癌症相关基因的系统发育地层学研究

Phylostratigraphy Study of Cancer-related Genes

关键词:  癌症返祖理论  系统发育地层学  不同功能类别基因  转录组年龄指数

Key words:  cancer atavism theory  phylostratigraphy  genes of different functional categories  transcriptome age index

摘要:

目的 结合“癌症返祖假说”，从系统发育地层学角度分析单细胞生物到多细胞生物的演化过程，研究癌症相关基因的进化年代特征，为癌症机制研究和治疗方案开发提供参考。方法 利用系统发育地层追踪方法Phylostratr定位人类所有蛋白质编码基因的进化起源，分析管家基因、癌症驱动基因、抑癌基因、原癌基因、中性基因和分化基因的进化年代特征，通过对数优势比、超几何分布比较不同功能类别基因及人类所有蛋白质编码基因的系统发育地层分布差异。利用TCGA获取肿瘤样本和正常样本基因表达数据，利用转录组年龄指数方法进行比较分析。结果 人类20291条蛋白质编码基因根据序列比对结果中最远同源序列物种所在的地层被划分到27个地层中。鉴定4159个管家基因、527个癌症驱动基因、87个抑癌基因、134个原癌基因、10755个中性基因和4274个分化基因在系统发育地层拓扑结构中的分布特征，结果显示不同功能基因的系统发育地层分布与人类所有蛋白质编码基因相比有显著差异，其中癌症相关基因具有更古老的系统发育地层分布。胆管癌、结肠癌、肺腺癌、肝癌、头颈鳞状细胞癌、肾嫌色细胞癌的转录组年龄指数分析显示，肿瘤组织中高度保守的古老基因呈现更高表达。结论 癌症相关基因在系统发育地层中具有更古老的进化起源，暗示其在物种进化过程中具有更保守的功能。肿瘤组织中高度保守的古老基因表达增强的现象，可用于探索肿瘤基因表达模式，为抗肿瘤药物新靶点发现及药物研究提供新思路。

Abstract:

OBJECTIVE To analyze the evolution of the transition from unicellular organisms to multicellular organisms from a phylogenetic stratigraphy perspective, combining the "cancer atavism hypothesis". To investigate the evolutionary chronology of cancer-related genes to guide research on cancer mechanisms and the development of treatment strategies. METHODS Phylostratr was used to identify the systematic evolutionary strata of all human protein-coding genes, housekeeping genes, cancer driver genes, tumor suppressor genes, oncogenes, neutral genes, and differentiation genes. Differential distribution of genes from different functional categories and human protein-coding genes was analyzed using log-odds ratios and hypergeometric distributions. TCGA was utilized to investigate transcriptional expression datas in cancer tumor samples and normal samples, and calculations and analysis were performed using transcriptome age index. RESULTS A total of 20291 protein-coding genes were classified into 27 different strata based on the farthest homologous species in the sequence alignment results. Within the phylogenetic stratigraphic structure, the datasets of 4159 housekeeping genes, 527 cancer driver genes, 87 tumor suppressor genes, 134 oncogenes, 10755 neutral genes, and 4274 differentiation genes exhibit distinct distribution patterns. The overall distribution of these genes significantly differs from that of all human protein-coding genes. Cancer-related genes exhibited a more ancient phylogenetic stratigraphic distribution. Transcriptome age index results for bile duct cancer, colon cancer, lung cancer, liver cancer, head and neck cancer, and kidney chromophobe samples showed strong expression of highly conserved and ancient genes within the tumors. CONCLUSION Cancer-related genes exhibit older evolutionary origins within the phylogenetic context suggesting a more conserved function during species evolution. And the phenomenon of enhanced expression of highly conserved ancient genes in tumor tissues can be used to explore tumor gene expression patterns, and provide new ideas for the discovery of new anti-tumor drug targets and drug research.