Genetics of Cancer

Phases of the cell cycle

G0: Quiescent cell

G1: Growth

G1-S checkpoint: Ensures DNA is ready for replication

S: Synthesis of DNA

G2: Growth

G2-M: Checking replicated DNA

M: Mitosis

Molecular pathways that permit cell division

• Growth factors and their receptors

• Signal transduction

• Transcription factors

• Proteins that activate cell division

Mutations at any point can cause cancer

Proto-oncogene

WT gene that stimulates cell division and can be regulated

Oncogene

Mutated or overexpressed proto-oncogene, constantly on

GOF phenotype, dominant nature

Gain of Function (GOF)

Constant unregulated cell divison

Mutation in only 1 allele is needed

Ras

Most mutated oncogene

Caused by a point mutation

GNAQ

Oncogene mutated in uveal melanomas

Tumor suppressor

WT normally stops cell division, responsible for stopping cycle at checkpoints

LOF phenotype when mutated, recessive nature

Loss of Function (LOF)

Both copies of gene are off and can’t stop cell division

Two Hit Hypothesis

Hit 1: One allele is mutated but that remaining WT gene can still suppress cycle

Hit 2: Both alleles are mutated, uncontrolled cell division

Why can’t “two hit” alleles be inherited?

It is embryonic lethal

TP53

Acts at G2-M checkpoint, can either repair DNA or induce apoptosis

Most mutated TS gene in cancer, 2nd most common mutation overall

Retinoblastoma (RB1)

Acts at G1-S checkpoint, will inhibit E2F to prevent DNA synthesis

2nd most common TS mutation

Sporadic transmission of retinoblastoma

Acquired 2 mutations in one cell → Unilateral retinoblastoma at 2-4 years old

Familial transmission of retinoblastoma

Inherit 1 mutated RB1 and acquires 2nd mutation → Bilateral retinoblastoma 2-6 months old

BRCA1 and BRCA2

DNA repair genes, need both to be knocked out for cancer

LOF

BAX/BAK

Induce apoptosis, makes mitochondria leaky to cytochrome C

BCL-2

Anti-apoptotic, prevents release of cytochrome C

Overexpression can cause cancer (GOF)

Surgical intervention

Primary Tx for localized solid tumors

Has the best outcome with removal of wide margin

Excisional biopsy

Removes a small tumor

Resection

Removes a large tumor

Enucleation

Removal of the eye

Externation

Removal of eye and adnexa

Often requires plastic surgery and/or prosthetic

Radiation therapy

Gamma radiation to cause localized lethal mutations in DNA to kill cancer

Can cause cancer again from DNA damage, radiation retinopathy/blindness, and cataracts

External beam radiation

Radiation delivered outside of body

Entry and exit points have burns

Proton beam therapy

Radiation delivered from outside the body using a proton beam

Maximized targeting and minimizes surrounding damage

Brachytherapy

Radioactive implants on or near the cancer

Ocular tumor brachytherapy

Plaques made of gold and are unique for each tumor

Holds radioactive seeds and serves as a shield

Radiation retinopathy presentations

Pain, neovascularization, vision loss from ischemia or hemorrhages