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FRCPath > Hot Topics > Flashcards

Hot Topics Flashcards

1
Q

Name 5 genes associated with FH

A 
APOB
LDLR
PCSK9
APOE
LDLRAP (AR)
70-95% FH - APOB, LDLR, PCSK9 - Going to do MLPA on LDLR
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2
Q

When should FH be suspected?

A

Total cholesterol >7.5mmol/l

Personal or family history of premature CHD (event before age 60)

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3
Q

What is FH caused by clinically?

A

1) Decreased number of LDL receptors
2) Poor binding of receptors
3) Increased degradation of receptors

LDL (cholesterol rich lipoprotein) is recycled by the liver - LDL binds to receptor on surface and is internalised

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4
Q

What is incidence of FH

A

1/200-250

AD Disorder

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5
Q

Treatment for FH

A

Statins - inhibit cholesterol synthesis

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6
Q

Genes associated with Lynch Syndrome

A

MLH1, MSH2, MSH6, PMS2, EPCAM

Caused by defects in DNA mismatch repair MutS (MSH) and MutL(MLH) family of proteins

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7
Q

Which 2 main cancer types are associated with Lynch Syndrome?

A

Colorectal cancer and Endometrial cancer

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8
Q

What is molecular cause of Lynch?

A

Germline mutn in MLH1, MSH2, MSH6 or PMS2 followed by 2nd somatic loss of remaining copy - in almost all cases

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9
Q

Define anticipation

A

Signs and symptoms of genetic condition become more severe and appear at earlier age as disorder is passed from one generation to the next
Good eg - triplet expansion disorders

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10
Q

Define age related mosaicism

A

Accumulation of somatic/germline mutns over the course of someone’s life resulting in mosaicism
Good eg - loss of 1 X or Y to give 45,X cell line (benign) or cancer

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11
Q

Define Variable Expressivity

A

Phenotype is expressed to a different degree among individuals with the same genotype
Good eg: various neurosusceptibility loci in arrays, Marfan Syndrome

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12
Q

Define Penetrance

A

Proportion of individuals carrying a variant that expresses and associated trait
Good eg: BRCA1 - 80% lifetime risk of developing breast cancer

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13
Q

What can complicate the calculation of penetrance?

A

Ascertainment bias, attributable risk (would cancer arise without genotype), polygenic traits, cancer

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14
Q

Define TMB

A

Tumour mutation burden - number of small non-synonymous variants per Mb

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15
Q

What is DPYD

A

Pyramidine catabolic enzyme - initial and rate limiting factor in pathway of uracil and the midline catabolism

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16
Q

What is consequence of DPYD path mutn?

A

Error in pyrimidine metabolism - increased risk of toxicity in cancer patients receiving 5-fluorouracil chemotherapy

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17
Q

What drugs are relevant wrt DPYD testing?

A

Capecitabine and 5-fluorouracil - widely used treatment for solid tumours including colorectal and metastatic breast cancer

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18
Q

How many variants do we test for DPYD in Liverpool?

A

4 - 5 day TAT - either high risk of fatal toxicity (half dose/alternate therapy) or risk of severe toxicity (3/4 dose and raise over cycles)

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19
Q

Give some limitations of short read NGS

A

Affected by GC rush/repetitive regions
Hard to map around regions of structural variation
Mapping to imperfect reference genomes is difficult
Phasing of variants not possible if more than a few hundred bps apart

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20
Q

Give 2 egs of commercially available Long Read Sequencing technologies

A

Single Molecule Real time (SMRT) sequencing - PacBio

Nanopore sequencing - Oxford Nanopore Technologies

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21
Q

What are some limitations of Long Read Sequencing

A

For optimal LRS - fresh material or even intact cells are required
DNA isolation pro tools require improvements
Error rate is higher than that seen in short read sequencing
Currently more expensive than SRS
Data analysis pipelines not as mature and need more work

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22
Q

Ranges for Huntington Disease

A 
Normal - 6-25
Intermediate - 27-35 - risk of expansion down paternal line
Reduced Penetrance - 36-39
Affected - >39
Juvenile onset >60 rpts
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23
Q

Pathogenesis for HD

A

CAG rots Translated into polyglutamine tract thought to acquire deleterious function when abnormally expanded, neuronal degradation, accumulation of mutant protein in insoluble aggregates

