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Oncology > cancer > Flashcards

cancer Flashcards

1
Q

Whats the normal function of an oncogene and how are they activated in cancers

A

Control cell proliferation, or apoptosis, or both.

Activated by 1) structural alterations (mutation or gene fusion). 2) juxtaposition to an enhancer element. 3) amplification

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2
Q

what are the 6 classes of oncogenes and give an example

A

1) growth factor receptors: EGFR, PDGFRA/B, RET.
2) Signal tranducers: N/H/KRAS, ABL1, BRAF, AKT.
3) Growth factors: PDGFA/B, WNT.
4) Inhibitors of apoptosis: BCL2, MDM2.
5) Transcription factor: MYCN, MYC, EWSR1.
6) Chromatin remodellers: KMT2A.

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3
Q

Give an example of an oncogene thats activated by amplification

A

ERBB2 (HER2): breast cancer.

MYCN: neuroblastoma.

MET: renal cell carcinoma, glioma.

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4
Q

Give an example of an oncogene thats activated by mutations

A

H/K/NRAS: metatstatic CRC, lung, breast, bladder, AML.

BRAF: malignant melanoma, metastatic CRC, hairy cell leukeamia.

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5
Q

Give an example of an oncogene thats activated by chr rearrangements

A

Chimieric gene: BCR-ABL1

Position effect: MYC-IGH

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6
Q

Whats the normal function of a tumour suppressor gene and what are the types

A

involved in the restrain of cell growth and stimulate cell death.

Gatekeeper genes: TP53, Rb, CDKN2A, APC.

Caretaker genes: MLH1, MSH2,6.

(?) Landscaper genes: PTEN

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7
Q

Discuss CDKN2A function

A

encodes 2 structurally unrelated proteins:

p16INKA: inhibits CDK4,6: LoF causes Rb activaton

p14ARF: destabilises MDM2 & maintains TP53 levels: LoF increases MDM2 levels causing loss/destruction of TP53.

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8
Q

discuss TP53 function

A

in the centre of the network of signalling pathways essential for growth, regulation and apoptosis. its induced by genotoxic and non-genotoxic stress.

stressed cell: TP53: phosphorylated and acetylated: migration and increased levels of TP53.

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9
Q

discuss TP53 LoF types

A

mutations upstream of TP53: ATM & CHK2.

deletion of TP53: CLL

TP53 mutation: 50% somatic cancers: mutant p53: dominant negative effect (forms tetramers)

mutations downstream of TP53: PTEN

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10
Q

Name as microRNA TSG and its asscoiated cancer

A

miRNA-145: NSCLC

iRNA-34 family: lumg cancer

miRNA- 15a/16-1 cluster: B-CLL

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11
Q

what inherited and sporadic cancer is APC associated with

A

FAP: familial adenomatous polyposis

colorectal cancers

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12
Q

what inherited and sporadic cancer is MLH1, MSH2,6 associated with

A

HNPCC: Hereditary non polyposis colorectal cancer

CRC, gastric, endometrial

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13
Q

what inherited and sporadic cancer is VHL associated with

A

Von Hippel Lindau syndrome

kidney cancer

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14
Q

What are the two forms of anti EGFR agent used fro treatment

A

1) monoclonal antibody against the extracellular domaina: cetuximab.
2) competitive TKI of the receptor: erlotinib, gefitinib

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15
Q

what are the single stranded repair mechanisms and what genes are associated with them

A

Checkpoint activated by ATR.

1) Mismatch repeair (caused by replication errors): MSH2,6, MLH1
2) Nucleotide excision repair (caused by Uv radiation): XPC.
3) Base excision repair (caused by ionising radiation, oxygen radicals, anti-tumour agents): PARPi

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16
Q

what are the double stranded repair mechanisms and what genes are associated with them

A

Checkpoint activated by ATM.

Caused by ionising radiation, oxygen radicals, anti-tumour agents.

