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Mol Path FRCPath Part 1 - 2022 > Solid Tumours > Flashcards

Solid Tumours Flashcards

1
Q

What are the prognostic implications/grading associated with an IDH1/2 variant in a glioma and what testing methods can be used?

A

IDH1/2 variants define grade 2/3 astrocytomas and oligodendrogliomas and the secondary grade 4 glioblastomas into which astrocytomas can evolve. Their presence distinguishes lower grade gliomas from primary glioblastomas which are IDH wildtype.

IDH1/2 variants are associated with a relatively favourable prognosis and are commonly associated with MGMT methylation. In grade 2/3 gliomas, wild type IDH1/2 is associated with increased risk of progressive disease.

Diffusely infiltrative astrocytomas with IDH1/2 are mostly grade 2/3, however some develop grade 4 histological features associated with worse prognosis.

The most common IDH1 variant R132 can be detected by IHC with sequencing of IDH1/2 recommended if negative

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2
Q

What is 1p/19q co-deletion diagnostic of, how is it tested for and what is the associated prognosis.

A

The occurance of a 1p/19q co deletion is diagnostic of oligodendroglioma and is always seen alongside an IDH1/2 variant which is also needed for a diagnosis of oligodendroglioma.

The co-deletion is associated with a favourable prognosis.

Detection can be carried out by FISH, PCR, Array based (e.g. SNP array) or NGS

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3
Q

For which types of brain tumour is MGMT promoter methylation carried out, what is the role of the MGMT protein, how is it tested for and what genetic changes is it associated with?

A

MGMT promoter methylation is essential in the workup of all high grade gliomas - grade 3/4.

MGMT is a DNA repair enzyme which reverses the DNA damage caused by alkylating agents.MGMT unmethylated is active and results in resistance to temozolomide chemotherapy. MGMT methylation silences the protein and makes it more sensitive to treatment with alkylating agents.

MGMT promoter methylation can be tested by methylation specific PCR, methylation specific high res melt analysis, pyrosequencing and ddPCR. Pyrosequencing is considered the best method and prognostic stratifier in GBMs treated with temozolomide.

MGMT methylation is strongly associated with IDH mutations and genome-wide methylation epigenetic changes (G-CIMP phenotype)

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4
Q

What type of brain tumour is ATRX mutations associated with, what genetic changes are they seen with and not seen with and how can it be tested for?

A

ATRX mutations are associated with astrocytomas.

They are strongly associated with IDH mutations and are mutually exclusive with 1p/19q codeletions.

ATRX mutations can be detected by IHC and/or sequencing.

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5
Q

What is the clinical significance of the K27M in H3F3A/HIST1H3B and G34V variants in H3F3A in brain tumours?

A

Histone variants tend to occur in paediatric midline gliomas. The K27M variant is an adverse prognostic marker and the G34V variant does not have a prognostic association after a diagnosis of GBM is made.

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6
Q

What is the clinical significance of the BRAF V600E and BRAF Fusion variants in brain tumours?

A

BRAF V600E - present in 60-80% of supratentorial grade 2/3 pelomorphic xanthoastrocytomas (PXA), 30% of dysembryoplastic neuroepithelial tumours, 20% of grade 1 gangliomas and 5% of grade 1 astrocytomas.

The presence of a BRAF fusion is reliable evidence that the tumour is a pliocytic astrocytoma.

BRAF fusions tend to be indolent but BRAF V600E is associated which a much greater range of outcomes and may be associated with response to BRAF inhibitors.

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7
Q

What are the molecular hallmarks of a glioblastoma?

A

EGFR amplification/mutation
IDH wt
TERT mut
chr10/PTEN del

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8
Q

What cancer type and associated variant is the FGFR inhibitor Pemigatinib approved for?

A

Cholangiocarcinomas with FGFR2 fusions (drivers)

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9
Q

What occurs structurally in driver FGFR2 fusions?

A

Typically occur from in frame fusion between 5’ end of FGFR2 and a partner gene.

FGFR2 is located on chromosome 10, 50% of FGFR2 fusions are caused by intrachromosomal events

FGFR2 retains the extracellular domain and kinase domain and the partner contributes to a dimerisation signal causing pathway activation.

The breakpoint in FGFR2 is nearly universally within intron 17 or exon 18 but there have been over 150 partner genes detected

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10
Q

How does activation of TRK proteins occur and what are the downstream effects?

