Purpose: To investigate the mutational status of the Ki-ras gene in retinoblastoma and to evaluate a correlation of the genotype with clinical and histopathologic variables.
Methods: Tumor samples were microdissected from sectioned archival paraffin-embedded tissue. Ki-ras genomic sequences (exons 1 and 2) were amplified by polymerase chain reaction then analyzed by single-strand conformation polymorphism and direct sequencing. Tissue sections, flanking the analyzed samples, were stained with hematoxylin and eosin for examination by light microscopy.
Results: Four of 12 tumors had mutation in exon 1, codon 12 of the Ki-ras gene; none had mutation in exon 2. Signal intensity of the mutated alleles indicates clonal mutation in the tumor cell populations. One of four bilateral tumors was mutated, and all three samples with undifferentiated histologic appearance harbored a clonal Ki-ras mutation. However, only one of nine moderately to poorly differentiated tumors harbored a mutation.
Conclusions: Ki-ras, an oncogene seldom altered in neuroectodermal neoplasms, is mutated in one third of the retinoblastomas studied. The Ki-ras mutations are clonal, suggesting that affected cells have a selective growth advantage. The mutations are present and are likely to play a pathogenetic role in heritable and sporadic retinoblastomas. These results suggest that mutations in Ki-ras are preferentially associated with undifferentiated tumors.