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Spring 2024 (All Classes Except Therapeutics+ Lab) > Pharmacogenomics Quiz 2 (Lec 5-8) > Flashcards

Pharmacogenomics Quiz 2 (Lec 5-8) Flashcards

1
Q

What was the goal of the 1000 Human Genomes Project?

A

To find most genetic variants with frequencies of at least 1% in the populations studies

(sequence 1000 genomes)

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2
Q

The 1000 Human Genomes Project wanted to find most genetic variants with what % frequency in the populations studied?

A

At least 1%

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3
Q

How many populations did the 1000 Human Genomes Project study?

A

26 populations

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4
Q

How does the 1000 Human Genomes Project differ from the Human Genome Project?

A

The human genome project only sequenced the genome of one singular person

The 1000 Human Genomes Project studied genetic variants in 26 populations and sequenced 1000 genomes

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5
Q

What were the 3 major findings of the 1000 Human Genomes Project?

A

-People from different populations carry different profiles of rare + common gene variants

-Low-frequency variants show substantial geographic differentiation
(rare mutations tend to cluster in one genomic area)

-Each person carries around 250-300 loss-of-function variants in annotated genes and 50-100 variants previously implicated in inherited disorders

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6
Q

True or False: Individuals from different populations carry the same profiles of rare and common variants

A

FALSE

they carry different profiles

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7
Q

True or False: Low-frequency variants show substantial GEOGRAPHIC differentiation

A

TRUE

(rare mutations tend to cluster in one genomic area)

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8
Q

On average, how many loss-of-function variants does each person carry?

*KNOW THIS

A

250-300

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9
Q

Where do people carry loss-of-function variants?

A

Annotated genes

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10
Q

How many loss-of-function variants PREVIOUSLY IMPLICATED IN INHERITED DISORDERS does each person carry around on average?

A

50-100

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11
Q

What website provides a genome browser where the 1000 Genomes Project data can be viewed?

A

Ensembl

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12
Q

What section of the website Ensembl allows you to view the 1000 Genomes Project data on the current human reference genome?

A

Ensembl GRCh38

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13
Q

True or False: Viewing data on the Ensembl website is intuitive

A

FALSE

-data viewing is not intuitive, we have to use more databases

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14
Q

If you need to find information about whether a patient is a candidate to take a specific medication based on their genetics, what is the first website you should check for information?

A

PHARMGKB.org

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15
Q

What US organization publishes guidelines about pharmacogenetics-based drug dosing?

A

Clinical Pharmacogenetics Implementation Consortium (CPIC)

*note: these are the guidelines used by pharmgkb.org

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16
Q

Your order a DNA test for your patient to sequence all
possible alleles in all exons of CYP2C19 genes. After
sequencing, no known mutant allele was identified (1/1). However, a novel mutation (heterozygous) in CYP2C19 exon 3 was identified. This allele has never been described in the literature. What would you do with this finding?

A) Treat it as a 1/1
B) Treat it as a 1/X
C) More information is needed to evaluate its clinical consequence
D) The test result is wrong

A

C

*in this case, just change the therapy to one that does not rely on CYP2C19

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17
Q

What allele does the drug Lumakras target?

A

KRAS G12C

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18
Q

What are the 3 possible PGx drug labels?

A

One gene-multiple drugs
One drug-multiple genes
One gene-multiple alleles

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19
Q

What labs perform PGx Tests?

A

CLIA certified labs

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20
Q

What are the 2 important parts of prescribing a PGx test?

A

-Collecting enough information

-Making an informed decision

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21
Q

What are the 4 PGx Testing Levels?

A

-Genetic Testing Required
-Genetic Testing Recommended
-Actionable PGx
-Informative PGx

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22
Q

What does the Actionable PGx level indicate?

A

The drug label mentions that you can do genetic testing on the patient regarding a drug, you determine if it is needed

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23
Q

What does the Informative PGx level indicate?

A

This level is suggestive as to whether pharmacogenetic testing should be done or not

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24
Q

What are the 3 limitations of PGx?

A

PK/PD issues are complex

Not all FDA-approved PGx testing is mandatory for all related drugs

Cost may not bring enough benefit (determine value)

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25
Q

Can we rely on PGx testing alone?

A

NO

-especially when there is a sign of an adverse drug reaction
*do not forget non-genetic factors
(age, BMI, supplements, etc.)

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26
Q

What is an example of a drug that already has PGx information available for it?

A

Warfarin

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27
Q

What CYP’s may be more important for African descendants?

A

CYP2C9*5-11

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28
Q

What are 4 additional important factors to consider in PGx testing?

A

-Family history
(genetic factors)

-Race and Ethnicity
(allele frequency/mutation rate vary between populations)

-Vulnerable Populations
(children have different metabolisms, patients with diminished competence and/or decision-making capacity)

-Consent/Assent

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29
Q

What is the target sample for PGx testing?

A

DNA

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30
Q

Where is DNA found?

A

Any nucleated cells/tissue (contain germline DNA)

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31
Q

What 4 principles are considered ideal for collecting samples for PGx testing?

