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diagnosis of genetic diseases > Lecture 13 > Flashcards

Lecture 13 Flashcards

1
Q

what is the definition of personalized medicine?

A

a healthcare approach that uses molecular information (genomics, proteomics, metabolomics, lipidomics, etc), clinical information, and phenotypical features as well as health and lifestyle data for the improvement of health outcome

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2
Q

what three levels can personalized medicine be applied on?

A

individuals, family members of at risk patients, and the community

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3
Q

how can personalized medicine be used for an individual?

A

important for the identification of the genetic predisposition for a disease → considers factors such as family history, genetic predisposition, and the lifestyle of the patient

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4
Q

how can pm be applied to the family members of the at risk patient?

A

able to identify the possible risk of having a familial condition as well as to give them recommendations of how to reduce the risk of developing a condition based on the test results obtained

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5
Q

how can pm be applied to the community?

A

clinicians recommendations can lead to a reduction of the affected individuals overall

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6
Q

in what situation are we able to apply pm?

A

if we have a good knowledge of the pathogenic mechanism of the disorder, otherwise there are a lot of challenges that need to be overcome in order to apply it

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7
Q

in healthy individuals, what is pm used for?

A

prevention

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8
Q

what are the three areas where PM is used in healthy individuals?

A
  1. neonatal screening
  2. susceptibility and prevention of disorder
  3. carrier screening
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9
Q

describe pm in neonatal screening:

A

we have a list of pathologies for which treatment is available

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10
Q

describe the use of pm in susceptibility and prevention:

A

there are a list of genetic patterns that are associated to an increased risk of developing a specific phenotype - however it is open for debate (in different cases we don’t have a clear correlation and a good risk stratification in the presence of specific susceptibility facts and the clear risk to develop the onset)

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11
Q

what are the three levels in which PM can be used in affected patients?

A
  1. genetic diagnosis
  2. pharmacogenomics or gene therapy
  3. liquid biopsy
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12
Q

what is the aim of using PM in genetic diagnosis?

A

for the identification of inherited genetic disorders

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13
Q

what does pharmacogenomics deal with?

A

the list of drugs whose effectiveness is greater if we have a mutation in specific genes

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14
Q

how is personalized medicine applied to pharmacogenomics?

A

clinicians want to know if a patient has a specific mutation to give them the best specific treatment or in some cases, requests are submitted because a clinician needs to know what is the best management for the clinical surgery for a patient, based genetic mutations

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15
Q

how is gene therapy an example of pm?

A

it is a medical approach based on molecular information and usually applied to a rare disease

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16
Q

what is a liquid biopsy?

A

the analysis of circulation free DNA (cfDNA) to identify the typical somatic mutation that characterized a specific tumor in a patient and it is useful t improve the diagnosis of that form, monitoring it over time, for treatment, as well as potentially for prognosis

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17
Q

what are the disadvantages to a standard biopsy?

A
  • time expensive
    -intensive
  • can only analyze a specific sample of tissue and not give a general overview of the tissue or body itself
  • very invasive, painful, and dangerous
    -difficult to obtain and repeat
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18
Q

what is a liquid biopsy based on?

A

a peripheral blood sample

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19
Q

why is a liquid biopsy a better alternative than a traditional biopsy?

A
  • it is easy to obtain
  • extreme reduction of pain and healing
  • minimal risk
  • gives a comprehensive overview of the molecular features and gives a profile of the tumor
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20
Q

what two things can be analyzed from a liquid biopsy?

A

the study of circulating tumor cells (CTCs) or the analysis of circulating cell-free nucleic acids (cfNAs)

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21
Q

what can we gain from the analysis of circulating tumor cells?

A

we obtain the CTCs and apply the cytomeric / protein based approach to identify the kind of cells / proteins expressed the in the tumor

22
Q

what happens when we analyze the circulating cell-free nucleic acids (cfNAs)?

A

we have the extraction of the free circulating RNA/DNA from the plasma or serum sample isolated from the blood of the patient

23
Q

what are free circulating nucleic acids?

A

circulating free fragments of DNA or RNA instead of the entire molecule, that does not have the same integrity of the gremlin DNA, making it more difficult to analyze

24
Q

how do the circulating nucleic acids get into the bloodstream?

A

there’s an active release of nucleic acids from living cells or from the breakdown of dying cells that release nucleic acids into the blood

25
Q

when analyzing a tumor, what are we looking for in the blood?