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24
Q

Risk of expansion through transmission in HD depends on:

A

Repeat length
Age/sex transmitting parent
Family history
Sequence surrounding repeat - polys eg Glu2645del overrepresented in HD alleles compared to normal

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25
Q

What genes are involved in NTRK rearrangements

A

NTRK1, NTRK2, NTRK3 - Code for TRKA, TRKB and TRKC - collectively known as TRK
Neutrophil Receptor Tyrosine Kinases

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26
Q

Describe NTRK fusions

A

Inter-intra chromosomal rearrangements form hybrid genes - 3’ sequence of NTRK1/2/3 that include kinase domain are juxtaposed to 5’ sequences of a different gene
Chimaeric oncoprotein characterised by ligand-independent constitutive activation of the TRK kinase

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27
Q

Treatment for NTRK rearrangement cancers

A

First generation TRK tyrosine kinase inhibitors - Larotractinib or entrectinib - Immunotherapies - result in histology-agnostic responses in both adult and paediatric patients - generally well tolerated

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28
Q

Why would you mainstream genomics?

A

Strategy/policy - eg 100k
Equity of access
Clinical utility - improve diagnosis and better healthcare - reduce diagnostic odyssey
Increase knowledge
Workload - clinical genetics can deal with numbers
Technology - advances, cheaper etc

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29
Q

What are barriers to mainstreaming genomics?

A 
Education - complicated reports, access support
Appointment times
Focus on own specialism
Informed consent
Correct cascading/onward referral
Misinterpretation of results
Finance
IT
Routing samples
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30
Q

How could you educate clinicians as part of mainstreaming genomics?

A 
Embed in school/uni curriculum
Involved professional bodies
Engagement/training events
MDTs
Staffing - specialist educators
Apps/website/social media
National level - genomics England courses etc
Different formats that can be accessed at any time
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31
Q

Why is consent needed?

A

Person understands the nature and purpose of the procedure or intervention thereby asserting a right to self determination

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32
Q

What are 3 criteria required before consent is deemed legally valid?

A

1) person giving consent must have sufficient, appropriate information to be able to make a decision
2) They must be competent to make decision
3) Consent must be voluntarily given

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33
Q

What consent issues should be considered when families undergo trio analysis?

A 
VUS
IFs
Family implications of results
Non-paternity
Implications of negative result
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34
Q

What is the criteria for undertaking population screening?

A

Benefits should outweigh harm

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35
Q

What are potential benefits of whole genome sequencing of newborn screening blood spots?

A

Detect highly penetrant diseases/treatable diseases
Family choices - cascade testing etc
Additional findings - early monitoring/intervention
Data useful for later life - eg risk, prevention etc
Could reduce/stop diagnostic odyssey in some cases

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36
Q

What are the potential problems of whole genome sequencing of newborn blood spots?

A 
Consent and autonomy of child
No clinical context
Incidental findings 
Technical issues
Data storage and security
How can data be accessed throughout lifetime - IT infrastructure
Is it cost effective?
Do benefits outweigh harms?
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37
Q

What are the advantages of NIPT over current screening method for common aneuploidies?

A

High sensitivity and specificity
Reduced need for invasive testing
If strategy right should reduce costs

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38
Q

When can’t NIPT be used?

A 
Maternal malignancy
Blood transfusion in last 3 months
Transplant
Vanished/demised twin
Too early
More than twin preg
Also affected by maternal weight
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39
Q

What are 5 steps in Root cause analysis?

A

1) Gather info and define problem
2) Fill in the gaps
3) Analyse/identify root cause
4) Develop action plan - SMART
5) Recommend and implement solutions - PDSA cycles

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40
Q

What considerations can you make to reduce costs in lab?

A

Staff costs
Non staff costs - eg renegotiate contracts, eliminate waste, stationary costs, estate costs, rationalise/improve tests
Income generation

41
Q

What are 4 tiers of CNVs and CN-LOH in neoplasticism disorders?

