Point Mutation in Essential Genes with Loss or Mutation of the Second Allele

Abstract

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 cell–recognized tumor-specific antigens that were retained during evolution of two ultraviolet-light–induced murine cancers to more aggressive growth. The 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-mutated L9 ribosomal protein gene. The tumor lacks the normal L9 allele because of an interstitial deletion from chromosome 5. In the second tumor, 6139B-PRO, both alleles of the L26 gene have point mutations, and each encodes a different tumor-specific CD4+ T cell–recognized antigen. Thus, for both L9 and L26 genes, we observe “two hit” kinetics commonly observed in genes suppressing tumor growth. Indeed, reintroduction of the lost wild-type L9 allele into the 6132A-PRO variant suppressed the growth of the tumor cells in vivo. Since both L9 and L26 encode proteins essential for ribosomal biogenesis, complete loss of the tumor-specific target antigens in the absence of a normal allele would abrogate tumor growth.

Nuclear Factor-κB is an Important Modulator of the Altered Gene Expression Profile and Malignant Phenotype in Squamous Cell Carcinoma

“…Decreased expression of the cell-cell receptor Ly-6 was also confirmed previously in LY SCC cells (27). Finally, the detection of several classes of molecules previously detected as tumor specific and tumor-associated antigens in SCC such as Ly-6, integrins, DEAD-box helicases, and ribosomal components (2,(27)(28)(29) suggests that NF-B may contribute to expression of antigenic molecules detected by antibodies and T cells. Identification of NF-Bregulated genes could help determine the identity of antigens for immune therapy as well as their function in the malignant phenotype.…”

Mutant α-actinin-4 promotes tumorigenicity and regulates cell motility of a human lung carcinoma

“…The biological function of the mutated Ag identified by tumor-reactive CD4 þ and CD8 þ T cells suggests that these gene products are not only targets of antitumor immune response but also contribute to tumor development and metastasis. Such Ag would serve as ideal targets for human cancer immunotherapy (Beck-Engeser et al, 2001). The identification of a mutated aactinin-4 as a tumor Ag may allow to improve our understanding of the biological function of ACTN4 gene and the mechanisms by which it may participate in tumorigenesis and metastasis.…”

Antigenic drift as a mechanism for tumor evasion of destruction by cytolytic T lymphocytes

“…This may be overcome either by immunization with a multitude of tumor antigens (38)(39)(40) or by choosing those antigens that must be retained if the cancer cells are to remain cancerous (41).…”