1) NHEJ: LIG4 syndrome, XLF-SCID.
2) Homologous recombination: BRCA1,2 (Rad51)

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17
Q

Whats Synthetic Lethality

A

when the contribution of mutations in 2 or more genes causes cell death, but a mutation in 1 gene dosen’t.
Useful when known target is difficult to target by small molecules- target SL partner instead.

PARPi (paradigm for SL) in Breast cancer. PARP is a DNA repeair enzyme. PARPi have few side effects.

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18
Q

Name 3 disorders that have predisposition to cancer

A

Fanconis. Ataxia telangiesctasia. Xeroderma pigmentosum.

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19
Q

what are the advantages are liquid biopsies

A

1) detection of early and metastatic disease (serial sampling- real time analysis)
2) capture entire heterogeneity of disease
3) molecular characterisation to aid prognosis
4) prediction and monitoring of treatment response.
5) Detection of eveloving resistance mutations

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20
Q

how are circulating tumour cells detected

A

require an enrichment step: usually an immunological one: use epithelial marker: EpCAM (absent on blood cells). Use immunological bead capture system: EpCAM antibody conjugated to a magnetic bead.

Allows morphological ID of malignant cells: analysis entire genome of the cell

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21
Q

why carry out MRD

A

1) high resolution determination of efficacy of therapy.
2) allow target driven titration of dose/duration of therapy.
3) determine prognosis after completion of standard treatment.
4) relapse risk after induction: allow optimal consolidation therapy.
5) spare toxicity and cost of SCT in low relapse risk pts.
6) assignment of appropriate maintenance therapy

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22
Q

What MRD methods are there

A 
FISH (0.3-5%).
q rt-PCR (10-4-10-5).
q-PCR.
Tandem duplication PCR (FLT3-ITD only).
Flow (10-4).
QF-PCR
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23
Q

what gets monitored in ALL MRD

A

MRD test 2-3 weeks post remission induction therapy= good predictor of outcome.

Generally by Flow.

rt-PCR: IG-TCR rearr (90% pts- unique)/ gene fusion

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24
Q

what gets monitored in CML MRD

A

K: (>5%) 20mets.

iFISH (0.5%) 100 cells

q rt-PCR: (1x10-5) PB or BM

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25
Q

what gets monitored in Lymphoma MRD

A

all NHL are monitored by IG-TCR rearrangement

MCL: early acheivement of MRD: highly predictive for PFS (100%) when treated with CALGB 50403

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26
Q

what gets monitored in AML MRD

A

gene fus. tandem duplication PCR. WT1 mRNA expression. flow

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27
Q

what are the challenges of tumour mutation testing

A

Hetergeneity of sample (intra and inter).
Tumour load in sample & % tumour cells with mutation.
Availability of tumour.
FFPE tissue (qual and quant DNA).

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28
Q

name two NGS tumour panels and 2 SNP arrays

A

SureSeq tumour Panel (OGT) 60 genes.
Illumina Cancer SNP panel

OGT CytoSure Haematological Cancer+SNP.
Agilent Human Genome CGH+SNP microarray

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29
Q

Whys detecting LOH important in cancer

A

Acquired LOH: duplication of an activating somatic mut or homozygosity of a disease prone minor allele in the germline.
increase/decrease gene expression by expression/ repression particular methylation pattern

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30
Q

whats an aim of the use of SNP arrays on cancers

A

development of a molecular classification scheme to complement histology in diagnosis

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31
Q

what is stratified medicine

A

using molecular characteristics of a patient to enable targeted treatment to improve clinicial care

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32
Q

What are the advantages of stratified medicine

A

1) Enable clinicians to make informed decisions.
2) cost saving for the NHS.
3) improve outcomes.
4) reduce side effects.

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33
Q

what are some of the barriers to stratified medicine

A

Genetics: 1) TaT of results. 2) having reliable gene panels for testing. 3) cost of testing in the financial climate. 4) infrastructure to carry out tests. 5) genotype- clinical info databases to enable informed reporting.

therapy: 1) cost of developing the therapies for a small cohort of patients. 2) ability to trial/develop new therapies in an acceptable time frame. 3) Detection of new bio-markers if labs are only doing panels (need to be research).