A

1 - Variants with strong clinical significance
1a - specific entity in WHO classification/professional guidelines or germline path variant with cancer predisposition
1b - Assoc with specific neoplasm/prog/treatment response as shown by evidence with expert consensus
2 - Variants with some clinical significance
3 - Clonal variants with no documented neoplastic disorder associated
4 - Benign/likely benign variants

42
Q

WHO recommendations for Lynch testing

A

1) Immunohistochemistry 4-panel test for MLH1, MSH2, MSH6 and PMS2 OR do macrosatellite instability test
2) If MLH1 immunohistochem test or MSI test abn do BRAF V600E
3) If BRAF -ve do MLH1 promotor hypermethylation
4) If Hypermethylation -ve -confirm Lynch by genetic testing of germline DNA

43
Q

Name 7 classes of Myeloproliferative Neoplams

A

1) CML
2) Polycythaemia Vera
3) Essential Thrombocytopenia
4) Primary Myelofibrosis
5) Chronic neutrophilic leukaemia
6) Chronic eosinophilic leukaemia
7) MPN - Unclassifiable

44
Q

What variant causes majority of Polycythemia Vera?

A

JAK2 p.V617F - 95%

If negative can do JAK2 exon 12 granulocyte DNA sequencing - need fresh sample

45
Q

What would your testing pathway be for Essential Thrombocytopenia/Primary Myelofibrosis?

A

JAK2 p.V617F
CALR mutn testing
MPL mutn testing
Can see triple negative so can’t exclude diagnosis
CALR - 80% type 1 (52bp del) or Type 2 (5bp insertion)
MPL - Commonly W515L, also see W515A and W515R

46
Q

What 3 rare cancers are NTRK rearrangements seen in at over 90%

A

Infantile fibrosarcoma - ETV6-NTRK3 most common
Mammary analogue secretory carcinoma
Breast secretory carcinoma

47
Q

Who will get NTRK testing/treatment as it stands?

A

Metastatic refractory relapse patients

48
Q

What is WHO classification of AML?

A

1 - AML with recurrent genetic rearrangement/abnormality
2 - AML with myelodysplasia related changes
3 - AML related to previous chemo/radiation
4 - AML NOS
5 - AML Myeloid Sarcoma
6 - Myeloid proliferations related to Down Syndrome

49
Q

Name 3 favourable abnormalities in AML

A

T(8;21)(q22;q22) - RUNX1/RUNX1T1
T/inv(16)(p13.1q22) - CBFB/MYH11
T(15;17)(q24;q21) - PML/RARA

50
Q

Name 3 unfavourable abnormalities in AML

A 
Deletion of part of chrm 5 or 7
T/inv(3)(q21q26.2) RPN1-EVI1
T(6;9)(p23;q34) DEK-NUP214
T(9;22)(q34;q11) BRC-ABL1
Abn of 11q23 - KMT2A
Monosomy
Complex karyotype
51
Q

Name 2 treatments for AML

A

High dose cytarabine - t(8;21) or t/inv(16)

ATRA - t(15;17)

52
Q

Name 5 partners to IGH in Multiple Myeloma

A 
FGFR3 - Poor prog - 4p16.3
CCND1 - Good prog - 11q13
MAF - Poor prog - 16q23
CCND3 - Good prog - 6p21
MAFB - Poor/very poor prog - 20q11
(IGH 14q32)
53
Q

What are the European Myeloma Recommendations for FISH

A

1) IGH-MAF + IGH/FGFR3, TP53, 1p/1q del’s
2) IGH-CCND1, IGH-MAFB, Ploidy, chrm 12 and 13 abn’s

Karyotype doesn’t work well for Myelomas - enrich for FISH with CD138+ to reduce false -ves

54
Q

What must your ALL testing strategy encompass?

A
  1. Ploidy levels
  2. KMT2A rearr’s
  3. ETV6-RUNX1
  4. BCR-ABL1, TCF3-PBX1, TCF3-HLF
  5. CNVs
  6. iAMP21
  7. ABL like rearrangements
  8. IGH
55
Q

What is the common translocation in Ewing Sarcoma?

A

t(11;22)(q24;q12) EWS-FLI1

56
Q

What FISH would you do for a Rhabdomyosarcoma?

