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Evidence for Selection against Human Lung Cancers Bearing p53 Missense Mutations Which Occur within the HLA A*0201 Peptide Consensus Motif¹

Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75235 [E. A. W., M. F-V., D. P. C.] and Metabolism Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892 [J. A. B.]

Short peptide fragments of intracellular proteins that fit a defined sequence motif bind to the most common human major histocompatibility complex class I molecule, HLA A*0201, and mediate killing by cytotoxic T-cells (D. F. Hunt et al., Science (Washington DC), 255: 1261–1263, 1992; K. Falk et al., Nature (Lond.), 351: 290–296, 1991]. The existence of such a motif allows prediction of whether novel peptides derived from mutant oncoproteins might be presented on the surface of cancer cells bearing that HLA allele. Clinical cancer might develop only when these mutations occur outside a major histocompatibility complex binding motif or in those cells that acquire defects in antigen presentation. Here, we find that missense mutations of p53 from a variety of tumors fall within the HLA A*0201 motif less often than would be expected if the location of mutations and motifs were independent. When we analyzed the HLA subtype of lung cancer cell lines with known p53 missense mutations, we found that all of the mutant oncopeptides predicted to be presentable by HLA A*0201 came from tumors that either did not carry the A*0201 allele or had lost that allele in the process of tumorigenesis. Presentation of mutant oncogene peptides on class I major histocompatibility complex might thus represent a physiologically significant selection pressure in the development of human cancer.

¹ Supported by the Perot Family Foundation (E. A. W.) and NIH Grant R01 CA57856 (D. P. C.).

² To whom requests for reprints should be addressed, at Simmons Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-8593.

Received 12/31/93. Accepted 1/20/94.

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