Point mutation in essential genes with loss or mutation of the second allele: Relevance to the retention of tumor-specific antigens

Antigens that are tumor specific yet retained by tumor cells despite tumor progression offer stable and specific targets for immunologic and possibly other therapeutic interventions. Therefore, we have studied two CD4(+) T ce ll-recognized tumor-specific antigens that were retained during evolution o f two ultraviolet-light-induced murine cancers to more aggressive growth. T he antigens are ribosomal proteins altered by somatic tumor-specific point mutations, and the progressor (PRO) variants lack the corresponding normal alleles. In the first tumor, 6132A-PRO, the antigen is encoded by a point-m utated L9 ribosomal protein gene. The tumor lacks the normal L9 allele beca use of an interstitial deletion from chromosome 5. In the second tumor, 613 9B-PRO, both alleles of the L26 gene have point mutations, and each encodes a different tunior-specific CD4(+) T cell-recognized antigen. Thus, for bo th L9 and L26 genes, we observe "two hit" kinetics commonly observed in gen es suppressing tumor growth. Indeed, reintroduction of the lost wild-type L 9 allele into the 6132A-PRO variant suppressed the growth of the tumor cell s in vivo. Since both L9 and L26 encode proteins essential for ribosomal bi ogenesis, complete loss of the tunior-specific target antigens in the absen ce of a normal allele would abrogate tumor growth.