A

FOXO1 B/A and if positive do PAX3 and PAX7 to determine partner - positive consistent with Alveolar Rhabdomyosarcoma. Don’t see FOXO1 rearrangements in Embryonal Rhabdomyosarcoma

57
Q

What proportion of PWS results from del/UPD

A

75-80% PATERNAL del

20-25% MATERNAL UPD

58
Q

What proportion of AS is due to del/UPD/UBE3A mutn

A

70-75% MATERNAL del
3-7% PATERNAL UPD
10% UBE3A mutation
Around 10% NAD

59
Q

Translocation seen in CML

A

t(9;22)(q34;q11) - BCR-ABL1
5’ end of BCR fused with 3’ end of ABL1 - fusion oncogene on dear (22) has elevated and disregulated tyrosine kinase activity

60
Q

Treatments of CML

A

Imatinib - Tyrosine Kinase inhibitor

Second generation TKIs - Nilotinib and Dasatinib

61
Q

Fanconi Anaemia - gene and test

A 
Whole range of FA complement genes - mutns in FANCA account for nearly 2/3 cases
Mytomycin C (or DEB) - breakage testing - set up different conc’s and see a proportional response - need control
62
Q

Bloom Syndrome - gene and test

A

BLM - 15q26.1

Harlequin staining - sister chromatid exchange - 6-10/cell in normal, >50 in Bloom Syndrome

63
Q

Pathogenic mutation in Fragile X Syndrome

A

Hypermethylation of FMR1 - no FMRP protein product
Over 200 CGG repeats
More likely to expand down maternal line

64
Q

What are the mutn ranges of FMR1

A

Normal - 5-44 repeats
Intermediate - 45-54 rpts - Risk of expansion (esp maternal)
Premutation - 55-200 rpts - FXTAS/POI risk
Full mutation - >200 rpts - FRAX

65
Q

Double paternal contribution triploidy?

A

Diandry - Cystic villi that have trophoblastic hyperplasia -> Partial hydatidiform mole - most common form of triploidy

66
Q

Double maternal contribution triploidy?

A

Dygyny - Non hydronic villi, placenta non molar and generally small

67
Q

What is a complete hydatidiform mole?

A

Diploid androgenetic pregnancy where both sets paternally derived
No fetal development, extensive hydrops, placenta have swollen villi and marked widespread hyperplasia of trophoblast

68
Q

What is risk of invasive mole following molar pregnancy?

A

15% following complete mole
0.5% following partial mole
Invasion of myometrium which can lead to perforation of uterus - indicated by raised hCG so monitoring recommended

69
Q

What are technical challenges associated with cffDNA isolation

A

1) The concentration of cfDNA is low
2) cffDNA is outnumbered by cfmDNA
3) Half the fetal genetic material is maternal in origin and therefore indistinguishable

70
Q

Some benefits for NIPT/NIPD

A
  • Reduce number of invasive tests - safer, cheaper and less expertise to take blood
  • Earlier diagnosis
  • Reduced trauma for parents
  • Improved quality of care
71
Q

Some limitations of NIPT/NIPD

A
  • In multiple pregnancies can’t distinguish fetuses
  • Proportion of cfDNA in mother with high BMI is low - increases false -ves and inconclusives
  • Source of cffDNA is placental - brings around usual limitations
  • False +ves/-ves - ff too low, contamination, maternal abnormalities, vanishing twin, triploidy
72
Q

What is the most common 46,XY DSD

A

Androgen Insensitivity Syndrome

73
Q

What is the most common 46,XX DSD

A

Congenital Adrenal Hyperplasia

74
Q

Define validation

A

Testing performed as part of QA programme to determine performance metrics and document evidence that the assay fulfils the requirements for its intended purpose prior to implementation
Are you doing he right test?

75
Q

Define verification

A

Testing performed as part of a QA programme to confirm that an assay performs as expected according to the performance metrics as defined during previous test validation
Are you doing the test correctly?

76
Q

Discuss testing strategies for BRCA1/2

A

Sequence analysis of all genes - NGS
Targeted analysis for certain ethnic groups
Dosage analysis
Tumour DNA can be examined for LOH
- Co-segregation complicated by phenocopies and incomplete penetrance

77
Q

What are some ethical considerations of predictive BRCA1/2 testing

A

Need genetic counselling - age on onset highly variable
Treatment may be mastectomy or increased screening - need to be sure about pathogenicity
Prenatal testing and testing of minors not usually offered
Mutn carrier may not disclose mutn to other family members - then they can’t access testing
Individual might not want testing but other family members might inadvertently determine their result

78
Q

What pan-cancer markers are there in the TSO500 panel

A

TMB
NTRK1,2,3
MSI

79
Q

What cancers are covered as part of the TSO500 Panel?

