cancer Flashcards
Whats the normal function of an oncogene and how are they activated in cancers
Control cell proliferation, or apoptosis, or both.
Activated by 1) structural alterations (mutation or gene fusion). 2) juxtaposition to an enhancer element. 3) amplification
what are the 6 classes of oncogenes and give an example
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.
Give an example of an oncogene thats activated by amplification
ERBB2 (HER2): breast cancer.
MYCN: neuroblastoma.
MET: renal cell carcinoma, glioma.
Give an example of an oncogene thats activated by mutations
H/K/NRAS: metatstatic CRC, lung, breast, bladder, AML.
BRAF: malignant melanoma, metastatic CRC, hairy cell leukeamia.
Give an example of an oncogene thats activated by chr rearrangements
Chimieric gene: BCR-ABL1
Position effect: MYC-IGH
Whats the normal function of a tumour suppressor gene and what are the types
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
Discuss CDKN2A function
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.
discuss TP53 function
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.
discuss TP53 LoF types
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
Name as microRNA TSG and its asscoiated cancer
miRNA-145: NSCLC
iRNA-34 family: lumg cancer
miRNA- 15a/16-1 cluster: B-CLL
what inherited and sporadic cancer is APC associated with
FAP: familial adenomatous polyposis
colorectal cancers
what inherited and sporadic cancer is MLH1, MSH2,6 associated with
HNPCC: Hereditary non polyposis colorectal cancer
CRC, gastric, endometrial
what inherited and sporadic cancer is VHL associated with
Von Hippel Lindau syndrome
kidney cancer
What are the two forms of anti EGFR agent used fro treatment
1) monoclonal antibody against the extracellular domaina: cetuximab.
2) competitive TKI of the receptor: erlotinib, gefitinib
what are the single stranded repair mechanisms and what genes are associated with them
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
what are the double stranded repair mechanisms and what genes are associated with them
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)
Whats Synthetic Lethality
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.
Name 3 disorders that have predisposition to cancer
Fanconis. Ataxia telangiesctasia. Xeroderma pigmentosum.
what are the advantages are liquid biopsies
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
how are circulating tumour cells detected
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
why carry out MRD
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
What MRD methods are there
FISH (0.3-5%). q rt-PCR (10-4-10-5). q-PCR. Tandem duplication PCR (FLT3-ITD only). Flow (10-4). QF-PCR
what gets monitored in ALL MRD
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
what gets monitored in CML MRD
K: (>5%) 20mets.
iFISH (0.5%) 100 cells
q rt-PCR: (1x10-5) PB or BM
what gets monitored in Lymphoma MRD
all NHL are monitored by IG-TCR rearrangement
MCL: early acheivement of MRD: highly predictive for PFS (100%) when treated with CALGB 50403
what gets monitored in AML MRD
gene fus. tandem duplication PCR. WT1 mRNA expression. flow
what are the challenges of tumour mutation testing
Hetergeneity of sample (intra and inter).
Tumour load in sample & % tumour cells with mutation.
Availability of tumour.
FFPE tissue (qual and quant DNA).
name two NGS tumour panels and 2 SNP arrays
SureSeq tumour Panel (OGT) 60 genes.
Illumina Cancer SNP panel
OGT CytoSure Haematological Cancer+SNP.
Agilent Human Genome CGH+SNP microarray
Whys detecting LOH important in cancer
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
whats an aim of the use of SNP arrays on cancers
development of a molecular classification scheme to complement histology in diagnosis
what is stratified medicine
using molecular characteristics of a patient to enable targeted treatment to improve clinicial care
What are the advantages of stratified medicine
1) Enable clinicians to make informed decisions.
2) cost saving for the NHS.
3) improve outcomes.
4) reduce side effects.
what are some of the barriers to stratified medicine
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).
Name the gene and the drug used in Breast Cancer
ERBB2 (HER2) amplification (20-25%): Trastuzamab (herceptin)
BRCA1,2 germline: PARPi
Name the gene and the drug used in Malignant melanoma
BRAF mut V600E (60%): Vemurafenib (inhibits BRAF).
c-KIT mut (30%): Imatinib TKI
Name the gene and the drug used in Colorectal Cancer
KRAS wildtype (30% mCRC): EGFR monoclonal anitbodies:
cetuximab, panitumumab.
Name the gene and the drug used in NSCLC
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
whats the ALK rearrangement in NSCLC
inv(2)(p21p23) EML4-ALK
what percentage of lung cancer is NSCLC
85-90%.
adenocarcinoma.
squamous cell carcinoma
what are the two variants that affect warfarin dosage
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
whats the drug and variant associated with HIV treatemnt
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)
Name a CLL trial
RIALTO
PiCLLe: del/mut ATM: PARPi
Name AML trial
AML18 over 60yrs. AML19 under 60yrs. MyeChild01: childhood AML (upto 18yrs)
Name CML trial
SPIRIT 3: imat Vs Nilot Vs ponat. After about 4 yrs look at reducing/stopping treatment
what tissues/sites are carcinomas found
epithelial cells: breast, colon
what tissues/sites are sarcomas found
muscle, bone, nerves, blood vessels.
soft tissue.