A

TRK activation occurs through the autophosphorylation of intracellular tyrosine residues ultimately resulting in activation of signalling pathways regulating transcription of genes involved in differentiation.

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11
Q

What does a typical NTRK gene rearrangement look like?

A

Typically NTRK rearrangements are caused by intra or inter chromosomal rearrangements to from hybrid genes in which the 3’ sequence of NTRK1/2/3 that includes the kinase domain are juxtaposed to the 5’ sequence of a different gene. This produced a chimeric oncoprotein characterised by ligand dependant constitutive activation of the TRK kinase.

Upstream partners often contain oligodimerisation domains such as coiled-coil, zinc finger or WD repeats.

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12
Q

In which cancer types are NTRK1/2/3 rearrangements most common?

A

Rare cancer types are highly enriched for NTRK1/2/3 fusions with a prevalence of up to 90% in some cancer types.

NTRK fusions are found in more common cancers at a much lower frequency (5-25%0

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13
Q

What testing methods can be used to detected an NTRK1/2/3 fusion?

A
  • FISH
  • RT-PCR
  • However, most commonly used is NGS. RNA-Seq is typically used as large intronic regions in NTRK2 or NTRK3 can lead to difficulties in detection using DNA
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14
Q

What are the approved TRK inhibitors (NICE) for use for patients with NTRK1/2/3 rearrangements?

A

Larotrectinib and Entrectinib.

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15
Q

What causes the secondary resistance to TRK inhibition?

A

The only mechanism identified to date is the acquisition of mutations in the kinase domain of the fusion.

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16
Q

What characterises low grade and high grade breast cancer?

A

Low grade - gain of 1q, loss of 16q, infrequent amp of 17q12

High grade - loss of 13q, gain of 11q13, amplification of 17q12 (containing ERBB2 encoding HER2)

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17
Q

Determination of expression of what markers is required in breast cancer?

A

Oestrogen reception (ER), Progesterone reception (PR) and HER2

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18
Q

What is the clinical significance of ERBB2 (HER2) amplification in breast cancer?

A

HER2 amplification can be targeted with the anti-HER2 monoclonal antibody trastuzumab

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19
Q

What gene expression signature assay is part of the genomics test directory for breast cancer and what is the significance?

A

OncotypeDX

Gene expression signatures in breast cancer classifies breast cancer patients as high or low risk which helps in identifying patients where chemotherapy should be added to the treatment regime.

Low - No chemo
High - Chemo added

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20
Q

What inherited cancer syndromes are associated with colorectal cancer?

A

Lynch syndrome and familial adenomatous polyposis (FAP)

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21
Q

Pathogenic mutations in which genes are causative of lynch syndrome and what is the function of this group of genes?

A

MLH1, MSH2, MSH6 and PMS2

DNA mismatch repair genes (MMR)

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22
Q

What is the NICE CRC Lynch testing pathway?

A

IHC for lynch genes and/or MSI analysis

  • If MLH1 abnormal proceed to germline testing
  • If MSI-H or MSH2, MSH6 or PMS2 abnormal proceed to BRAF analysis
  • If negative (IHC or MSI) - likely sporadic

BRAF V600E analysis

  • If not variant detected proceed to MLH1 promoter hypermethylation analysis
  • If positive - likely sporadic

MLH1 promoter hypermethylation analysis

  • If negative proceed to germline testing
  • If positive - likely sporadic
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23
Q

What treatment/prognostic implications does the detection of MSI-H in CRC have?

A
  • MSI-H is more frequent in stage II than stage III disease where it is considered a favourable prognostic marker
  • MSI-H status predicts decreased benefit from adjuvant chemotherapy with a fluoropyrimidine alone in patients with stage II disease (5-FU)
  • MSI-H tumours are sensitive to PD-1 inhibitors (immunotherapy)
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24
Q

What is the significance of KRAS and NRAS driver variants in CRC and what are the hotspots?

A

CRC with KRAS or NRAS driver variants in the known hotspots in exons 2, 3 and 4 are insensitive to cetuximab and panitumumab (EGFR inhibitors)

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25
Q

What is the significance of BRAF V600E variants in CRC?

A
  • Confers a poor prognosis regardless of treatment
  • Makes response to cetuximab and panitumumab (EGFR inhibitors) unlikely unless given alongside a BRAF inhibitor.
  • Tend to be mutually exclusive with KRAS/NRAS driver variants
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26
Q

What type of treatment does DPD efficiency cause toxicity to?

