Molecular basis of cancer

Cancer hallmarks

• Sustaining proliferative signal → Can keep dividing without signal

• Deregulating cellular energetic

• Inducing angiogenesis

• Resisting cell death

• Genomic instability

• Activating invasion and metastasis

• Tumor promoting inflammation

• Enabling replicative immortality

• Evading growth suppressors

• Avoid immune destruction

What is proto oncogene

NORMAL promote cell growth and survival

What are oncogenes

CELLULARLY DOMINANT; GoF mutation → overexpression of cell

KRAS pathway

Point mutation on RAS in ‘ON’ state → MAPK pathway signal → Sustained proliferative signaling

KRAS mutation type

Codon 12 changes from glycine to smth else pG12X → Glycine is binding site at GPA → KRAS cannot be dephosphorylated

What is Rb1

Retinoblastoma gene → Holds brake at G1/S → LoF = uncontrolled cell cycle progression

What is p53

Damage sensor → Trigger cell cycle arrest, apoptosis → LoF = damaged cells survive and replicate

What is Knudson two hit hypothesis

Sporadic case: need 2 hits for cancer to form

Hereditary: born with 1 hit → need 1 more to become cancer

What is mismatch pair

Mismatch found → Wrong part cut out → Replaced → Ligase seals

What is base excision repair

Deamination chance C to U → U is removed → C is added by polymerase to correct → Sealed by ligase

What is nucleotide excision repair

UV → T form Dimer → bubble forms → Remove damaged segment out of bubble → Replaced by new correct DNA

What is homologous combination

Radiation break chromosome → Pairs with homolog → Damaged region is replaced with homolog

What is non homologous end joining

Radiation → Chromosome break → Glued back together

What is DNA proofreading

Polymerase detect mistake → Use exonuclease to remove incorrect nucleotide

Types of point mutation

Transition → Purine to purine

Transversion → Purine to pyrimidine

Missense → Nucleotide change → Amino acid changes

Non sense → Code for stop codon

Silent → Nucleotide change but amino acid result does not

Frame Shift → Add one → everything shifts

Deletion → Delete one → Everything shifts

What is gene inversion

Recombination between sequence → Segment flips 180 degrees → everything is reversed

What is CBFB-MYH11 fusion protein

Normal CBFB on q and MYH11 on p → Chromosome invert → CBFB and MYH11 combine

Effect of CBFB-MYH11 fusion protein

Normal: CBFB bind to RUNX1 → Recruit DNMT3A

Fusion protein: CBFB bind to RUNX1 → Leave nuclei → NO DNMT3A recruited → Acute myeloid leukemia

Types of chromosomal abnormalities

Duplication, deletion, inversion, ring chromosome, reciprocal translocation, Robertsonian

What is BCR-ABL1 fusion protein

Normal: ABL1 on chromosome 9, BCR on chromosome 22 → chromosome break and swap places = Philadelphia chromosome

Effect of Philadelphia chromosome

Activate cell proliferation → Chronic myeloid leukemia

Types of histone changes in epigenetic

Lactylation, acetylation, ubiquitination, citrullination, methylation

What is global hypomethylation

Loss of methylation in repeating DNA → Genetic instability → Cancer

Leads to activation of transposons

What is spontaneous mutagenesis

Error in DNA replication, spontaneous base loss, deamination, ROS

Steps of carcinogenesis

Initiation (DNA damage, mutation driver gene) → Promotion → Progression (more mutation, mutation of passenger gene0

Vogelstein model

Mutations that cause colorectal cancer:

• APC mutation → early adenoma

• KRAS mutation → intermediate adenoma

• p53 mutation → Carcinoma