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34
Q

Name the gene and the drug used in Breast Cancer

A

ERBB2 (HER2) amplification (20-25%): Trastuzamab (herceptin)

BRCA1,2 germline: PARPi

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35
Q

Name the gene and the drug used in Malignant melanoma

A

BRAF mut V600E (60%): Vemurafenib (inhibits BRAF).

c-KIT mut (30%): Imatinib TKI

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36
Q

Name the gene and the drug used in Colorectal Cancer

A

KRAS wildtype (30% mCRC): EGFR monoclonal anitbodies:

cetuximab, panitumumab.

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37
Q

Name the gene and the drug used in NSCLC

A

EGFR mut (16.6%): gefitinib, erlotinib, osimertinib (T790M resistance).

KRAS mut (22%): No target treat (chemo).

EML4-ALK (4-6%): crizotinib TKI.

ERBB2 amp (3%): trastuzamab

38
Q

whats the ALK rearrangement in NSCLC

A

inv(2)(p21p23) EML4-ALK

39
Q

what percentage of lung cancer is NSCLC

A

85-90%.

adenocarcinoma.

squamous cell carcinoma

40
Q

what are the two variants that affect warfarin dosage

A

CYP2C9: CYP2C92 AND CYP2C93: strong risk of over-anti-coagulation.

VKORC1: AA (low dose), AB (intermediate dose), BB (high dose). B: wt. A: variant: most common: 1173 C>T

41
Q

whats the drug and variant associated with HIV treatemnt

A

Abacavir: HLA-B*57:01. higher in Caucasian popn

if have this variant allele at risk of developing HSR in 1st 6 wks treatment.

HSR (immunological hypersensitivity syndrome): fever, rash, fatigue, respiratory problems)

42
Q

Name a CLL trial

A

RIALTO

PiCLLe: del/mut ATM: PARPi

43
Q

Name AML trial

A

AML18 over 60yrs. AML19 under 60yrs. MyeChild01: childhood AML (upto 18yrs)

44
Q

Name CML trial

A

SPIRIT 3: imat Vs Nilot Vs ponat. After about 4 yrs look at reducing/stopping treatment

45
Q

what tissues/sites are carcinomas found

A

epithelial cells: breast, colon

46
Q

what tissues/sites are sarcomas found

A

muscle, bone, nerves, blood vessels.

soft tissue.

47
Q

what abnormality is associated with Alveolar Rhabdomyosarcoma ARMS

A

t(2;13)(q35;q14) PAX3-FOXO1 (60%)

t(1;13)(p36;q14) PAX7-FOXO1 (20-40%)

Diagnostic of ARMS. more aggressive than ERMS

48
Q

what abnormality is associated with Embryonal Rhabdomyosarcoma ERMS

A

Not diagnostic of ERMS

hyperdiploidy: 2, 8,11,12,13,20. del/LOH 11p15

better prognosis to ARMS. more common in younger children (

49
Q

what is Rhabdomyosarcoma

A

a sarcoma of the connective tissues (skeletal muscle progenitors)
Most common form os soft tissue sarcoma in children and adolescents (

50
Q

discuss demoplastic small round cell tumour

A

t(11;22)(p13;q12) EWSR1-WT1

highly maliganant mesenchymal neoplasm of abdominal cavity. median age 21yrs

poor prognosis (survibal

51
Q

Discuss synovial sarcoma

A

95% SS: t(X;18)(p11;q11) SSX1 (75%), SSX2(25%)- SS18 (SYT)

FISH: SYT BA

highly malignant. mesenchymal spindle cell tumour with epithelial differentiation. seen in extremities age 15-30yrs..
SSX1: poorer prog to SSX2

52
Q

discuss infantile fibrosarcoma

A

t(12;15)(p13;q26) ETV6-NTRK3

soft tissue tumour seen in children arising from fibroblasta. much more favourable prognosis. mortality rate 4-25%.

53
Q

discuss medulloblastoma

A

i(17q) (50%). MYCamp (10-20%)

malignant invasive embryonal tumour of the cerebellum. both chr abns: poor prognosis, if have both very poor prognosis.