A

Treatment with fluoropyrimidines - 5-fluorouracil (5FU) and capecitabine

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27
Q

What does the dihydropyrimadine dehydrogenase (DPD) enzyme do and what happens when DPD is deficient?

A

DPD is the first step and rate limiting enzyme for the catabolism of fluoropyrimidines. Reduced DPD activity results in reduced clearance and increased half life of fluoropyrimidines (5FU and capecitabine) and can cause profound dose related toxicities.

28
Q

What are the four clinically relevant DPYD variants and their associated impact on DPD function?

A

c. 1905+1G>A (DPYD2A) - null function
c. 1979T>A (DPYD13) - null function
c. 2846A>T - Moderate function
c. 1129-5923C>G (HapB3) - Moderate function

29
Q

What variant is in perfect linkage disequilibrium with the DPYD c.1129-5923C>G variant?

A

The synonymous variant c.1236G>A

This can be used as a proxy when testing

30
Q

What percentage of the European population is estimated to have a clinically relevance DPYD variant?

A

7%

31
Q

What are the three categories of DPD metabolisers and associated activity and dosing of these?

A

DPYD Poor metabolisers (DPYD AS:0.5 or 0)

  • Carriers of two no function DPYD variants (AS 0)
  • Carriers of one no function and one decreased function DPYD variant (AS 0.5)
  • AS 0.5 - Avoid use of 5FU. If alt not available should be used at a strongly reduced dose with careful monitoring
  • AS 0 - Avoid use of 5FU

DPYD Intermediate metabolisers (DPYD AS:1 or 1.5)

  • Carriers of one no function DPYD variant (AS 1)
  • Carriers of one decreased function DPYD variants (AS 1.5)
  • Carriers of two decreased function DPYD variants (AS 1)
  • AS 1 - Reduce dose by 50%
  • AS 1.5 - Reduce dose by 25-50%
  • Intermediate metabolisers may tolerate full dose so dosing should be increased in subsequent cycles when patients experience none or clinically tolerable toxicity in the first two cycles.

DPYD normal metabolisers (DPYD AS:2)

  • No clinically relevant DPYD variants
  • Normal dosing as per = manufacturers instructions
32
Q

Fusions involving which gene is characteristic of a diagnosis of Ewings Sarcoma?

A

EWSR1 fusions

Note this is not diagnostic as also seen in other tumour types

33
Q

What group of genes is EWSR1 frequently fused to in Ewings Sarcoma?

A

It can be found most frequently fused to members of the E26 transformation specific / Erythroblast transformation specific (ETS) family of transcription factors including FLI1, ERG, ETV1, ETV4 and FEV.

The ETS family comprises of 29 genes all of which contain a highly conserved DNA binding domain called the ETS domain

There are a number of non-ETS gene fusions also seen in other types of soft tissue sarcomas.

34
Q

What are fusions in EWSR1 in Ewings Sarcoma often caused by and what is the prognostic significance?

A

Fusions are generated by chromoplexy in 42% of cases which disrupts multiple genes and is associated with a more aggressive disease.

35
Q

What secondary events are often seen in Ewings Sarcoma and what is the associated prognosis?

A

Gain of chr8 (30-35%) - No significance
Gain of chr12 (25-33%) - Adverse prognosis
Gains of chr2 - Positive prognosis
Unbalanced translocation t(1;16)(q12;q11.2) (10-30%) - Poor prognosis
Deletions in short arm of chr9 (9p21, CDKN2A) - Poor prognosis
Inactivating mutations in STAG2 and TP53
CDKN2A Deletions

36
Q

What testing is carried out for Ewings Sarcoma?

A
  • Cytogenetics - Detect translocations etc

- Break apart of EWRS1 (FISH, RT-PCR, NGS), where possible techniques which can identify the partner are preferable

37
Q

What could cause an EWSR1 fusion to not be detected in an Ewings Sarcoma?

A

A fusion involving the FUS gene will give a false negative result when using breakapart probe FISH as EWSR1 is not translocated in these cases

EWSR1-FUS fusion neg undifferentiated round cell sarcoma are characterised by CIC-DUX4 fusions (t(4;19), t(10,19))

38
Q

What are the main types of EGFR variants which are sensitizing to treatment with TKIs in lung cancer?

