CANCER EPIGENETICS Flashcards
TUMORIGENESIS
THE PROCESS WHICH COMPRISES MULTIPLE STEPS OF MUTATIONS IN CANCER DRIVER GENES THAT PROVIDE THE CELL WITH A SELECTIVE GROWTH ADVANTAGE (SELECTION AND CLONAL EXPANSION) OVER ITS NEIGHBOURING CELLS
Tumorigenesis is the gain of malignant properties in normal cells, including primarily dedifferentiation, fast proliferation, metastasis, evasion of apoptosis and immunosurveillance, dysregulated metabolism and epigenetics, etc., which have been generalized as the hallmarks of cancer
(AT A CELLULAR LEVEL, CANCER IS A GENETIC DISEASE)
STEPS OF TUMORIGENESIS
NORMAL CELL - (INITIATION) - INITIATED CELL - (PROMOTION; selection and clonal expansion) - PRENEOPLASTIC CELL - (PROGRESSION; neoplastic changes) - NEOPLASTIC CELL - (METASTASIS) - MALIGNANT TUMOR
WHAT IS ‘PROGRESSION’ IN TUMORIGENESIS?
AKA ‘CELLULAR EVOLUTION’
PROGRESSIVE ACCUMULATION OF GENETIC CHANGES RESULTS IN TUMOR PROGRESSION FROM NORMAL CELLS TO BENIGN TUMOR TO MALIGNANT, METASTATIC TUMOR
WHAT KIND OF DISEASE IS CANCER AT A CELLULAR LEVEL?
GENETIC
WHICH STAGES OF TUMORIGENEIS ARE EPIGENETIC ABNORMALITIES INVOLVED IN?
ALL (FROM INITIATION TO PROGRESSION AND METASTASIS)
HOW CAN CELL EPIGENETIC PROFILE INFLUENCE CANCER INITIATION?
ALTERING EPIGENETIC PROFILES OF CELLS CAN ALTER HOMEOSTATIC BALANCE IN A CELL WHICH CAN LEAD TO TUMOUR INITIATION
HALLMARKS OF CANCER
- EVADING GROWTH SUPPRESSORS
- ACTIVATING INVASION AND METASTASIS
- SUSTAINED PROLIFERATIVE SIGNALLING
- AVOIDING IMMUNE DESTRUCTION
- TUMOR PROMOTING INFLAMMATION
- GENOME INSTABILITY AND MUTATION
- INDUCING ANGIOGENESIS
- ENABLING REPLICATIVE IMMORTALITY
- DEREGULATING CELLULAR ENERGETICS
- RESISTING CELL DEATH
(CANCER NEEDS AT LEAST 6!!!)
IS GLOBAL HYPO OR HYPERMETHYLATION ACROSS THE GENOME DETECTED IN CANCERS?
HYPOMETHYLATION
EXAMPLES OF GENE SPECIFIC HYPO AND HYPER METHYLATION IN CANCER
- DNA METHYLATION IS REMOVED FROM ONCOGENES, WHICH ACTIVATES THEM (E.G. BCL-2 ONCOGENE IS HYPOMETHYLATED AND OVER-TRANSCRIBED IN HUMAN B-CELL CHRONIC LYMPHOCYTIC LEUKAEMIA AND IN BREAST CANCER)
- TUMOR SUPRRESSOR GENES BECOME METHYLATED AND THUS INACTIVATED
EXAMPLES OF METHYLATION OF TUMOUR SUPPRESSOR GENES IN CANCER
DNA REPAIR GENES:
- MGMT (COLON, LUNG, BRAIN, OESOPHAGEAL AND GASTRIC CANCER)
- MLH1 (GASTRIC, COLON, OVARIAN AND ENDOMETRIAL CANCER)
- BRCA1 (BREAST AND OVARIAN CANCER)
APOPTOSIS AND SURVIVAL GENES: DAPK1 (LYMPHOMA AND LUNG CANCER)
- GSTP1 GENE (involved in a wide range of detoxification reactions which protect cells from carcinogens) IS METHYLATED IN >90% OF PROSTATE CANCERS
GSTP1 GENE (involved in a wide range of detoxification reactions which protect cells from carcinogens) ASSOCIATION TO PROSTATE CANCER?
