For the retinal cancer retinoblastoma, the inheritance of one mutated copy of RB1 from one of the parents is often referred to as a mutation that produces a 'dominant predisposition to cancer.' This means that the first mutation does not produce cancer but makes it very likely that cancer will develop.


What is the genotype of a normal cell in the retina in a person who has sporadic retinoblastoma? What is the normal cell genotype if the person has hereditary retinoblastoma? Explain the reason for the difference between the genotypes.

Verified step by step guidance

1. Understand that retinoblastoma involves mutations in the RB1 gene, which is a tumor suppressor gene. Cancer develops when both copies of RB1 in a retinal cell are inactivated (the 'two-hit hypothesis').
2. For sporadic retinoblastoma, both mutations occur in retinal cells after conception (somatic mutations). Therefore, the normal retinal cells in this person have two normal RB1 alleles (genotype: RB1+/RB1+), and cancer arises only after two somatic mutations in the same cell.
3. For hereditary retinoblastoma, the person inherits one mutated RB1 allele from a parent (germline mutation). Thus, all cells, including normal retinal cells, have one mutated and one normal RB1 allele (genotype: RB1+/RB1-).
4. The difference in genotype arises because hereditary retinoblastoma involves a germline mutation present in every cell, predisposing cells to cancer with only one additional somatic mutation, whereas sporadic retinoblastoma requires two somatic mutations in the same cell to develop cancer.
5. Summarize that the key concept is the difference between germline (hereditary) and somatic (sporadic) mutations, which explains why normal retinal cells have different genotypes in these two forms of retinoblastoma.

Key Concepts

Two-Hit Hypothesis

The two-hit hypothesis explains that both copies of a tumor suppressor gene, like RB1, must be inactivated for cancer to develop. In hereditary retinoblastoma, one mutated copy is inherited (first hit), and a second mutation occurs somatically (second hit). In sporadic cases, both mutations happen in the same retinal cell during the person's life.

Genotype Differences in Hereditary vs. Sporadic Retinoblastoma

In hereditary retinoblastoma, normal retinal cells carry one mutated RB1 allele and one normal allele, predisposing them to cancer after a second mutation. In sporadic retinoblastoma, normal retinal cells have two normal RB1 alleles initially, and cancer arises only after both alleles acquire mutations in the same cell.

Role of Tumor Suppressor Genes in Cancer

Tumor suppressor genes like RB1 regulate cell growth and prevent tumor formation. Mutations that inactivate both gene copies remove this control, leading to uncontrolled cell division and cancer. Understanding this helps explain why one inherited mutation increases cancer risk but does not cause cancer alone.