30 Clinical Examples of Cancer Drivers Flashcards
Name 2 oncogenes and the FORM of leukemia that they drive
MYC - Burkitt’s lymphoma (AGGRESSIVE)
Bcl2 - Follicular lymphoma (indolent)
What are the PRECURSORS of oncogenes?
What is their function?
PROTO-oncogenes drive growth + differentiation
Upon mutation of proto-oncogenes to form oncogenes, what cellular changes can oncogenes DRIVE?
HyperACTIVE protein
More EXPRESSION of normal protein
Name 5 genetic changes that can cause conversion of a proto- to an ONCOGENE
- CODING seq mutation
- Gene AMPLFICATION
- Rearrangements (FUSION protein)
- Rearrangements (near strong PROMOTER)
- KO neg feedback
Effects of:
- CODING seq mutation
- Gene AMPLFICATION
- Rearrangements (FUSION protein)
- Rearrangements (near strong PROMOTER)
- KO neg feedback
- HYPERactive protein (normal amount)
- EXCESS expression (normal protein)
- HYPERactive protein (normal amount)
- EXCESS expression (normal protein)
- EXCESS expression (normal protein)
Secondary immune organs are the SITES of _____
ANTIGEN-driven replication + maturation
Where does B-cell production begin?
What happens?
Haematopoietic SCs develop into NAIVE B-cells
Define NAIVE B-cells
BCR has no exposure to antigens yet
Where do naive B-cells go for maturation?
What happens?
Lymph nodes
= BCR on naive cells EXPOSED to antigens in follicles
The exposure of BCRs to antigens, and subsequent maturation is called
Transformation
Describe the morphology of LNs before vs after antigen-exposure
BEFORE antigen-exposure = SMALL primary follicles
AFTER antigen-exposure = LARGE secondary follicles
“Transformation” is AKA
Germical Centre reaction
At the germinal centre, what are the 2 “populations” of cells, and how do they differ?
LIGHT zone = proliferating MATURE B-cells
DARK zone = DYING weak-binding cells
What events occur in the BONE MARROW and LNs to promote Ig gene-rearrangements?
Bone marrow
= VDJ recombination to create UNIQUE BCRs
Lymph nodes (upon antigen-exposure)
= POINT MUT in V/D/J genes
= Different CLASSES of Ig formed
What is a “dangerous” aspect of Ig gene-rearrangements
Forms many DSBs and REPAIR of these
What kind of DSB-repair ERROR occurs?
Reciprocal Balanced Transition (no DNA lost)
What kind of recombination specifically occurs in Burkitts and Follicular lymphoma?
Burkitts = recombination of IGH promoter + MYC
= t(8;14)
Follicular = recombination of IGH promoter + Bcl2
= t(14;18)
What chr is the IGH promoter on?
14
How are such FUSIONS detected?
FISH
Effects of MYC as an oncogene?
What hallmarks does it control?
Controls all cancer hallmarks except 1 (MILESSEGII)
*Metastasis - dec cell adhesion
*Insensitive to anti-growth - immortalised cells have inc telomerase activity
*Limitless growth potential
*
*Self-sufficient growth - glycolysis+glutaminolysis to support BIOMASS synthesis
*Sustained angiogenesis
- Energetics dysregulation
- Genome instability
- Immune evasion
- Inflammation
What hallmark does MYC NOT control?
APOPTOSIS is maintained normally
Describe the HISTOLOGY of Burkitt’s lymphoma cells
- many LARGE BLASTS
- dark BLUE cytoplasm
- OPEN chromatin
- can REPLACE LN structure
- Smear + DYING celsl common
What immune cell type is COMMON in Burkitt’s ?
Why?
Macrophages - phagocytic for apoptotic cells
What molecular MARKER is 100% expressed in Burkitt’s cells? What does it suggest?
Ki67 = proliferation cycling marker
Burkitt’s lymphoma slides are often said to have a ________ appearance
Why?
“Starry Sky” - spaces due to ongoing APOPTOSIS
Describe the aggressiveness of Burkitts progression?
Rapidly GROWING abdominal tumors
Rapid SPREAD to blood + bone marrow
What is an ASSOCIATED syndrome of Burkitts?
TOXINS (urate) from spontaneous cell death (tumor lysis syndrome) can cause RENAL FAILURE
Due to the HUGE # of blasts, what is often clinically required for Burkitts patients?
What is their STATUS?
Haematological EMERGENCY
= requires URGENT chemoTx
“Advantage” of Burkitt’s as a leukemia?
Responds WELL to treatment
highly CURABLE to immediate chemoTx due to intact APOPTOSIS
What is Bcl-2’s normal function
ANTI-apoptotic protein
= inhibits Bak/bax to prevent apoptotsis
Describe CLINICAL features of follicular lymphoma
- SLOW proliferation
- SLOW progressive spread to other Lns
- Usually ISOLATED lymphadenopathy (often accidental finding)
“DANGER” of follicular lymphoma as a leukemia?
RESISTANT to apoptosis
= cells just don’t die and accumulate
= NOT CURABLE
Morphology of follicular lymphoma cells
- Small, mature lymphocutes
- Nuclear cleaving common
- Bcl2 OVEREXP
The PROGNOSIS of follicular lymphoma is determined using…
STAGING (depends on BULK of tumor)
List the stages of follicular lymphoma and define
Stage I - isolated tumor
Stage 2- dissemination to secondary sites
Stage 3-4 - dissemination
do cellular properties change during dissemination?
NO CHANGE
remains the SAME in mets
PROGNOSIS of follicular lymphoma depends on ___ of tumor
BULK (size)
name 3 infiltrative complications of follicular lymphoma
Bone marrow - impair haematopoiesis = LOW peripheral blood counts
COMPRESSION of structures - SC, ureters
EFFUSIONS - pleural, pericardial, peritoneal
Therapies for follicular lymphoma throughout progression?
Primary tumor = excision, radioTx
Advanced = chemoTx, anti-CD20 antibodies
The process of a leukemia becoming ACUTE is termed
Transformation
What EVENT does transformation require?
SECONDARY genetic HITS = “Double-hit” lymphoma
Examples of secondary genetic hits that can occur to transform follicular lymphoma into ACUTE
- KO TP53
* activating MYC
HIGHER grade lymphomas will show what characteristic in BIOPSIES?
more LARGE cells
Symptoms of TRANSFORMED acute follicular lymphomas
- LNs enlarge RAPIDLY
* SYSTEMIC symptoms (fever, night sweats, weight loss)