THE GENE IS METHYLATED (SUPPRESSED) IN >90% OF CASES
DESCRIBE THE GLOBAL GENOME HYPOMETHYLATION IN CANCER?
- HAPPENS EARLY ON
- PROGRESSES OVER TIME
- DETECTED IN ALL CANCERS
- HYPOMETHYLATION OF REPETITIVE REGIONS CAUSES GENOME INSTABILITY!!! (E.G. DELETION, INSERTION ETC)
PROGRESSION OF CANCER AND GLOBAL METHYLATED CYTOSINE (C) LEVELS?
THE MORE INVASIVE A TUMOUR BECOMES THE LOWER THE GLOBAL METHYLATED CYTOSINE LEVEL (GLOBAL HYPOMETHYLATION)
- CYTOSINE CAN TRANSFORM INTO THYMINE AS A RESULT OF GENE SPECIFIC HYPERMETHYLATION AT CpG ISLANDS IN PROMOTERS WHICH IS PRESENT IN CANCERS
DO EPIGENETIC OR GENETIC CHANGES HAPPEN FIRST IN INITIATION OF TUMORIGENESIS?
NOT KNOWN YET, DIFFERENT THEORIES EXIST (E.G. EPIGENETIC PROGENITOR MODULE OF TUMORIGENESIS)
- BOTH TYPES OF CHANGES HAVE THE ABILITY TO INITIATE TUMORIGENESIS
- CAN’T FULLY SEPRATE THE TWO TYPES OF CHANGES
CANCER STEM CELLS (CSCs) ARE ALSO KNOWN AS:
TUMOUR-INITIATING CELLS (TICs)
% OF TUMOUR CELLS THAT ARE MADE UP OF CANCER STEMM CELLS (AKA TUMOUR-INITIATING CELLS)?
0.1-0.8%
CANCER STEM CELLS?
- DRUG RESISTANT CELLS WITHIN TUMOURS
- HAE CAPABILITIES IF SELF-RENEWAL, DIFFERENTIATION, AND TUMORIGENICITY WHEN TRANSPLANTED INTO AN ANIMAL HOST
- CAN ORIGINATE THROUGH MULTIPLE MECHANISMS. E.G. DE-DIFFERENTIATION OF SOMATIC OR DIFFERENTIATED CANCER CELLS, MUTATIONS AND EPIGENETIC CHANGES IN NORMAL STEM ELLS OR PROGENITOR CELLS
EXAMPLES OF MECHANISMS LEADIMG TO FORMATION OF CANCER STEM CELLS?
- DE-DIFFERENTIATION OF SOMATIC OR DIFFERENTIATED CANCER CELLS
- MUTATIONS AND EPIGENETIC CHANGES IN NORMAL STEM ELLS OR PROGENITOR CELLS
TUMOURS ARE A HETEROGENOUS CELL POPULATION. THERE ARE FORMED FOM CANCER STEM CELLS AND OTHER TYPES OF CELLS, THAT CAN ALL TOGETHER BE REFERRED TO AS:
THE BULK OF THE TUMOUR
DEDIFFERENTIATION?
Dedifferentiation is a cellular process by which cells grow in reverse, from a partially or terminally differentiated stage to a less differentiated stage within their own lineage. In general, the phenomenon is manifested by a change in the shape, gene expression pattern, protein expression pattern and function.
EXAMPLE OF ONCOGENIC CEULLULAR REPROGRAMMING
HOW CAN EPIGENETICS BE USED IN CANCER MANAGEMENT?