A

-Easy to collect
-Avoid contamination
-Less invasive
-Availability of standard procedure

**often difficult to achieve all 4 because they sometimes contradict each other

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32
Q

What is the most commonly used sample for PGx testing?

A

Peripheral blood

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33
Q

What cells in peripheral blood are targeted to gather DNA from?

A

White blood cells

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34
Q

What is the standard amount of white blood cells collected for a PGx test?

A

2-6 ml

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35
Q

What tube is preferred to hold the peripheral blood/ white blood cells for PGx testing?

A

EDTA-anticoagulation tube

(purple top)

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36
Q

How is peripheral blood stored + shipped before PGx testing?

A

Room temperature

Same day/overnight delivery (1-2 days)

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37
Q

What special patients need to be considered when collecting peripheral blood for PGx testing?

A

Patients treated with chemotherapy or radiotherapy
(have fewer cells, DNA sequence may be altered)

Bone marrow transplant patients
(have different DNA)

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38
Q

Can we get DNA from red blood cells?

A

NO (do not have a nucleus)

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39
Q

What is an alternative method of collecting DNA for PGx testing?

A

Cheek swab/brush

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40
Q

Does a cheek swab/brush give more or less DNA yield than blood?

A

Less DNA yield

1-5 ug (still enough for many types of assays)

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41
Q

True or False: patients undergoing a cheek swab/brush should rinse their mouths

A

TRUE

-gets rid of possible sources of contamination
(food, bacteria, etc)

42
Q

What is a limitation relating to storage when gathering a tissue biopsy from a tumor?

A

Needs to be frozen immediately because it goes bad quickly!!

43
Q

Does tissue from a tumor give a high yield of DNA?

A

Yes

44
Q

At what temperature should a fresh biopsy from a tumor be stored at long-term?

A

-80 degrees C

45
Q

What is an important addition when transporting a fresh biopsy?

A

Add dry ice for transportation

46
Q

What is an alternative tissue specimen to a fresh biopsy and what are its limitations?

A

Formalin-Fixed Paraffin Embedded (FFPE) specimens

*DNA is usually degraded (difficult to process)
–however, many detections are still doable
–often most available option

47
Q

What is the first FDA-approved broad companion diagnostic with Medicare coverage for qualifying patients with solid tumors?

A

Formalin-Fixed Parafin Embedded (FFPE) specimens

48
Q

What are the 2 major factors of DNA isolation?

A

Purity

Integrity

49
Q

Is DNA stable?

A

YES, very stable, especially when dried and pure

50
Q

Which is more stable: DNA or RNA?

A

DNA

51
Q

What 3 factors can affect DNA quality?

A

pH (avoid oxidants and UV)

Repeated freezing and thawing

Bacterial contamination

52
Q

What temperature should DNA be at for short term storage and how long is considered “short”?

A

4 degrees C

(1-2months)

53
Q

What temperature should DNA be at for long term storage and how long is considered “long”?

A

-80 degrees C

(years)

54
Q

What are the 2 goals of PGx testing methods?

A

-Testing known variants

-Testing both known and unknown alleles

55
Q

What PGx testing method can be used to test KNOWN variants only?

A

Genotyping (DNA chip)

56
Q

What PGx testing methods can be used to test BOTH KNOWN and UNKNOWN alleles?

A

Sanger sequencing

High-throughput next-gen sequencing (whole exome sequencing)

57
Q

What are the 2 critical steps of DNA amplification?

A

-Target DNA amplification

-Allele discrimination (homozygous or heterozygous)

58
Q

What is considered the most useful technique for DNA amplification?

A

Polymerase Chain Reaction (PCR)

59
Q

True or False: The polymerase chain reaction (PCR) is used to read DNA

A

FALSE
-used to amplify it, not read it

60
Q

How many base pairs can the Polymerase Chain Reaction (PCR) amplify?

A

50-1000 bp

61
Q

By how much does the Polymerase Chain Reaction (PCR) amplify DNA?

A

about 2^(35)

(billions of copies)

62
Q

What are the 5 substrates needed for the Polymerase Chain Reaction (PCR)?

KNOW THIS

A

-DNA Template

-dNTPs (dATP, dGTP, dCTP, dTTP)

-Primers: 2 short sequences specific to the region of interest

-Buffer: pH, Mg2+

-Enzyme: Taq DNA polymerase

63
Q

True or False: We do not directly amplify RNA

A

TRUE

-we have to reverse transcribe it to DNA and then amplify it

64
Q

What is the first step in DNA amplification?

A

Denaturation

-temperature is increased to separate DNA strands
(98 degrees C)

65
Q

What is the second step in DNA amplification?

A

Annealing

-temperature is decreased to allow primers to base pair to the complementary DNA template

*Note: A-T pairing can be done at a lower temperature because it only has 2 H bonds, whereas C-G pairing needs a higher temperature because it has 3 H bonds

(48-72 degrees C)

66
Q

What is the third step in DNA amplification?