A

the contents released by the secretion, necrosis, or apoptosis of tumor cells depending on the size and stage of the tumor → correlation between the severity of the disease and the amount of cell-free tumor DNA

26
Q

what is the main limitation of studying fcDNA?

A

the half-life of fcDNA is variable, from 15 minutes to several hours - the analysis must start immediately after the blood draw

27
Q

what is one of the main problems when analyzing cf tumor DNA?

A

there is a predominant presence of the WT DNA, and the cf tumor DNA is the minor allele, so we must choose the appropriate analysis technique - we also have to keep in mind that the WT and the tumor sequence may only differ by one base pair

28
Q

after the discovery of a tumor or disease, how can liquid biopsy continue to help the patient?

A

we can have the identification of a relapse and have an early intervention

29
Q

how can liquid biopsy help us during the diagnosis stage?

A

we can perform the molecular characterization of the tumor, and identify the causative and somatic mutations as well as the severity of the tumor - can also help us determine the prognosis and best treatment

30
Q

how can a liquid biopsy be used after surgery?

A

we can see if the tumor was completely removed or if it is still present in the patient

31
Q

in regards to treatments, how can liquid biopsy be used?

A

it can help determine the best treatment as well as monitor the bodies response to the therapy - can help catch a developing resistance or tolerance

32
Q

can liquid biopsy detect the presence of all types of tumors equally?

A

no - depending on the location of the tumor there will be a greater presence in the peripheral blood

33
Q

what types of tumors can liquid biopsy not recognize as well?

A

gliomas (barrier that isolates the brain), thyroid tumors, renal cell carcinomas

34
Q

what types of tumors can liquid biopsies identify easily?

A

bladder cancer, colorectal cancer, breast cancer, etc

35
Q

what is used to store peripheral blood samples intended for liquid biopsies?

A

EDTA tubes or different tubes that contain preventing agents to reduce or avoid the degradation of the peripheral circulating DNA or RNA and to increase the stabilization of molecules

36
Q

what is one thing to consider when taking peripheral blood samples for liquid biopsies?

A

the pre-analytical variability → we know that after 50 minutes the degradation of DNA starts and the maximum time is unknown, it is important to define the optimal time period in order t reduce artifacts that we have in the analysis

37
Q

what is another issue to consider besides the introduction of artifacts that could lead to analytical variability?

A

we have intrinsic PCR errors that we can introduce during the amplification based on the PCR - it is important to have uniform genomic coverage if we are intending to use a second gen approach

38
Q

what is another type of variability that must be considered when analyzing samples?

A

we have a level of biological variability among different individuals who are affected by the same disorder, and the spatial or temporal localization of the tumor may influence the amount of nucleic acids present in the sample

39
Q

how do we determine what technique to use to analyze peripheral blood for liquid biopsy?

A

depends on the biological question

40
Q

what is the best approach to use if you want a comprehensive overview of the tumor?

A

NGS in order to have an analysis of the entire genome or the entire exome in a short amount of time

41
Q

what do we use if we are interested in the complexity of a sample?

A

we use a sequencing approach

42
Q

what do we use if we are looking for a single nucleotide mutation?

A

ddPCR → is specific for that mutation and allows us to quantify also a few molecules of mutated DNA

43
Q

what do we use for analysis if we are interested in the complexity of the profile?

A

exploit all exome sequencing

44
Q

what does massive parallel sequencing show us?

A

the complexity of the general molecular profile

45
Q

what do we use if we want a high sensitivity in our analysis?

A

ddPCR

46
Q

how does analysis change throughout the progression of a disease?

A

we have different applications at different stages → when we have an advanced stage, we have a higher release of the cell tumor DNA in the pb, so it is possible t use a less sensitive technique in order to measure the present levels

47
Q

what are the advantages of ddPCR for liquid biopsy?

A
  • fast
  • high sensitivity
  • possible to detect a specific mutation or copy number variation
  • cost effective
  • an easy bioinformatic analysis
48
Q

what is the downside to using ddPCR to interpret the results of a liquid biopsy?

A

we can only monitor a mutation that has already been identified

49
Q

what do we use if we do not know the specific mutation we want to analyze?

A

deep sequencing - allows us to detect the molecular profile of a tumor, however we must have a sufficient amount of starting material

50
Q

what does the percentage of the cell tumor DNA depend on?

A

location and severity

51
Q

how does knowing the tumor heterogeneity help with the management of the tumor?

A

it is useful to better identify the stage and the severity of the disorder as well as to identify the possible prognosis of the case

diagnosis of genetic diseases (18 decks)

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