Investigation of somatic single nucleotide variations in human endogenous retrovirus elements and their potential association with cancer

Human endogenous retroviruses (HERVs) have been investigated for potential links with human cancer. However, the distribution of somatic nucleotide variations in HERV elements has not been explored in detail. This study aims to identify HERV elements with an over-representation of somatic mutations (hot spots) in cancer patients. Four HERV elements with mutation hotspots were identified that overlap with exons of four human protein coding genes. These hotspots were identified based on the significant over-representation (p<8.62e-4) of non-synonymous single-nucleotide variations (nsSNVs). These genes are TNN (HERV-9/LTR12), OR4K15 (HERV-IP10F/LTR10F), ZNF99 (HERV-W/HERV17/LTR17), and KIR2DL1 (MST/MaLR). In an effort to identify mutations that effect survival, all nsSNVs were further evaluated and it was found that kidney cancer patients with mutation C2270G in ZNF99 have a significantly lower survival rate (hazard ratio = 2.6) compared to those without it. Among HERV elements in the human non-protein coding regions, we found 788 HERVs with significantly elevated numbers of somatic single-nucleotide variations (SNVs) (p<1.60e-5). From this category the top three HERV elements with significantly over-represented SNVs are HERV-H/LTR7, HERV-9/LTR12 and HERV-L/MLT2. Majority of the SNVs in these 788 HERV elements are located in three DNA functional groups: long non-coding RNAs (lncRNAs) (60%), introns (22.2%) and transcriptional factor binding sites (TFBS) (14.8%). This study provides a list of mutational hotspots in HERVs, which could potentially be used as biomarkers and therapeutic targets.

人类内源性逆转录病毒（Human endogenous retroviruses, HERVs）与人类癌症的潜在关联已得到广泛研究。然而，HERV元件中的体细胞核苷酸变异分布尚未得到深入探究。本研究旨在鉴定癌症患者中体细胞突变过度富集的HERV元件（即突变热点）。研究共鉴定出4个携带突变热点的HERV元件，它们与4个人类蛋白编码基因的外显子区域重叠。这些突变热点基于非同义单核苷酸变异（non-synonymous single-nucleotide variations, nsSNVs）的显著过度富集（p<8.62e-4）得以鉴定。涉及的基因为：TNN（HERV-9/LTR12）、OR4K15（HERV-IP10F/LTR10F）、ZNF99（HERV-W/HERV17/LTR17）以及KIR2DL1（MST/MaLR）。为鉴定影响患者生存的突变，研究团队对所有nsSNVs进行了进一步评估，结果发现携带ZNF99基因中C2270G突变的肾癌患者，其生存率显著低于未携带该突变的患者（风险比=2.6）。在人类非蛋白编码区域的HERV元件中，本研究共发现788个体细胞单核苷酸变异（single-nucleotide variations, SNVs）数量显著升高的HERV元件（p<1.60e-5）。其中，SNVs过度富集程度排名前三的HERV元件分别为HERV-H/LTR7、HERV-9/LTR12以及HERV-L/MLT2。这788个HERV元件中的绝大多数SNVs位于三类DNA功能区域：长链非编码RNA（long non-coding RNAs, lncRNAs）（占比60%）、内含子（占比22.2%）以及转录因子结合位点（transcriptional factor binding sites, TFBS）（占比14.8%）。本研究鉴定出了HERVs中的一系列突变热点，这些热点有望作为生物标志物与治疗靶点加以应用。