54
Q

discuss Rhabdoid tumour

A

del/unbalanced t of 22q11.2 SMARCB1

commonly lethal childhood tumour. 80% cases

55
Q

discuss liposarcoma

A

soft tissue lipogenic tumour seen in adults 20%

56
Q

discuss myxoid liposarcoma

A

t(12;16)(q13;p11) FUS-DDIT3

FISH: DDIT3 BA

.t(12;22)(q13;q12) DDIT3-EWSR1

57
Q

discuss well differentiated liposarcoma

A

40-45% of all liposarcomas

80%: supernumerary marker with amplified sequence for MDM2 (12q15) and CDK4 genes

FISH: MDM2

58
Q

discuss Wilms tumour

A

malignant neoplasm of the kidney. most common genitourinary malignancy in children. 90% over 10yrs old. survival: 85%.

WT1: 11p13

if bilateral tumours: consider WT1 mutation testing

59
Q

discuss retinoblastoma

A

99% children w. intraocular Rb survive. 90% retain vision in at least 1 eye.

40% hereditary. 60% sporadic.

del(13q14) in 5% uni- and 7.5% bi-lateral Rb

60
Q

whats the good neuroblastoma prognosis group

A

near triploidy. (55%). +7, +17 (and -3, -4, -11, -14)

excellent survival (near 100%).

infants: spontaneous regression
older children: spontaneous maturation

61
Q

whats the poor neuroblastoma prognosis group

A

di-/tetra-ploid. (45%)

majoirty: unbalanced abns: MYCN amp, del(1p36), del(11q), +17q

MYCN and del11q: mutually exclusive w. diff expression profiles.

MYCN amp: very poor: rapid tumour progression (del1p36, +17q)

del(11q23): unfavourable outcome

62
Q

what is the recommended genetic markers to be tested for in neuroblastoma

A

MYCN amp. del(11q23). ploidy level.

63
Q

discuss gliomas

A

70% of CNS tumours (gliomas and meningiomas). 2nd most common form cancer in children less 15yrs (25%)

astrocytoma, oligoastrocytoma, oligodendroglioma, gliosarcoma, glioblastoma, epenymoma

64
Q

discuss oligodendrogliomas

A

better overall survival and outcomes than other glioma subtypes.

co-deletion: 1p/19q (80% cases)

80-90% pts with co-deletion respond better to treatment.

commonly mutated genes: IDH1,2 (70%) often with 1p/19q loss. TP53, PIK3A

65
Q

discuss glioblastoma

A

seen in adults (45-70yrs).

very poor prognosis (survial 14.6mnths)

common genetic and epigenetic abns seen

66
Q

what epigenetic changes seen in glioblastoma

A

hypermethylation of MGMT, GATA6, CASP8

MGMT: better PFS and OD (50% cases)

MGMT: repair enzyme thats resistant to alkylating agents. hypermethylation: MGMT silenced: cells more sensitive to alkylating agents- apoptosis.

MS-PCR: prognostic test for blastomas

67
Q

what are the 2 genetic profiles for glioblastoma

A

type1) TP53 inactivation: seen in secondary tumours, may see MDM2 amp, CDKN2A silencing.
type2) EGFR amp/overxpression: de novo tumours. PTEN mut often seen.

68
Q

discuss Ewings

A

ewing sarcoma/PTEN (primative neuroectodermal tumour)

highly agressive primary tumour of the bone (pelvis, femur)- undifferentiated small round cell phenotype.

5yr DFS: 60-7-% (localised) / 10-30% (metastasized)

69
Q

discuss genetics of ewings

A

85%: t(11;22)(q24;q12) 5’EWSR1-3’FLI1

10-15% t(21;22)(q22;q12) EWSR1-ERG

70
Q

discuss the ESWR1 oncogene

A

EWSR!: TET2 family. FLI1: transcription factor normally functions in heamatopoietic, vascular, neural-crest development.