A 
Exon 19 deletions (most common)
Exon 21 L858R (most common)
Exon 19 insertions
L861Q
G719X
S768I
39
Q

Activation of what domain occurs in EGFR activating variants?

A

Tyrosine kinase domain

40
Q

What type of EGFR variants are resistant to first line TKI treatment?

A

Exon 20 insertions

41
Q

What is the clinical significance of the EGFR T790M variant and when does it occur?

A

T790M is associated with acquired resistance to EGFR TKI therapy and is identified in ~60% of patients who have progressed.

T790M may rarely occur in patients who have not had TKI treatment. Counseling is recommended for patients who have this variant pre-treatment as it suggests it may be germline in origin and is associated with predisposition to Lung Cancer.

42
Q

What is the clinical significance of BRAF variants (V600E and non-V600E) in lung cancer?

A

BRAF driver variants occur in 1-2% of lung cancer cases.

BRAF V600E typically occurs in current/former smokers and do not typically occur alongside EGFR, MET ex14, RET, ALK or ROS variants.

For patients with the BRAF V600E variant, combination therapy with dabrafenib and trametinib is recommended (BRAF inhibitor and MEK inhibitor)

Non-BRAF V600E variants impact on therapy is yet to be established.

43
Q

What types of variants can be found in MET in lung cancer skipping and what is the function of MET

A

MET (C-MET), the hepatocyte growth factor (HGF) receptor is a tyrosine kinase receptor that is involved in cell survival and proliferation.

Driver variants in MET include exon14 skipping mutations, MET gene copy number gain/amplification and MET overexpression.

44
Q

What is the clinical significance of MET variants in lung cancer?

A

Capmatinib (MET inhibitor) has been approved for treatment by the FDA but is still under review by NICE.

45
Q

What is the function of RET/ALK/ROS1, what types of RET/ALK/ROS1 variants are identified in lung cancer and what is the clinical significance?

A

RET, ALK and ROS1 aretyrosine kinase receptors involved in cell proliferation.

RET, ALK and ROS1 rearrangements can be identified in lung cancer and may occur with a number of genes (e.g. KIF5B, CCDC6) which leads to overexpression of the RET, ALK or ROS1 protein.

Patients with rearrangements in these genes have been shown to respond to RET, ALK or ROS1 tyrosine kinase inhibitors.

46
Q

What phenotype are KRAS variants associated with in lung cancer and what are there clinical significance?

A

KRAS variants are associated with cigarette smoking and are associated with a shorter survival than patients who are KRAS wildtype. Patients with KRAS driver variants do not respond to EGFR TKIs.

47
Q

What is the most common and leather type of ovarian cancer?

A

High grade serous ovarian cancer.

48
Q

What is homologous recombination deficiency (HRD)?

A

The homologous recombination pathway allows the repair of double stranded DNA breaks. HRD is a deficiency in the HR system for repairing double stranded breaks.

49
Q

Genomic instability is a hallmark for disruption of which pathway?

A

Homologous recombination

50
Q

What are the main (known) causes of HRD?

A

Germline or somatic mutations in BRCA1/2
Mutations on the Fanconi Anaemia pathway genes
Mutations in the mismatch repair genes

51
Q

What is the currently only known mechanism for PARPi resistance (primary or acquired)

A

Reverse mutations in the BRCA genes that can reinstate the homologous recombination pathway.

52
Q

How do PARP inhibitors work?

A

PARP is an enzyme required to repair single-stranded DNA breaks. When PARP is inhibited, it leads to an accumulation of single-strand breaks. When PARPi are used in a patient deficient in double-stranded DNA breaks, this leads to tumour death because neither single strand or double strand breaks can be repaired. This is a phenomenon called synthetic lethality.

53
Q

What are the main categories of HRD test?

A

1) HRR pathway related genes - specific cause of HRD
2) Genomic ‘scars’ or mutational signatres which measure the pattern of somatic mutations that accumulate rather than the underlying defect.
3) Functional assays that can provide a real time read out of HRD.

54
Q

What gene level tests can be used to detect HRR deficiency?

A

1) Germline testing to detect inherited pathogenic variants including the large dels/dups senn in BRCA1/2
2) Tumour testing through extraction of DNA from the ovarian tumour and tested for driver/pathogenic variants. - About 2/3 of BRCA variants have been shown to be germline in origin

55
Q

What types of variants are associated with HRD?