A

Extension

-The polymerase extends the primer to form a nascent DNA strand

(68-72 degrees C)

67
Q

What is the fourth/final step in DNA amplification?

A

Exponential Amplification

-extension is repeated and the region of interest is amplified exponentially

(DNA copy number increases with each cycle)

68
Q

Note:

A

See Lecture 8 Slide 7

(if you want to be a smarty pants)

69
Q

Since DNA is amplified exponentially with the Polymerase Chain Reaction (PCR), DNA is taken from 2 copies to what number of copies?

A

From 2 copies to 2^(n+1) copies

N= number of thermal cycles (stages occur in the exponential amplification stage)

ex: Stage 3= 2^(3+1) = 2^(4) = 16 copies

70
Q

What enzyme is the key in the Polymerase Chain Reaction (PCR)?

A

Taq polymerase

71
Q

True or False: PCR amplifies DNA from both DNA molecules of homologous chromosomes

A

TRUE

*know this
(this is why you can determine the genotype)

72
Q

What is a DNA Chip used to detect?

A

Only KNOWN SNPs (targeted SNPs)

*know this

73
Q

What is sequencing used to detect?

A

BOTH KNOWN and UNKNOWN SNPs

*know this

74
Q

What is considered “conventional sequencing” of DNA?

A

Sanger Sequencing

75
Q

What are some factors to consider about Sanger Sequencing?

A

*Low throughput (lots of manual power, labor-intense)

*Targeted sequencing (sequencing of one specific DNA fragment)

76
Q

What are some factors to consider with Next Generation Sequencing?

A

*High-throughput (gives lots of data fast)

  • Parallel sequencing

*Massive sequencing (sequences multiple DNA fragments simultaneously)

77
Q

How does Sanger Sequencing work?

A

DNA sequencing based on the selective incorporation of chain-terminating dideoxynucleotides (ddNTPs) by DNA polymerase during in vitro DNA replication

78
Q

Note:

A

See Lecture 8 Slide 15
to get big brain energy

79
Q

What do two peaks occurring in the same spot on a Sanger Sequence done by a machine mean?

A

Heterozygous, two different nucleotides can occur at that spot

80
Q

What are two downsides to Sanger Sequencing?

A

-Low throughput

-Higher cost per base pair

81
Q

About how many base pairs can be identified by Sanger Sequencing?

A

700 bp

82
Q

What is the second kind of sequencing available besides Sanger?

A

Next Generation Sequencing (NGS)

*No longer based on Sanger concept
*More imaging based

83
Q

How is Next Generation Sequencing (NGS) done?

A

Sequencing by the synthesis in parallel

84
Q

What do dATP, dGTP, dCTP, and dTTP represent?

A

These are the 4 different DNA base pairs (A,G,C,T)

*especially important in Next Generation Sequencing (NGS)

85
Q

Note:

A

See Lecture 8 Slide 19
for cool colors

86
Q

True or False: Next Generation Sequencing (NGS) can simultaneously sequence DNA of multiple individuals

A

TRUE
(high throughput)

87
Q

If you wanted to see someone’s whole genome/whole exome, what method would you use?

A

Next Generation Sequencing (NGS)

88
Q

What are 4 considerations for Next generation Sequencing (NGS)?

A

-Higher Total Cost
-Very low cost per SNP (because you see so many)
-Detect all known or unknown alleles!!!
-Detect almost all kinds of polymorphisms

89
Q

What is sequencing coverage?

A

The average number of reads that align to or “cover” known reference bases

90
Q

What do the next-generation sequencing (NGS) coverage levels determine?

A

Whether variant discovery can be made with a certain degree of confidence at particular base positions

91
Q

What depth of coverage is recommended to detect human genome mutations, SNPs, and rearrangements?

A

10x to 30x

92
Q

What are the 2 reasons why Next Generation Sequencing (NGS) approaches require sequencing every base in a sample several times?

A

-You need multiple observations per base to come to a reliable base call

-Reads are not distributed evenly over an entire genome (because the reads will sample the genome in a random and independent manner)

93
Q

True or False: It is better to have a high sequencing depth

A

TRUE

-multiple observations allows us to be more confident that a base pair is correct if it appears multiple times

94
Q

Note:

A

See Lecture 4 Slide 23
because I said so

95
Q

What does germline mean?

A

Sequence of germ cells that may be passed to a child

(egg or sperm)
(mutations in germline cells can be passed to offspring)

96
Q

What does somatic mean?

A

A sequence of nongermline cells that is not passed to a child

(not inheritable)

97
Q

Does de novo refer to germline or somatic mutations?

A

Somatic

98
Q

What kind of mutations are DNA chips used for?

A

NOT used for somatic mutation detection

(only used for germline mutations)

99
Q

What kind of mutations are Next Generation Sequencing (NGS) used for?

A

Almost all kinds of mutations

(both somatic and germline)

100
Q

What is the powerhouse of the cell?

A

MITOCHONDRIA

*know this

Spring 2024 (All Classes Except Therapeutics+ Lab) (9 decks)

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