what abnormality is associated with Alveolar Rhabdomyosarcoma ARMS
t(2;13)(q35;q14) PAX3-FOXO1 (60%)
t(1;13)(p36;q14) PAX7-FOXO1 (20-40%)
Diagnostic of ARMS. more aggressive than ERMS
what abnormality is associated with Embryonal Rhabdomyosarcoma ERMS
Not diagnostic of ERMS
hyperdiploidy: 2, 8,11,12,13,20. del/LOH 11p15
better prognosis to ARMS. more common in younger children (
what is Rhabdomyosarcoma
a sarcoma of the connective tissues (skeletal muscle progenitors)
Most common form os soft tissue sarcoma in children and adolescents (
discuss demoplastic small round cell tumour
t(11;22)(p13;q12) EWSR1-WT1
highly maliganant mesenchymal neoplasm of abdominal cavity. median age 21yrs
poor prognosis (survibal
Discuss synovial sarcoma
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
discuss infantile fibrosarcoma
t(12;15)(p13;q26) ETV6-NTRK3
soft tissue tumour seen in children arising from fibroblasta. much more favourable prognosis. mortality rate 4-25%.
discuss medulloblastoma
i(17q) (50%). MYCamp (10-20%)
malignant invasive embryonal tumour of the cerebellum. both chr abns: poor prognosis, if have both very poor prognosis.
discuss Rhabdoid tumour
del/unbalanced t of 22q11.2 SMARCB1
commonly lethal childhood tumour. 80% cases
discuss liposarcoma
soft tissue lipogenic tumour seen in adults 20%
discuss myxoid liposarcoma
t(12;16)(q13;p11) FUS-DDIT3
FISH: DDIT3 BA
.t(12;22)(q13;q12) DDIT3-EWSR1
discuss well differentiated liposarcoma
40-45% of all liposarcomas
80%: supernumerary marker with amplified sequence for MDM2 (12q15) and CDK4 genes
FISH: MDM2
discuss Wilms tumour
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
discuss retinoblastoma
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
whats the good neuroblastoma prognosis group
near triploidy. (55%). +7, +17 (and -3, -4, -11, -14)
excellent survival (near 100%).
infants: spontaneous regression
older children: spontaneous maturation
whats the poor neuroblastoma prognosis group
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
what is the recommended genetic markers to be tested for in neuroblastoma
MYCN amp. del(11q23). ploidy level.
discuss gliomas
70% of CNS tumours (gliomas and meningiomas). 2nd most common form cancer in children less 15yrs (25%)
astrocytoma, oligoastrocytoma, oligodendroglioma, gliosarcoma, glioblastoma, epenymoma
discuss oligodendrogliomas
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
discuss glioblastoma
seen in adults (45-70yrs).
very poor prognosis (survial 14.6mnths)
common genetic and epigenetic abns seen
what epigenetic changes seen in glioblastoma
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
what are the 2 genetic profiles for glioblastoma
type1) TP53 inactivation: seen in secondary tumours, may see MDM2 amp, CDKN2A silencing.
type2) EGFR amp/overxpression: de novo tumours. PTEN mut often seen.
discuss Ewings
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)
discuss genetics of ewings
85%: t(11;22)(q24;q12) 5’EWSR1-3’FLI1
10-15% t(21;22)(q22;q12) EWSR1-ERG
discuss the ESWR1 oncogene
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.
what rearrangement is seen in myxoid chondrosarcoma
t(9;22)(q22;q12) NR4A3-EWSR1
.t(9;17)(q22;q11) NR4A3-TAF15
what rearrangement is seen in Clear cell sarcoma
t(12;22)(q13;q12) ATF1-EWSR1
According to BPG what do you do if you detect 1 cell with -7 in a myeloid neoplasm
Take count up to 30 screening for 7s OR FISH to confirm clonality
If have a neuroblastoma with near triploidy and segmental aberrations and/or MYCN amplification what’s the prognosis
Aggressive behaviour (poor)
What aberrations are seen in Wilms tumour
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.
Discuss Wilms tumour and 11p15 methylation status
3 categories:
- Retention of imprinting (no changes).
- Loss of imprinting.
- LOH (due to del/dup).
Significant association between LOH 11p15 and relapse.
What percentage of Wilms tumours have WT1 muts
Sporadic: 10-20%
Germline: almost 100%
What syndrome are ass with Wilms
WAGR; Denys-Drash; Frasier’s syndrome
> 10% Beckwith-Wiedemann
Name the rarer Ewing rearrangements
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
Discuss dermatofibrosarcoma protuberans and giant cell fibroblastoma
.t(17;22)(q22;q13) PDGFB- COLIA1
Discuss inflammatory myofibroblastic tumour
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
Discuss papillary renal cell carcinoma
+7,+17, disomy 1
Discuss renal cell carcinoma with Xp11 translocation
Xp11.2 TFE3
Usually t(X;1)(p11.2;q21) TFE3-PRCC
What are the variants of renal cell carcinoma with Xp11 translocation
.t(X;1)(p11.2;q34) TFE3-PSF; t(X;17)(p11.2;q25) TFE3-ASPL; t(X;17)(p11.2;q23) TFE3-CLTC
Discuss schwannoma
22q deletion
What abnormalities other then inv(2) are seen in lung adnocarcinomas
6q22.1 ROS1; 10q11 RET. EGFR; MET; ERBB2
What carcinomas is ERBB2 amplification seen in
Breast carcinoma; gastric carcinoma
FISH: ERBB2, D17Z1
What rearrangements are seen in extraskeletal myoepithelial carcimona/tumour
22q12 (EWSR1) rearrangements
.t(6;22)(p21;q12) POU5F1
.t(1;22)(q23;q12) PBX1
Discuss low grade myxoid fibrosarcoma
FUS-CREB3L2 t(7;16)(q34;p11)
WHAT TECHNIQUE CAN BE USED TO detect methylation status of MGMT in glioblastoma
MS-MLPA, pyro, MS-PCR
What chromosome abnormalities are seen in hepatocarcinoma
Loss/gains
Losses: 4q; 8p; 13q (Rb1); 16q (AXIN1); 17p (TP53)
Gains: 1q; 8q; 20q
