Meta-analysis of Germline Whole-exome Sequencing in 1435 Cases of Testicular Germ Cell Tumour to Evaluate Disruptive Mutations Under Dominant, Recessive, and X-linked Inheritance Models
Background and objective: Testicular germ cell tumour (TGCT) is the most common cancer in young men, and over half of its high estimated heritability is unexplained. Our objective was to identify rare pathogenic germline variation driving TGCT susceptibility. Methods: This study is a case-control me...
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Elsevier
2025-03-01
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| Series: | European Urology Open Science |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666168325000540 |
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| author | Zeid Kuzbari Charlie F. Rowlands Isaac Wade Alice Garrett Chey Loveday Subin Choi Beth Torr Kevin Litchfield Alison Reid Robert Huddart Peter Broderick Richard S. Houlston Clare Turnbull |
| author_facet | Zeid Kuzbari Charlie F. Rowlands Isaac Wade Alice Garrett Chey Loveday Subin Choi Beth Torr Kevin Litchfield Alison Reid Robert Huddart Peter Broderick Richard S. Houlston Clare Turnbull |
| author_sort | Zeid Kuzbari |
| collection | DOAJ |
| description | Background and objective: Testicular germ cell tumour (TGCT) is the most common cancer in young men, and over half of its high estimated heritability is unexplained. Our objective was to identify rare pathogenic germline variation driving TGCT susceptibility. Methods: This study is a case-control meta-analysis of whole-exome sequencing data from three datasets (Institute of Cancer Research, The Cancer Genome Atlas, and UK Biobank). We retained unrelated male individuals of European ancestry comprising 1435 TGCT cases and 18 284 cancer-free controls. We performed gene-level association testing of protein-truncating variants and nonsynonymous disruptive variants across six candidate gene sets (733 genes) potentially biologically related to TGCT. We then analysed exome wide (19 355 genes) under dominant and recessive models, including X-linked genes. Key findings and limitations: No individual gene-disease association was identified following multiple testing corrections. However, functional gene-set analyses identified an excess of associations with genes involved in microtubular/ciliary pathways (p = 1.69 × 10–8). Our study was well powered to detect rare variation of moderate/high effect sizes (odds ratio [OR] ≥5), but power diminished for modest effect sizes (OR <5). Conclusions and clinical implications: Although this is the largest whole-exome analysis of TGCT to date and first exome-wide examination for recessively acting gene associations, larger studies are required to identify robust associations for individual genes. Patient summary: We investigated samples from 1435 men with testicular cancer and 18 284 men without cancer to compare the rate of disruptive mutations in 19 355 genes. No evidence of specific genes associated with testicular cancer was discovered, although one gene group showed a strong association. Larger studies are needed to identify individual genes associated with causing testicular cancer. |
| format | Article |
| id | doaj-art-eb701f2fd92c43d6a2483be2aa96e5a1 |
| institution | OA Journals |
| issn | 2666-1683 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | European Urology Open Science |
| spelling | doaj-art-eb701f2fd92c43d6a2483be2aa96e5a12025-08-20T02:02:12ZengElsevierEuropean Urology Open Science2666-16832025-03-0173515910.1016/j.euros.2025.01.015Meta-analysis of Germline Whole-exome Sequencing in 1435 Cases of Testicular Germ Cell Tumour to Evaluate Disruptive Mutations Under Dominant, Recessive, and X-linked Inheritance ModelsZeid Kuzbari0Charlie F. Rowlands1Isaac Wade2Alice Garrett3Chey Loveday4Subin Choi5Beth Torr6Kevin Litchfield7Alison Reid8Robert Huddart9Peter Broderick10Richard S. Houlston11Clare Turnbull12Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UKDivision of Genetics and Epidemiology, The Institute of Cancer Research, London, UKDivision of Genetics and Epidemiology, The Institute of Cancer Research, London, UKDivision of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Department of Clinical Genetics, St George’s University Hospitals NHS Foundation Trust, London, UKDivision of Genetics and Epidemiology, The Institute of Cancer Research, London, UKDivision of Genetics and Epidemiology, The Institute of Cancer Research, London, UKDivision of Genetics and Epidemiology, The Institute of Cancer Research, London, UKCancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Tumour Immunogenomics and Immunosurveillance Laboratory, University College London Cancer Institute, London, UKAcademic Radiotherapy Unit, The Institute of Cancer Research, London, UKAcademic Radiotherapy Unit, The Institute of Cancer Research, London, UKDivision of Genetics and Epidemiology, The Institute of Cancer Research, London, UKDivision of Genetics and Epidemiology, The Institute of Cancer Research, London, UKDivision of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Corresponding author. Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Rd, Sutton SM2 5NG, UK. Tel. +44208 722 4485.Background and objective: Testicular germ cell tumour (TGCT) is the most common cancer in young men, and over half of its high estimated heritability is unexplained. Our objective was to identify rare pathogenic germline variation driving TGCT susceptibility. Methods: This study is a case-control meta-analysis of whole-exome sequencing data from three datasets (Institute of Cancer Research, The Cancer Genome Atlas, and UK Biobank). We retained unrelated male individuals of European ancestry comprising 1435 TGCT cases and 18 284 cancer-free controls. We performed gene-level association testing of protein-truncating variants and nonsynonymous disruptive variants across six candidate gene sets (733 genes) potentially biologically related to TGCT. We then analysed exome wide (19 355 genes) under dominant and recessive models, including X-linked genes. Key findings and limitations: No individual gene-disease association was identified following multiple testing corrections. However, functional gene-set analyses identified an excess of associations with genes involved in microtubular/ciliary pathways (p = 1.69 × 10–8). Our study was well powered to detect rare variation of moderate/high effect sizes (odds ratio [OR] ≥5), but power diminished for modest effect sizes (OR <5). Conclusions and clinical implications: Although this is the largest whole-exome analysis of TGCT to date and first exome-wide examination for recessively acting gene associations, larger studies are required to identify robust associations for individual genes. Patient summary: We investigated samples from 1435 men with testicular cancer and 18 284 men without cancer to compare the rate of disruptive mutations in 19 355 genes. No evidence of specific genes associated with testicular cancer was discovered, although one gene group showed a strong association. Larger studies are needed to identify individual genes associated with causing testicular cancer.http://www.sciencedirect.com/science/article/pii/S2666168325000540Cancer susceptibility genesGene association testingGerm cell tumourGermline mutationsMeta-analysisTesticular cancer |
| spellingShingle | Zeid Kuzbari Charlie F. Rowlands Isaac Wade Alice Garrett Chey Loveday Subin Choi Beth Torr Kevin Litchfield Alison Reid Robert Huddart Peter Broderick Richard S. Houlston Clare Turnbull Meta-analysis of Germline Whole-exome Sequencing in 1435 Cases of Testicular Germ Cell Tumour to Evaluate Disruptive Mutations Under Dominant, Recessive, and X-linked Inheritance Models European Urology Open Science Cancer susceptibility genes Gene association testing Germ cell tumour Germline mutations Meta-analysis Testicular cancer |
| title | Meta-analysis of Germline Whole-exome Sequencing in 1435 Cases of Testicular Germ Cell Tumour to Evaluate Disruptive Mutations Under Dominant, Recessive, and X-linked Inheritance Models |
| title_full | Meta-analysis of Germline Whole-exome Sequencing in 1435 Cases of Testicular Germ Cell Tumour to Evaluate Disruptive Mutations Under Dominant, Recessive, and X-linked Inheritance Models |
| title_fullStr | Meta-analysis of Germline Whole-exome Sequencing in 1435 Cases of Testicular Germ Cell Tumour to Evaluate Disruptive Mutations Under Dominant, Recessive, and X-linked Inheritance Models |
| title_full_unstemmed | Meta-analysis of Germline Whole-exome Sequencing in 1435 Cases of Testicular Germ Cell Tumour to Evaluate Disruptive Mutations Under Dominant, Recessive, and X-linked Inheritance Models |
| title_short | Meta-analysis of Germline Whole-exome Sequencing in 1435 Cases of Testicular Germ Cell Tumour to Evaluate Disruptive Mutations Under Dominant, Recessive, and X-linked Inheritance Models |
| title_sort | meta analysis of germline whole exome sequencing in 1435 cases of testicular germ cell tumour to evaluate disruptive mutations under dominant recessive and x linked inheritance models |
| topic | Cancer susceptibility genes Gene association testing Germ cell tumour Germline mutations Meta-analysis Testicular cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2666168325000540 |
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