Stricker Erik, Peckham-Gregory Erin C, Lai Stephen Y, Sandulache Vlad C, Scheurer Michael E
Department of Molecular and Human Genomics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Microorganisms. 2024 Nov 27;12(12):2435. doi: 10.3390/microorganisms12122435.
Papillary thyroid cancer (PTC) is one of the fastest-growing cancers worldwide, lacking established causal factors or validated early diagnostics. Human endogenous retroviruses (HERVs), comprising 8% of human genomes, have potential as PTC biomarkers due to their comparably high baseline expression in healthy thyroid tissues, indicating homeostatic roles. However, HERV regions are often overlooked in genome-wide association studies because of their highly repetitive nature, low sequence coverage, and decreased sequencing quality. Using targeted whole-genome sequence analysis in conjunction with high sequencing depth to overcome methodological limitations, we identified associations of specific HERV variants with PTC. Analyzing WGS data from 138 patients with PTC generated through The Cancer Genome Atlas project and 2015 control samples from the 1000 Genomes Project, we examined the mutational variation in HERVs within a 20 kb radius of known cancer predisposition genes (CPGs) differentially expressed in PTC. We discovered 15 common and 13 rare germline HERV variants near or within 20 CPGs that distinguish patients with PTC from healthy controls. We identified intragenic-intronic HERV variants within , , , , , , , , , , , , and , and three variants downstream of and . Sanger sequencing analyses of 20 thyroid and 5 non-thyroid cancer cell lines confirmed associations with PTC, particularly for MSTA HERV-L variant rs200077102 within the gene and HERV-L MLT1A LTR variant rs78588384 within the gene. Variant rs78588384, in particular, was shown in our analyses to be located within a POL2 binding site regulating an alternative transcript of . In addition, we identified 16 variants that modified the poly(A) region in elements, potentially altering the potential to retrotranspose. In conclusion, this study serves as a proof-of-concept for targeted variant analysis of HERV regions and establishes a basis for further exploration of HERVs in thyroid cancer development.
甲状腺乳头状癌（PTC）是全球增长最快的癌症之一，缺乏明确的致病因素或经过验证的早期诊断方法。人类内源性逆转录病毒（HERV）占人类基因组的8%，由于其在健康甲状腺组织中具有相对较高的基线表达，表明其具有稳态作用，因此有潜力作为PTC的生物标志物。然而，由于HERV区域具有高度重复性、低序列覆盖率和测序质量下降等特点，在全基因组关联研究中常常被忽视。我们采用靶向全基因组序列分析并结合高测序深度来克服方法学上的局限性，从而确定了特定HERV变异与PTC之间的关联。通过分析来自癌症基因组图谱项目的138例PTC患者的全基因组测序（WGS）数据以及来自千人基因组计划的2015个对照样本，我们研究了在PTC中差异表达的已知癌症易感基因（CPG）周围20 kb范围内HERV的突变变异情况。我们在20个CPG附近或内部发现了15个常见和13个罕见的种系HERV变异，这些变异可将PTC患者与健康对照区分开来。我们在 、 、 、 、 、 、 、 、 、 、 、 和 中鉴定出基因内内含子HERV变异，以及在 和 下游的三个变异。对20个甲状腺癌细胞系和5个非甲状腺癌细胞系进行的桑格测序分析证实了这些变异与PTC的关联，特别是 基因内的MSTA HERV-L变异rs200077102和 基因内的HERV-L MLT1A LTR变异rs78588384。尤其是变异rs78588384，在我们的分析中显示位于一个调节 的替代转录本的POL2结合位点内。此外，我们还鉴定出16个变异，这些变异改变了 元件中的多聚腺苷酸化（poly(A)）区域，可能改变逆转录转座的潜力。总之，本研究为HERV区域的靶向变异分析提供了概念验证，并为进一步探索HERV在甲状腺癌发生发展中的作用奠定了基础。
