence)
What is the treatment of stage 3 breast cancer?
chemotherapy (adjuvant and neoadjuvant)
targeted therapy (HER2+, ER+ or BRCA mutations)
surgery (before or after chemotherapy)
radiation therapy (after breast-conserving surgery)
hormonal therapy
What is breast-conserving surgery?
removing cancer while leaving as much normal breast as possible
-lumpectomy or partial mastectomy
What is the treatment of stage 4 breast cancer?
hormonal therapy
chemotherapy (reducing cancer growth within pts lvl of AE tolerance)
-monotherapy: common, fewer AE
-combination therapy: used if tolerable
targeted therapy
What are the three surface receptors used to classify breast cancer?
estrogen receptor (ER)
progesterone receptor (PR)
human epidermal growth factor receptor 2 (HER2)
What is luminal A breast cancer?
ER+ and/or PR+, HER2-
What is luminal B breast cancer?
ER+ and/or PR+, HER2+
What is HER2 breast cancer?
ER-, PR-, HER2+
What is triple negative breast cancer?
ER-, PR-, HER2-
What is normal-like breast cancer?
similar to luminal A
What was the first CDK4/6 inhibitor?
palbociclib
What is the MOA of palbociclib?
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
What is the use of palbociclib?
in combination with an aromatase inhibitor or fulvestrant to treat HR+, HER2- advanced or metastatic breast cancer
What is trastuzumab approved for?
HER2 subtype breast cancer
What is the MOA of trastuzumab?
monoclonal antibody targeting HER2/neu/Erbb2 protein
-bind to subdomain IV of HER2 protein
What is the MOA of pertuzumab?
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
What is a combination therapy for metastatic and recurrent HER2+ breast cancer?
trastuzumab + pertuzumab + docetaxel
What is T-DM1?
conjugate of trastuzumab and emtansine
What is emtansine?
potent cytotoxic agent, cleaved from T-DM1 and released inside breast cancer cells
What is the use of T-DM1?
HER2+ metastatic breast cancer and early-stage HER2+ breast cancer after surgery
What is the MOA of lapatinib?
dual tyrosine kinase inhibitor that can reversibly bind to the ATP binding pockets of both EGFR and HER2
What are some combination therapies with lapatinib?
with capecitabine for advanced and metastatic HER2+ breast cancer
with letrozole for hormone receptor + metastatic breast cancer that overexpress HER2
What is the MOA of gefitinib?
inhibitor of EGFR
-signaling via EGF-EGFR promotes DNA synthesis, proliferation, migration and survival
What is the MOA of cetuximab?
monoclonal antibody against EGFR
What is the use of cetuximab?
head and neck cancer and colorectal cancer