EARLY DIAGNOSIS (DETECTION OF CpG-ISLAND HYPERMETHYLATION IN BIOLOGICAL FLUIDS AND SERUM)
PROGNOSIS ( HYPERMETHYLATION OF SPECIFIC GENES, WHOLE DNA-METHYLOME PROFILES, HISTONE-MODIFICATION MAPS)
PREDICTION ( CpG-ISLAND HYPERMETHYLATION AS A MARKER OF RESPONSE TO CHEMOTHERAPY, HORMONE THERAPY, AND TARGETED THERAPY)
FOLLOW UP (DETECTION OF CpG-ISLAND HYPERMETHYLATION IN BIOLOGICAL FLUIDS AND SERUM)
SPECIFIC EXAMPLES OF USE OF EPIGENETICS IN CANCER MANAGEMENT
DETECTION AND DIAGNOSIS:
- GSTP1 GENE IS HYPERMETHYLATED IN 80-90% OF PATIENTS WITH PROSTATE CANCER, BUT IS NOT HYPERMETHYLATED IN BENIGN HYPERPLASTIC PROTATE TISSUE —> HELPS DISTINGUISH BETWEEN MALIGNANT AND BENIGN PROCESSES
- ANALYSIS OF METHYLATION LEVELS OF BREAST BIOPSY SAMPLES FROM PATIENTS THAT ARE CARRIERS OF BRCA1 MUTATIONS (HYPERMETHYLATION OF TSGs IS AN EARLY EVENT IN CANCER DEVELOPMENT)
PROGNOSIS:
- HYPERMETHYLATION OF DPAK AND EMP3 GENES HAVE BEEN LINKED TO POOR OUTCOMES IN LUNG AND BRAIN CANCER, RESPECTIVELY
PREDICTION:
- MGMT (DNA REPAIR GENE) METHYLATION IS A GOOD BIOMARKER OF PREDICTING RESPONSE TO TEMOZOLOMIDE DRUG IN PATIENTS WITH GLIOMA CANCER (IF METHYLATED, CANCER CELLS UNDERGO APOPTOSIS; THERE IS NO/LESS REPAIR)
FOLLOW UP:
- IN LEUKEMIA CELLS, P15 METHYLATION INITIATES PROLIFERATION SO IF IN FOLLOW UP THIS GENE IS METHYLATED IT CAN INDICATE CANCER RECURRNCE
METHYLATION OF WHICH GENE IS A GOOD BIOMARKER OF PREDICTING RESPONSE TO TEMOZOLOMIDE DRUG IN PATIENTS WITH GLIOMA CANCER (a type of tumor that occurs in the brain and spinal cord)?
MGMT (DNA REPAIR GENE)
REVERSIBILITY OF GENETIC VS EPIGENETIC MUTATIONS?
GEN MUTATIONS ARE IRREVERSIBLE
EPIGEN MUTATIONS ARE REVERSIBLE (MAKES THEM A GOOD TARGET FOR CANCER THERAPY)
EPIDRUGS
SMALL MOLECULE INHIBITORS THAT TARGET THE EPIGENETIC MACHINERY
- MAINLY DESIGNED TO TARGET ENZYMATIC EPIGENETIC REGULATORS
(AIMS: ACTIVATE TSGs, DEACTIVATE ONCOGENES, PREVENT PROLIFERATION, TRIGGER APOPTOSIS IN CANCER CELLS)
MAIN CLASSES OF EPIDRUGS:
- DNA METHYLTRANSFERASE INHIBITORS (DNMTi)
- HISTONE DEACETYLTRANSFERASE INHIBITORS (HDACi)
- HISTONE ACETYL TRANSFERASE INHIBITORS (HATi)
- HISTONE DEMETHYLTRANSFERASE INHIBITORS (HDMi)
- HISTONE METHYLTRANSFERASE INHIBITOR (HMTi)
EXAMPLES OF FDA APPROVED EPIDRUGS:
DNMTi:
- DECITABINE
- VIDAZA (5-AZA CYTIDINE)
BOTH APPROVED FOR TREATMENT OF MYELODYPLASTIC SYNDROME (MDS) AND ADULT MYELOID LEUKEMIA (AML)
HDACi:
- VORINOSTAT
- ROMIDEPSIN
BOTH APPROVED FOR TREATMENT OF CUTANEOUS T CELL LYMPHOMA
EPIDRUGS APPROVED FOR TREATMENT OF MYELODYPLASTIC SYNDROME (MDS) AND MYELOID LEUKEMIA (AML)
- DECITABINE
- VIDAZA
(BOTH DNMTi)
EPIDRUGS APPROVED FOR TREATMENT OF CUTANEOUS T CELL LYMPHOMA
