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

Ting-Chia Chang,Raja Mazumder,Jonas Blomberg,Qing Pan,Yu Hu,Santosh Goud,Robel Kahsay,John Torcivia-Rodriguez

doi:10.1371/journal.pone.0213770

Abstract

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.

Highlights

Endogenous retroviruses (ERVs) have been embedded in the primate genomes for over 30 million years [1, 2]
A total of 2,543 somatic non-synonymous single-nucleotide variation (nsSNV) were identified in 25 human endogenous retrovirus (HERV) groups that overlap with human protein coding regions (S1 and S6 Tables)
Five out of 20 groups belonging to Alpha-retrovirus/ Beta-retrovirus-related (AB) retroviruses contained 23.5% of the nsSNVs. 20.4% of nsSNVs were within two Spumavirus related (S) HERV groups. 5.8% of the nsSNVs were found in the “Uncertain Errantivirus-like” group and two unclassified HERV groups

Summary

Introduction

Endogenous retroviruses (ERVs) have been embedded in the primate genomes for over 30 million years [1, 2]. Human endogenous retroviruses (HERVs) account for approximately eight percent of the human genome [6] and have been classified into three main classes I, II and III. This classification is based on sequence similarity to different genera of infectious retroviruses [7]. Classifications of HERV elements are currently not entirely consistent due to varying approaches used to detect HERV sequences [8, 10]. This leads to a variable number of identified HERV groups based on the bioinformatic methodology and algorithm used and can cause inconsistencies in HERV classification [11, 12]. This work builds upon a huge volume of previous work on repetitive elements and evolutionary analysis of ERVs [14, 15] [16,17,18]

Objectives

Methods

Results

Discussion

Conclusion