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Oncobiology Summary
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Laura van den EndIntroduction
Most of the cancers have 10 hallmarks. One mutation - Branching evolution: different cells with different
or hallmark will not induce tumor formation mutations. The cell with the best mutations is the
most fit and will grow out and cause leukemia ⇒
Development of cancers heterogeneity in cancers
- This is a slow process occurring in healthy tissue - The most fit = major clone, the others are
→ most individuals are completely healthy at first minor clones. One of the minors can cause a
- Mutations occur randomly in the copying of the relapse in the patients so they need to be
DNA, cells have mechanisms to correct these studied and treated (use single cell to
mistakes but this does not always work identify)
- Most mutations have no consequences, but if
it does, it’s the 1st step in cancer development
- Cancer causing agents are for example:
inherited genetic effects, chemical carcinogen,
viral infections and UV light.
- These mutations result in genetic changes which
give rise to transformed cells, they can move to the
blood via a process called metastasis.
- Cancer is a heterogenous tissue: normal cells are
also present (blood vessels, inflammatory cells,
fibroblasts, B and T cells); for every tumor type the
normal cell composition can also be different.
- Tumor cells interact with each other but also with Hallmarks
the normal cells (needed for growth). Cancer cells - Different mutations are linked to different
can induce their own proliferation indirectly via hallmarks.
normal cells ⇒ you cannot study cancer by only - In 2000 there were 6:
studying the cancer cells. By stopping the 1. Sustaining proliferative signaling (p.4)
interaction you can stop the tumor growth (eg by (EGFR inhibitors)
binding ab to the GFs). 2. Evading growth suppressors
- Not every cancer cell is a stem cell, in normal (Cyclin dependent kinase inhibitors)
tissue we have some cells that behave as stem 3. Activating invasion and metastasis (p.10)
cells. The CSC are the most important to target (inhibitors of HGF/c-Met)
4. Enabling replicative immortality (p.12)
Stages (Telomerase inhibitors)
- Starts in 1 cell → mutation → eg live little bit 5. Inducing angiogenesis (p.9)
longer → divide → divide → divide → one of (Inhibitors of VEGF signaling)
these cells can accumulate another mutation → 6. Resisting cell death (p.5)
more and more cells with more and more (Pro-apoptotic BH3 nimetics)
mutations → tumor formation → after years - The order of acquiring these hallmarks can be
cancer development. different depending on the tumor. In the end they
- Normal → early adenoma → late adenoma → all more or less have all these hallmarks (small
carcinoma → metastasis. tumors don’t need angiogenesis, neither do
- The later the stage, the more difficult to treat leukemia cells)
- In 2011: 4 more
Leukemia 7. Deregulating cellular energetics (p.11)
- Acute leukemia cells contain 10 to 20 mutations: (aerobic glycolysis inhibitors)
8. Avoiding immune detection (p.6)
NOTCH1, Proliferation and survival, Epigenetics,
(Immune activating anti CTLA4 mAb)
Ribosomal defects, Cell cycle, RNA stability,
9. Tumor-promoting inflammation (p.8)
Transcription factors
- Pre-leukemic cell: have only one mutation, need (Selective anti-inflammatory drugs)
10. Genome instability and mutation (p.2)
multiple mutations to form a leukemia cell
(PARP inhibitors)
Oncobiology
, Laura van den End
Genome instability and mutation
Accumulation of mutations Detection chromosomal rearrangements
1. First mutation in a single cell (point mutation/ - Karyotyping: look at the form and length of the
chromosomal aberration like deletion, trans- chromosomes (each have unique band pattern)
location, inversion duplication etc) → usually has - Chromosomal translocation: exchange between 2
little effect but may already increase the chromosomes; no loss or gain of DNA material
proliferation or survival - Chronic myeloid leukemia: translocation from
2. Mutant cell divides → more cells with that chromosome 22 to chromosome 9. Bcr gene on
mutation → some acquire a second mutation chr22 and Abl gene on chr9 → Chromosome 22
3. Once a combination of mutations is successful in now has a new gene: Bcr-abl ⇒ Philadelphia
transforming the cells to growing cancer cells, chromosome. New kinase activity of abl in these
these cells will accumulate and overgrowth the cells; not every exon of Abl can be spliced with Bcr
rest of the cells bc the right GT———AG needs to be present.
DNA damage and repair - FISH: fluorescence in situ hybridization - visualize
- Single strand break → base excision repair: and map the location of specific DNA sequences
removing the damaged base and replacing it with within cells or tissues using fluorescently labeled
the correct one DNA probes that hybridize to the target DNA →
- PARP1 allow identification and localization of specific
- Double strand break → Homologous recombi- DNA seq under microscope ⇒ find deletions
nation (uses a homologous DNA template, often - In leukemia there is a deletion in chromosome 4 →
the sister chromatid, to accurately restore the leads to fusion of FIP1L1 and PDGFRA
damaged DNA sequence) or non-homologous end
joining (joins the broken DNA ends without the - Next-generation sequencing (NGS):
need for extensive sequence homology) 1. DNA or RNA sample is fragmented and adapters
- BRCA1 and BRCA2 containing specific DNA seq are attached, which
- Breast or ovarian cancer (mutation in serve as binding sites for the sequencing reaction.
BRCA1/2) These fragments are amplified through PCR.
- Treatment: use PARP1 inhibitors so that 2. A primer can bind the adapters and will start the
single strand breaks cannot be repaired and polymerization of the DNA. The used bases are
result in double strand breaks which can only fluorescently labeled so they can be disting-
be repaired by NHEJ. When too many breaks uished using a laser
the cell will die (good) 3. The resulting sequence reads are processed and
- Bulky adducts → nucleotide excision repair aligned to a reference genome or assembled de
- Base mismatches, insertion and deletions → novo to reconstruct the whole original DNA or
mismatch repair RNA sequence.
- MSH2 and MLH1
- Base alkylation → direct reversal - Variant Allele Frequency (VAF) refers to the
proportion or percentage of sequencing reads or
Consequences for the cancer cell alleles that carry a specific genetic variant
- Deletion: inactivation of gene A (complete or (mutation) within a sample
- 12 mutation and 12 wildtype → 12/24 = 50%
partial deletion of the gene) or gene fusion
- 2 mutation and 12 wildtype → 2/24 = 8,33%
(deletion region between two genes)
- Translocation and inversion: fusion of genes or - VAF x 2 = how many cells have the mutation
enhancer brought in neighborhood of gene A
results in ectopic (where normally no expression)
expression of gene A
- Duplication and amplification: one or more extra
copies of the gene or several genes
Oncobiology
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