Genetics of retinoblastoma formation

The RB1 gene is located on human chromosome 13. In hereditary retinoblastoma, the fertilized egg carries 1 defective copy of the RB1 gene and all retinal cells in this offspring carry only a single functional RB1 gene copy. If this surviving copy is eliminated in a retinal cell by a nonheritable mutation (the second hit of the Knudson 2-hit hypothesis), the cell will lack RB1 gene function and will proliferate into a tumor. In nonheritable retinoblastoma, the fertilized egg is genetically wild type at the RB1 locus. In the retina of this offspring, retinoblastoma development requires 2 successive nonheritable mutations striking both copies of the RB1 gene in the retinal precursor cells. Because only a single nonheritable mutation is needed to eliminate RB1 function in familial cases, multiple cells in both eyes are affected. In contrast, the 2 nonheritable mutations required in nonheritable disease are unlikely to affect a single cell lineage, yielding at most 1 tumor.