Targeted Variant Assessments of Human Endogenous Retroviral Regions in Whole Genome Sequencing Data Reveal Retroviral Variants Associated with Papillary Thyroid Cancer
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...
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2024-11-01
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| author | Erik Stricker Erin C. Peckham-Gregory Stephen Y. Lai Vlad C. Sandulache Michael E. Scheurer |
| author_facet | Erik Stricker Erin C. Peckham-Gregory Stephen Y. Lai Vlad C. Sandulache Michael E. Scheurer |
| author_sort | Erik Stricker |
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| description | 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 <i>RYR2</i>, <i>LRP1B</i>, <i>FN1</i>, <i>MET</i>, <i>TCRVB</i>, <i>UNC5D</i>, <i>TRPM3</i>, <i>CNTN5</i>, <i>CD70</i>, <i>RYR1</i>, <i>RUNX1</i>, <i>CRLF2</i>, and <i>PCDH1X</i>, and three variants downstream of <i>SERPINA1</i> and <i>RUNX1T1</i>. 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 <i>FN1</i> gene and HERV-L MLT1A LTR variant rs78588384 within the <i>CNTN5</i> gene. Variant rs78588384, in particular, was shown in our analyses to be located within a POL2 binding site regulating an alternative transcript of <i>CNTN5</i>. In addition, we identified 16 variants that modified the poly(A) region in <i>Alu</i> 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. |
| format | Article |
| id | doaj-art-8af1b98bb88e4762b775ef6c0630e01f |
| institution | DOAJ |
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| spelling | doaj-art-8af1b98bb88e4762b775ef6c0630e01f2025-08-20T02:43:49ZengMDPI AGMicroorganisms2076-26072024-11-011212243510.3390/microorganisms12122435Targeted Variant Assessments of Human Endogenous Retroviral Regions in Whole Genome Sequencing Data Reveal Retroviral Variants Associated with Papillary Thyroid CancerErik Stricker0Erin C. Peckham-Gregory1Stephen Y. Lai2Vlad C. Sandulache3Michael E. Scheurer4Department of Molecular and Human Genomics, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USADepartment of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USABobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USAPapillary 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 <i>RYR2</i>, <i>LRP1B</i>, <i>FN1</i>, <i>MET</i>, <i>TCRVB</i>, <i>UNC5D</i>, <i>TRPM3</i>, <i>CNTN5</i>, <i>CD70</i>, <i>RYR1</i>, <i>RUNX1</i>, <i>CRLF2</i>, and <i>PCDH1X</i>, and three variants downstream of <i>SERPINA1</i> and <i>RUNX1T1</i>. 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 <i>FN1</i> gene and HERV-L MLT1A LTR variant rs78588384 within the <i>CNTN5</i> gene. Variant rs78588384, in particular, was shown in our analyses to be located within a POL2 binding site regulating an alternative transcript of <i>CNTN5</i>. In addition, we identified 16 variants that modified the poly(A) region in <i>Alu</i> 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.https://www.mdpi.com/2076-2607/12/12/2435human endogenous retrovirusHERV<i>Alu</i> elementsretroelementspapillary thyroid canceranaplastic thyroid cancer |
| spellingShingle | Erik Stricker Erin C. Peckham-Gregory Stephen Y. Lai Vlad C. Sandulache Michael E. Scheurer Targeted Variant Assessments of Human Endogenous Retroviral Regions in Whole Genome Sequencing Data Reveal Retroviral Variants Associated with Papillary Thyroid Cancer Microorganisms human endogenous retrovirus HERV <i>Alu</i> elements retroelements papillary thyroid cancer anaplastic thyroid cancer |
| title | Targeted Variant Assessments of Human Endogenous Retroviral Regions in Whole Genome Sequencing Data Reveal Retroviral Variants Associated with Papillary Thyroid Cancer |
| title_full | Targeted Variant Assessments of Human Endogenous Retroviral Regions in Whole Genome Sequencing Data Reveal Retroviral Variants Associated with Papillary Thyroid Cancer |
| title_fullStr | Targeted Variant Assessments of Human Endogenous Retroviral Regions in Whole Genome Sequencing Data Reveal Retroviral Variants Associated with Papillary Thyroid Cancer |
| title_full_unstemmed | Targeted Variant Assessments of Human Endogenous Retroviral Regions in Whole Genome Sequencing Data Reveal Retroviral Variants Associated with Papillary Thyroid Cancer |
| title_short | Targeted Variant Assessments of Human Endogenous Retroviral Regions in Whole Genome Sequencing Data Reveal Retroviral Variants Associated with Papillary Thyroid Cancer |
| title_sort | targeted variant assessments of human endogenous retroviral regions in whole genome sequencing data reveal retroviral variants associated with papillary thyroid cancer |
| topic | human endogenous retrovirus HERV <i>Alu</i> elements retroelements papillary thyroid cancer anaplastic thyroid cancer |
| url | https://www.mdpi.com/2076-2607/12/12/2435 |
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