ESWR1-FLI1 fusion: constitutively expressed from native EWSR1 promoter (FLI1 is non functional in Ewing sarcoma cells). EWSR1wt is disrupted in sarcoma cells (dominant negative effect) resulting in haploinsufficiency of EWSR1.

71
Q

what rearrangement is seen in myxoid chondrosarcoma

A

t(9;22)(q22;q12) NR4A3-EWSR1

.t(9;17)(q22;q11) NR4A3-TAF15

72
Q

what rearrangement is seen in Clear cell sarcoma

A

t(12;22)(q13;q12) ATF1-EWSR1

73
Q

According to BPG what do you do if you detect 1 cell with -7 in a myeloid neoplasm

A

Take count up to 30 screening for 7s OR FISH to confirm clonality

74
Q

If have a neuroblastoma with near triploidy and segmental aberrations and/or MYCN amplification what’s the prognosis

A

Aggressive behaviour (poor)

75
Q

What aberrations are seen in Wilms tumour

A

LOH: 16q, 1P 22q (adverse outcome).

chr abns: -1p, -16q, der(16)t(1q;16q), -22.

Future direction: +1q (seen in 30%). Association between +1q and LOH 1p due to der(16) above.

76
Q

Discuss Wilms tumour and 11p15 methylation status

A

3 categories:

  1. Retention of imprinting (no changes).
  2. Loss of imprinting.
  3. LOH (due to del/dup).

Significant association between LOH 11p15 and relapse.

77
Q

What percentage of Wilms tumours have WT1 muts

A

Sporadic: 10-20%

Germline: almost 100%

78
Q

What syndrome are ass with Wilms

A

WAGR; Denys-Drash; Frasier’s syndrome

> 10% Beckwith-Wiedemann

79
Q

Name the rarer Ewing rearrangements

A

t(7;22) EWSR1-ETV1

t(17;22) EWSR1-E1AF

t(2;22) EWSR1-FEV

inv(22) EWSR1-ZSG

.t(16;21)(p11;q22) FUS-ERG

80
Q

Discuss dermatofibrosarcoma protuberans and giant cell fibroblastoma

A

.t(17;22)(q22;q13) PDGFB- COLIA1

81
Q

Discuss inflammatory myofibroblastic tumour

A

TPM3-ALK t(1;2)(q22;p23)

TPM4-ALK t(2;19)(p23;p13)

.t(2;17)(p23;q23) and t(2;11)(p23;p15) ALK-CARS

82
Q

Discuss papillary renal cell carcinoma

A

+7,+17, disomy 1

83
Q

Discuss renal cell carcinoma with Xp11 translocation

A

Xp11.2 TFE3

Usually t(X;1)(p11.2;q21) TFE3-PRCC

84
Q

What are the variants of renal cell carcinoma with Xp11 translocation

A

.t(X;1)(p11.2;q34) TFE3-PSF; t(X;17)(p11.2;q25) TFE3-ASPL; t(X;17)(p11.2;q23) TFE3-CLTC

85
Q

Discuss schwannoma

A

22q deletion

86
Q

What abnormalities other then inv(2) are seen in lung adnocarcinomas

A

6q22.1 ROS1; 10q11 RET. EGFR; MET; ERBB2

87
Q

What carcinomas is ERBB2 amplification seen in

A

Breast carcinoma; gastric carcinoma

FISH: ERBB2, D17Z1

88
Q

What rearrangements are seen in extraskeletal myoepithelial carcimona/tumour

A

22q12 (EWSR1) rearrangements

.t(6;22)(p21;q12) POU5F1
.t(1;22)(q23;q12) PBX1

89
Q

Discuss low grade myxoid fibrosarcoma

A

FUS-CREB3L2 t(7;16)(q34;p11)

90
Q

WHAT TECHNIQUE CAN BE USED TO detect methylation status of MGMT in glioblastoma

A

MS-MLPA, pyro, MS-PCR

91
Q

What chromosome abnormalities are seen in hepatocarcinoma

A

Loss/gains

Losses: 4q; 8p; 13q (Rb1); 16q (AXIN1); 17p (TP53)

Gains: 1q; 8q; 20q

Oncology (5 decks)

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