Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics
Abstract Recent studies show that rare, deleterious variants (RDVs) in certain genes are critical determinants of heritable cancer risk. To more comprehensively understand RDVs, we performed the largest-to-date germline variant calling analysis in a case-control setting for a multi-cancer associatio...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-01-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-023-00354-3 |
| _version_ | 1797422839540744192 |
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| author | Myvizhi Esai Selvan Kenan Onel Sacha Gnjatic Robert J. Klein Zeynep H. Gümüş |
| author_facet | Myvizhi Esai Selvan Kenan Onel Sacha Gnjatic Robert J. Klein Zeynep H. Gümüş |
| author_sort | Myvizhi Esai Selvan |
| collection | DOAJ |
| description | Abstract Recent studies show that rare, deleterious variants (RDVs) in certain genes are critical determinants of heritable cancer risk. To more comprehensively understand RDVs, we performed the largest-to-date germline variant calling analysis in a case-control setting for a multi-cancer association study from whole-exome sequencing data of 20,789 participants, split into discovery and validation cohorts. We confirm and extend known associations between cancer risk and germline RDVs in specific gene-sets, including DNA repair (OR = 1.50; p-value = 8.30e-07; 95% CI: 1.28–1.77), cancer predisposition (OR = 1.51; p-value = 4.58e-08; 95% CI: 1.30–1.75), and somatic cancer drivers (OR = 1.46; p-value = 4.04e-06; 95% CI: 1.24–1.72). Furthermore, personal RDV load in these gene-sets associated with increased risk, younger age of onset, increased M1 macrophages in tumor and, increased tumor mutational burden in specific cancers. Our findings can be used towards identifying high-risk individuals, who can then benefit from increased surveillance, earlier screening, and treatments that exploit their tumor characteristics, improving prognosis. |
| first_indexed | 2024-03-09T07:38:11Z |
| format | Article |
| id | doaj.art-47e06faee0814247a1d715838f2deb86 |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-09T07:38:11Z |
| publishDate | 2023-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-47e06faee0814247a1d715838f2deb862023-12-03T05:27:04ZengNature Portfolionpj Precision Oncology2397-768X2023-01-017111210.1038/s41698-023-00354-3Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristicsMyvizhi Esai Selvan0Kenan Onel1Sacha Gnjatic2Robert J. Klein3Zeynep H. Gümüş4Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiPrecision Immunology Institute, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiAbstract Recent studies show that rare, deleterious variants (RDVs) in certain genes are critical determinants of heritable cancer risk. To more comprehensively understand RDVs, we performed the largest-to-date germline variant calling analysis in a case-control setting for a multi-cancer association study from whole-exome sequencing data of 20,789 participants, split into discovery and validation cohorts. We confirm and extend known associations between cancer risk and germline RDVs in specific gene-sets, including DNA repair (OR = 1.50; p-value = 8.30e-07; 95% CI: 1.28–1.77), cancer predisposition (OR = 1.51; p-value = 4.58e-08; 95% CI: 1.30–1.75), and somatic cancer drivers (OR = 1.46; p-value = 4.04e-06; 95% CI: 1.24–1.72). Furthermore, personal RDV load in these gene-sets associated with increased risk, younger age of onset, increased M1 macrophages in tumor and, increased tumor mutational burden in specific cancers. Our findings can be used towards identifying high-risk individuals, who can then benefit from increased surveillance, earlier screening, and treatments that exploit their tumor characteristics, improving prognosis.https://doi.org/10.1038/s41698-023-00354-3 |
| spellingShingle | Myvizhi Esai Selvan Kenan Onel Sacha Gnjatic Robert J. Klein Zeynep H. Gümüş Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics npj Precision Oncology |
| title | Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics |
| title_full | Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics |
| title_fullStr | Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics |
| title_full_unstemmed | Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics |
| title_short | Germline rare deleterious variant load alters cancer risk, age of onset and tumor characteristics |
| title_sort | germline rare deleterious variant load alters cancer risk age of onset and tumor characteristics |
| url | https://doi.org/10.1038/s41698-023-00354-3 |
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