RB1 & Retinoblastoma
What is the main function of pRB in the cell cycle?
pRB inhibits cell cycle progression by inactivating E2F and inhibiting downstream transcription (G1 to S).
What is the "two-hit hypothesis"
Both alleles of a tumor suppressor gene must be inactivated for cancer to develop.
What type of inheritance pattern does heritable retinoblastoma follow?
Autosomal dominant
What imaging modality is preferred for diagnosing intraocular retinoblastoma?
MRI
What surgical treatment is used when vision cannot be preserved in retinoblastoma?
Enucleation
What clinical sign is most commonly associated with retinoblastoma in children?
Leukocoria (white pupillary reflex)
What's the difference between a tumor suppressor gene and a proto-oncogene?
Tumor suppressors prevent cell growth (loss leads to cancer), while proto-oncogenes promote growth and become oncogenes when mutated
What is the risk that a child of a retinoblastoma survivor with a germline RB1 mutation will inherit the mutation?
50%
What is the hallmark finding of retinoblastoma on MRI?
An intraocular mass with calcifications and variable contrast enhancement.
How is chemotherapy typically delivered (targeted fashion)?
The catheter is threaded through the femoral artery into the ophthalmic artery.
Which kinase complex(s) are responsible for pRB phosphorylation, and at what timepoints?
Cyclin D–CDK4/6: Early-mid G1
Cyclin E-CDK2: Late G1 (Near Restriction Point)
What is bilateral retinoblastoma suggestive of?
Heritable form of the disease (germline to second mutation)
How could a child develop heritable retinoblastoma without a family history?
A de novo germline mutation in the RB1 gene during gametogenesis
What is the difference between T1 and T2 imaging, and when/what is the role of contrast?
T1 helps with anatomy, T2 highlights fluid and edema;
Contrast allows us to see "active" parts of the tumor and areas of spread.
What drugs make up the SOC for Rb, and what are their mechanisms?
VEC-
Vincristine: Inhibits microtubule formation
Etoposide: Inhibits topoisomerase II
Carboplatin: Forms DNA crosslinks
How can p53 compensate for pRB loss?
Increased E2F leads to decreased MDM2, which leads to increased p53.
Why can dominant-negative mutations lead to a more severe phenotype than null alleles?
Dominant-negative mutants may still bind/sequester other interacting proteins.
What are the three most common symptoms of Retinoblastoma?
Leukocoria, Strabismus, Eye pain/redness.
What is trilateral retinoblastoma?
Bilateral intraocular tumors plus a midline intracranial tumor
What is another cancer associated with Rb mutations that typically affects adolescents and elderly patients?
Osteosarcoma
How does loss of RB1 function contribute to genomic instability, BESIDES unchecked cell growth?
pRB ALSO regulates chromatin remodeling of E2F-associated genes.
Why is the tumor spectrum of Rb1 mutations lower than you'd expect?
High proliferative nature of retinal tissue in early infancy. Compensatory pathways of p107 and p130 in other tissues.
What portion of the chromosome is deleted in some cases of Rb?
Chromosome 13q14
Why is CT scan avoided in retinoblastoma diagnosis, particularly in children?
Risk of radiation-induced secondary malignancies
What considerations are made when deciding on a treatment regimen? (Melphalan vs VEC)
Stage, uni- or bi- lateral, tumor location.