A

Lung, bladder, melanoma, breast, colon, ovarian, gastric, myeloid, sarcoma

80
Q

What is synthetic lethality?

A

Synthetic lethality arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. Good example is use of PARP inhibitors in BRCA cancer

81
Q

How do PARP Inhibitors work?

A

BRCA mutated cells lack homologous recombination repair and therefore rely on base excision repair. PARP enzymes involved in BER therefore if you inhibit them, BRCA mutant cells die

82
Q

What risk do BRCA1/2 mutns confer?

A

BRCA1 - 60-85% BC, 40-60% OC, <1% male BC

BRCA2 - 40-85% BC, 30% OC, 10% Male BC (prostate too)

83
Q

When should you consider BRCA test?

A

Early onset BC, 2+ primaries, BC and OC in same person, OC/BC in family, FHx of BRCA mutn, Ashkenazi Jewish, Male BC, personal Hx OC, Bilateral BC
NICE suggests testing if 10% risk of BRCA mutn

84
Q

What are some advantages of data sharing?

A

Making accurate/safe diagnosis
More effective disease management and precision medicine
Accurate advice for family members
Improved understanding of genetic disease

85
Q

What are some barriers to data sharing

A 
Time/resources 
Nomenclature
Transcripts/genomes build
Technology/confidence range
Inheritance
Phenotype
86
Q

Repeat ranges for Myotonic Dystrophy

A

5-34 repeats - Normal
35-49 repeats - Mutable normal
>50 repeats - Affected
Increased CTG repeat expansion in DMPK

87
Q

What is a polygenic risk score?

A

Mathematical aggregate of risk conferred by many DNA variants to estimate the likelihood of a specific outcome such as disease onset in an individual

88
Q

How can polygenic risk score models differ from each other?

A

Number of genetic variants considers
Specific type of statistical model used to combine risks
Ability to score to generalise to entire population

No universally agreed upon standards for developing polygenic risk scores

89
Q

Give some egs of disorders where polygenic risk scores may be in use in the near future

A

FH

Breast Cancer

90
Q

What issues are associated with DNA extracted from FFPE tissues

A

Hydrolysis of phosphodiester bonds - varying degrees of DNA fragmentation
Cross linking - artificial nucleotide mutations
Limited yield of DNA at extractions

91
Q

What are limitations of direct tumour sampling?

A

Accessibility of tumour
Frequency of sampling
Existence of clinical overt disease
Cost

92
Q

What can affect ctDNA testing

A 
Anatomical site of disease
Heterogeneity 
Field defects
TMB
Blood/brain barrier
Age related clonal haematopoesis
93
Q

Where could ctDNA testing be useful

A

Pre cancer diagnosis and monitoring
MRD
Recurrent/metastatic disease

94
Q

What are some benefits to pharmacogenomic testing

A 
Safer dosing options
Avoid drug toxicity and adverse side effects
Ensure maximum efficacy
Improve drug development
Explain variable response to drugs
Reduce healthcare costs
95
Q

What are pharmacokinetics and pharmacodynamics?

A

Pharmacokinetics: What the body does to the drug - absorption, distribution, metabolism, elimination

Pharmacodynamics: What the drug does to the body - Target proteins, downstream messengers

96
Q

Give some cancer pharmacogenomic drug egs

A

Breast - Herception (overexpression of HER2) or Olaparib (BRCA mutn, PARP inhibitor)
Lung - Gefitinib (EGFR activating mutations, is an EGFR tyrosine kinase inhibitor)
Pan cancer - Entractinib/Larotractinib (NTRK rearrangements)

97
Q

Give some examples of adverse drug reactions due to genetics

A

Gentamicin - m.1555A>G - mit deafness
Sodium valproate - anti-retroviral therapy in HIV - HLA-B*57:01 allele - liver toxicity
5FU and Capecitabine - Chemo - DPYD variants - risk of toxicity

98
Q

Give some egs of targeted germline therapies

A

Ivacaftor/Lumacaftor (orkambi) - CF p.Phe508del
Ataluren - DMD - stop codon read through
EXONDYS51 - DMD - exon skipping
Spiranza - SMA

99
Q

What is BSGM statement on DTC testing

A

Analytical validity, sensitivity and clinical utility is low
High chance of false positive and false negative results
Patients should be offered NHS care that they would otherwise receive regardless of DTC result

FRCPath (9 decks)

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