Evidence for selection against human lung cancers bearing p53 missense mutations which occur within the HLA A*0201 peptide consensus motif.
Evidence for selection against human lung cancers bearing p53 missense mutations which occur within the HLA A*0201 peptide consensus motif.
复制标题
DOI：
--
复制
发表时间：
1994-03
期刊：
影响因子：
11.2
通讯作者：
E. A. Wiedenfeld;Marcelo Fernandez-Viña;Jay A. Berzofsky;David P. Carbone
中科院分区：
文献类型：
--
作者：
E. A. Wiedenfeld;Marcelo Fernandez-Viña;Jay A. Berzofsky;David P. Carbone
符合定义的序列基序的细胞内蛋白的短肽片段与最常见的人类主要组织相容性复合体I类分子HLAA*0201结合，并介导细胞毒性T细胞的杀伤[D.F.Hunt等人，Science(Washington DC)，255：1261-1263,1992；K.Falk等人，Nature(Lond.)，351：290-296,1991]。这种基序的存在使人们能够预测携带该HLA等位基因的癌细胞表面是否存在来自突变癌转运蛋白的新多肽。只有当这些突变发生在主要组织相容性复合体结合基序之外，或者发生在那些抗原提呈缺陷的细胞中时，临床癌症才可能发生。在这里，我们发现来自各种肿瘤的p53错义突变落在HLAA*0201基序中的频率低于预期，如果突变和基序的位置是独立的。当我们分析已知有P53错义突变的肺癌细胞株的HLA亚型时，我们发现所有由HLAA*0201预测可呈现的突变的肿瘤肽都来自于不携带A*0201等位基因或在肿瘤发生过程中丢失了该等位基因的肿瘤。突变的癌基因多肽呈现在I类主要组织相容性复合体上，因此可能代表着人类癌症发展过程中生理上显著的选择压力。
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 oncoporteins 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.