- VORINOSTAT
- ROMIDEPSIN
(BOTH HDACi)
DNMT INHIBITORS (DNMTi)
- GROUP OF EPIDRUGS
- SUCCESSFUL STRATEGY FOR THE PREVENTION OF ABERRANT DNA HYPERMETHYLATION
- REACTIVATE THE HYPERMETHYLATED GENES (LEADING TO CANCER CELL REPROGRAMMING AND ULTIMATELY PROLIFERTION ARREST AND CELL DEATH)
2 GROUPS: - NUCLEOSIDE ANALOGS (REPLICATION DEPENDENT AS THEY GET INCORPORATED INTO THE DNA DURING REPLICATION PROCESS, POSE AS NUCLEOSIDES BUT ONCE THEY’RE METHYLATED THE METHYLATION PATTERN CANNOT MOVE ELSEWHERE SO THE ACTUAL NUCLEOSIDES REMAIN UNMETHYLATED); THE FDA APPROVED DRUGS (DECITABINE
AND VIDAZA (5-AZA CYTIDINE)) - NON-NUCLEOSIDE DNMTi (BLOCK THE ACTIVE SITE OF DNMT ENZYME, DO NOT NEED TO GET INCORPORATED)
DESCRIBE THE 2 GROUPS OF DNMT INHIBITORS (DNMTi)
2 GROUPS:
- NUCLEOSIDE ANALOGS (REPLICATION DEPENDENT AS THEY GET INCORPORATED INTO THE DNA DURING REPLICATION PROCESS, POSE AS NUCLEOSIDES BUT ONCE THEY’RE METHYLATED THE METHYLATION PATTERN CANNOT MOVE ELSEWHERE SO THE ACTUAL NUCLEOSIDES REMAIN UNMETHYLATED); THE FDA APPROVED DRUGS (DECITABINE
AND VIDAZA (5-AZA CYTIDINE))
- NON-NUCLEOSIDE DNMTi (BLOCK THE ACTIVE SITE OF DNMT ENZYME, DO NOT NEED TO GET INCORPORATED)
DNMT
the DNA methyltransferase: family of enzymes that catalyze the transfer of a methyl group to DNA
HDAC
Histone deacetylase (HDAC) is an enzyme that removes the acetyl group from histone proteins on DNA, making the DNA less accessible to transcription factors
HDAC INHIBITORS
- GROUP OF EPIDRUGS
- PROVEN TO REVERESE THE TRANSCRIPTIONAL REPRESSION OF MULTIPLE GENES INVOLVED IN CELL CYCLE PROGRESSION, DIFFERENTIATION AND APOPTOSIS
- 4 CLASSES BASED ON THE TYP OF HDAC THEY TARGET (I-IV)
VORINOSTAT (SAHA)
- EPIDRUG
- PAN-HDACi (IMPACTS ALL 4 DIFFERENT TYPES OF HDAC)
- FIRST GEN OF HDACi
- FDA APPROVED FOR TREATMENT OF RELAPSED AND REFRACTORY CUTANOUS T-CELL LYMPHOMA (CTCL)
WHICH TYPE OF TUMOUR CELLS DOES CONVENTIONAL CHEMOTHERAPY NOT WORK ON?
CANCER STEM CELLS
KEY AREA OF FOCUS FOR EPIDRUGS
- TARGETING CANCER STEM CELLS (WHICH CANNOT BE TARGETED WITH TRADITIONAL CHEMOTHERAPY)
- COUL HELP PREVENT SUBSEQUENT RELAPSE!!!!!!!!!!! (DIFFERENTIATED TUMOUR CELLS CANNOT PROLIFERATE ON THEIR OWN, I.E. WITHOUT CANCER STEM CELLS)
TOLERANCE TO EPIGENETIC CHANGES INDUCED BY EPIDRUGS IN CANCER CELLS COMPARED TO HEALTHY CELLS
- SOME EVIDENCE THAT CANCER CELLS AR MORE SENSITIVE AND THAT HEALTHY CELLS CAN RE-ADAPT TO NEW EPIGENETIC ENVIRONMENT
(IMPORTANT WHEN THINKING ABOUT SELECTIVITY OF EPIDRUGS, TRADEOFF OF EFFICACY AND TOXICITY, ALTHOUGH TOXICITY IS MORE TOLERATED WHEN A PATIENT IS TERMINALLY ILL AND THE PRIMARY GOAL IS TO EXTEND LIFESPAN)
