application on molecular pathology

Question 1

how do cancers develop:
true or false
* Cancer develops not from activation of one genetic switch but usually from a no. of genetic switches being activated
example: Colonic cancer multi-step
pathway of neoplasia:
- — – are required and these correlate with the stages of — of
e.g. colonic cancer from an —
polyp to — .
* — theory
* Different — are activated by these
mutations

Answer 1

true
multiple mutations
evolution
adenomatous to carcimoa
vogelstein theory
pathways

Question 2

Knowledge of these different genomic events as a tumour progresses can help us to develop tools which
allow for better:

Answer 2

 Diagnosis
 Prognostication
 Prediction

Question 3

molecular technique have led to discovery of new – tools for example:
* — activation in follicular lymphoma for t( — , — )
* — chromosome in — t( – ) → – gene
* — mutation in Gastrointestinal stromal tumour
* Translocation in burkitts lymphoma t(— , – )
* Certain translocations in –

Answer 3

diagnostic
BCL2
14:18
philadelphia c/some in chronic amyloid leukaemia
9:22
Abl gene
c-kit
8:14
sarcomas

Question 4

1- — Diagnosis:
PNET/Ewing’s Sarcoma
2- — was performed for EWSR1 and SYT genes. 52% showed – signal of SYT gene indicating — .
3- Final Diagnosis using — :
Synovial Sarcoma
Diagnosis changed by – analysis

Answer 4

pre molecular
FISH analysis
split
rearrangement
gene analysis
molecular

Question 5

gene abnormalities can be also used as – tools:
* — in some lymphomas identify worse prognostic groups eg small cell lymphocytic lymphoma
* Those with mutant – have a worse prognosis
* Certain – changes in multiple myeloma have a worse prognosis eg – 17p13

Answer 5

prognostic tools
translocation
mutant p53
molecular changes
deletion

Question 6

• molecular techniques and treatment of the disease:
  –>By understanding – of disease,
  treatments can be devised
  –>Targeted/Personalised Treatment
  1- targeted therapy:
• New – have allowed us compare the molecular – of cancer cells compared to – cells
• This has given us an understanding of how – develop and grow
• This information has provided – which target specific pathways of cell division which stops tumour growth
• — drugs- “Right drug for right patient”
• in target therapy it blocks the — aka —- or it bocks —- pathways aka —

Answer 6

mechanism
technologies
profile
normal
neoplasm
drugs
targeted
it either blocks:
1- membrane receptor ( Monoclonal antibodies name ends in “ab”)
2- signalling pathways ( Small molecule inhibitors name ends in “ib”)

Question 7

historical perespective:
* Tumours grow by:
– 1. —
– 2. Reduced—
* Anticancer drugs (Chemotherapy) act by:
– 1. Preventing cells from –
– 2. Causing — to dividing cells
* Chemotherapy kills dividing cells therefore tumours with a – rate of cell — respond well e.g. – , – tumours
* However, non tumour cells are also killed leading to side effects e.g. –
suppression, – upset, — .
* Chemotherapeutic agents are therefore — forms of treatment

Answer 7

cell division
apoptosis
dividing
toxic effects
rapid
division
leukoma and germ cell tumours
marrow suppression git upset and alopecia
nontargeted

Question 8

in targeted therapies:
* Use an understanding of the — a strategy to stop it
* Rely on differences in molecular behaviour of – cells vs — cells
* Are associated with “ — / — diagnostic”
example: HER2 ISH
* Determine if HER2 gene is –
* Compare number of chromosome – signals with number of HER2 signals
* –
– Ratio > –
– HER2 copy number > –

Answer 8

tumour biology
tumour vs normal
companion/complimetry diagnostics
amplified
17
positive
2
6

Question 9

EGFR pathway:
starting at the cell membrane we will have EGFR we will have —- the leaving to the cytoplasm we will have — –> — – > —- leading to cell cycle progression at the nucleus
at the same time in the cell membrane we will have — which lead to —- and PTEN is interfering but it will cause cell growth as well

Answer 9

ras , raf , mek , erk
PIK3CA –> AKT

Question 10

cetuximab is an — which Response rates 22.9% in — tumours
What about EGFR — tumours?
– Response rate – in a small cohort
* —
– initialstudy
* — responders, all KRas WT
* – (–%) KRas WT tumours responded

Answer 10

anti-egfr mab
EGFR positive
-ve
25%
KRas
11
11/17 (65%)

Question 11

1-
Cetuximab
Panitumumab
are both —
2-
* Worldwide ~50% of melanomas harbour a — mutation
* In Ireland that figure is closer to 24%
* Response is – and tumours find other ways of — the
pathway.
* — used in combination have shown a greater effect than BRAF inhibition alone.

Answer 11

anti-egfr monoclonal antibody
BRAF
not durable
up regulating
MEK inhibitors

Question 12

EGFR in lung cancer:
* Tested for in – cell lung cancer
* Most commonly positive in –
* Also positive in a small percentage of – carcinomas
other targeted therapies in lung cancer:
* —
– ALK1
– ROS1
*—
– PDL-1

Answer 12

non small
adenocarcinoma
squamous
crixotinib
checkpoint inhibititor

Question 13

other uses of checkpoints inhibitors:

Answer 13

• Melanoma
• CRC
• Urologic malignancies
• Others
  answer question 49

Question 14

resistance:
* Tumours do develop resistance to these agents
* Various methods:
– Activation of — pathways
– Aberrant behaviour of – activators
– New –

Answer 14

alterate
downstream
mutations

Question 15

further into the future:

Answer 15

• Larger tumour panels
• Non-neoplatic molecular pathology
  – ?Rejection
  – ?TMA
  – ?IBD
• Liquid biopsies