尼安德特人基因渗入在肝癌中的作用。

The role of Neanderthal introgression in liver cancer.

机构信息

Center for Evolution and Medicine, Arizona State University, Tempe, AZ, USA.

School of Life Sciences, Arizona State University, Tempe, AZ, USA.

出版信息

BMC Med Genomics. 2022 Dec 12;15(1):255. doi: 10.1186/s12920-022-01405-7.

DOI:10.1186/s12920-022-01405-7

PMID:36503519

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9743633/

Abstract

BACKGROUND

Neanderthal introgressed DNA has been linked to different normal and disease traits including immunity and metabolism-two important functions that are altered in liver cancer. However, there is limited understanding of the relationship between Neanderthal introgression and liver cancer risk. The aim of this study was to investigate the relationship between Neanderthal introgression and liver cancer risk.

METHODS

Using germline and somatic DNA and tumor RNA from liver cancer patients from The Cancer Genome Atlas, along with ancestry-match germline DNA from unaffected individuals from the 1000 Genomes Resource, and allele specific expression data from normal liver tissue from The Genotype-Tissue Expression project we investigated whether Neanderthal introgression impacts cancer etiology. Using a previously generated set of Neanderthal alleles, we identified Neanderthal introgressed haplotypes. We then tested whether somatic mutations are enriched or depleted on Neanderthal introgressed haplotypes compared to modern haplotypes. We also computationally assessed whether somatic mutations have a functional effect or show evidence of regulating expression of Neanderthal haplotypes. Finally, we compared patterns of Neanderthal introgression in liver cancer patients and the general population.

RESULTS

We find Neanderthal introgressed haplotypes exhibit an excess of somatic mutations compared to modern haplotypes. Variant Effect Predictor analysis revealed that most of the somatic mutations on these Neanderthal introgressed haplotypes are not functional. We did observe expression differences of Neanderthal alleles between tumor and normal for four genes that also showed a pattern of enrichment of somatic mutations on Neanderthal haplotypes. However, gene expression was similar between liver cancer patients with modern ancestry and liver cancer patients with Neanderthal ancestry at these genes. Provocatively, when analyzing all genes, we find evidence of Neanderthal introgression regulating expression in tumor from liver cancer patients in two genes, ARK1C4 and OAS1. Finally, we find that most genes do not show a difference in the proportion of Neanderthal introgression between liver cancer patients and the general population.

CONCLUSION

Our results suggest that Neanderthal introgression provides opportunity for somatic mutations to accumulate, and that some Neanderthal introgression may impact liver cancer risk.

摘要

背景

尼安德特人基因已被证明与多种正常和疾病特征有关，包括免疫和代谢——这两个在肝癌中发生改变的重要功能。然而，人们对尼安德特人基因渗入与肝癌风险之间的关系知之甚少。本研究旨在探讨尼安德特人基因渗入与肝癌风险之间的关系。

方法

利用癌症基因组图谱中肝癌患者的种系和体细胞 DNA 以及肿瘤 RNA，以及来自 1000 基因组资源的未受影响个体的种系 DNA，并利用基因型-组织表达项目中的正常肝脏组织的等位基因特异性表达数据，我们研究了尼安德特人基因渗入是否会影响癌症的病因。我们使用先前生成的尼安德特人等位基因集来识别尼安德特人基因渗入的单倍型。然后，我们测试了与现代单倍型相比，体细胞突变是否在尼安德特人基因渗入的单倍型上富集或耗尽。我们还通过计算评估体细胞突变是否具有功能效应或显示调节尼安德特人单倍型表达的证据。最后，我们比较了肝癌患者和一般人群中尼安德特人基因渗入的模式。

结果

我们发现与现代单倍型相比，尼安德特人基因渗入的单倍型中体细胞突变的数量过多。变体效应预测分析显示，这些尼安德特人基因渗入单倍型上的大多数体细胞突变都没有功能。我们确实观察到四个基因的肿瘤和正常组织之间的尼安德特人等位基因表达差异，这些基因的尼安德特人单倍型上也显示出体细胞突变的富集模式。然而，在这些基因中，具有现代血统的肝癌患者和具有尼安德特人血统的肝癌患者的基因表达相似。挑衅性的是，在分析所有基因时，我们在两个基因 ARK1C4 和 OAS1 中发现了尼安德特人基因渗入调节肿瘤表达的证据。最后，我们发现大多数基因在肝癌患者和一般人群之间的尼安德特人基因渗入比例没有差异。