A

Driver variants in HR pathway genes
Thousands of somatic mutations - SNVs and short deletions and tandem duplications
BRCA1 / RAD51 promoter methylation
Deletions of large stretches of DNA (<15Mb)
Telomeric Allelic Imbalance
Large scale transitions

56
Q

What is the commercial assay for HRD currently available through funding from AstraZeneca and how does it work?

A

MyChoice HRD - Myriad
Diagnostic test using FFPE - FDA approved
Assessed SNVs, insertions, deletions and large rearrangements to determine a genomic instability score (GIS). A positive test has a GIS >42

57
Q

What is the genomic signature which is a proposed biomarker for HRD?

A

SBS Signature 3 (COSMIC)
Associated with BRCA1/2 mutation and BRCA1 promoter hypermethylation

Unlikely to be a robust clinical biomarker in isolation

58
Q

How does the HRDetect algorithm work?

A

Algorithm uses a combination of all four mutation classes and measures the features with different weighting

  • Indels (2.398)
  • SBS Sig 3 (1/611) and Sig 8 (0.091)
  • SVS Sig 3 and Sig 5 (0.847)
  • CNV HRD Score (Same as myraid) (0.667)
59
Q

What are the advantages and disadvantages of using a mutational signature for detection of HRD?

A

Advantages
-Strong clinical evidence i can outperform scar assays (myriad)

Disadvantages

  • Needs to be done on fresh tissue as there are too many artefacts from FFPE
  • Provides a historical representation of HRD and doesn’t consider HRD status could be reinstated
60
Q

What biomarkers should be tested in metastatic melanoma and what are the clinical significance of these?

A

BRAF - Patients with activating variants in BRAF have been shown to respond to BRAF inhibitors. BRAF inhibitors are approved for patients with a V600 variant. Co-administration of MEK inhibitors with BRAF inhibitors increases the effects however has not demonstrated any response when given alone.

KIT - Metastatic melanoma patients with an activating variant in KIT have been shown to be more likely to respond to imatinib (TKI) compared to patients without a KIT variant (clinical trials, not yet approved). KIT driver variants are more frequently identified in mucosal and acural subtypes of melanoma.

NRAS - Driver variants correlate with poor survival in localised and advanced melanoma. MEK inhibitors produce response in a minority of patients with NRAS variants.

61
Q

In what genes are variants most commonly identified in GIST and what is the clinical significance?

A

KIT and PDGFRA - testing should be carried out for all patients where TKI (Imatnib) treatment is being considered.

KIT
KIT variants identified in 80% of GIST patients
90% of patients with an exon 11 mutation and 50% with an exon 9 variant respond to treatment with imatinib.

PDGFRA
PDGFRA variants identified in 5-10% of GIST patients
Most variants associated with response to imatinib with the exception of the D842V variant which is unlikely to respond to imatinib and most other approved TKIs.

62
Q

What can cause secondary resistance to TKI’s in GIST and what treatment is recommended in these circumstances?

A

Imatinib resistant mutations in KIT or PDGFRA.

Sunitinib is recommended for patients who are not responding to imatinib. Regorafenib is recommended for patients who are not responding to imatinib or sunitinib.

63
Q

Inactivation of what complex can be seen in GIST patients, how is it tested for and what is the significance?

A

About 10-15% of GIST patients have inactivation of the succinate dehydrogenase (SDH) complex which can be detected by a lack of SDHB expression on IHC. In activation may occur by mutation or epigenetic silencing.

GISTS with SDH inactivation typically arise in the stomach of younger individuals and are usually resistant to imatinib . Patients may benefit from treatment with Sunitinib or Regorafenib. Referral to clinical genetics is recommended as patients with an SDH deficient GIST may have a germline SDH variant,

64
Q

What molecular alteration is characteristic of uveal melanoma and what is the clinical significance?

A

Mutations of GNAQ or GNA11 (>80% of cases).

Studies of MEK inhibitors has yielded mixed results with no clear correlation. Patients may be able to access trials

65
Q

What is the function of IDH1 and IDH2, and what downstream effect do hotspot mutations in these genes have?

A

They encode isocitrate dehydrogenase 1 and 2, which are enzymes that convert isocitrate into alpha-ketoglutarate during the Krebs cycle. Mutations impair the cell’s ability to carry out aerobic respiration (contributing to the Warburg effect) and the reduced alpha-ketoglutarate results in increased methylation patterns.

Mol Path FRCPath Part 1 - 2022 (14 decks)

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