Intersection of rare pathogenic variants from TCGA in the All of Us Research Program v6
Summary: Using rare cancer predisposition alleles derived from The Cancer Genome Atlas (TCGA) and high cancer prevalence (14% of participants) in All of Us (version 6), we assessed the impact of these rare alleles on cancer occurrence in six broad groups of genetic similarity provided by All of Us:...
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Elsevier
2025-04-01
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| Series: | HGG Advances |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247725000089 |
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| author | Blaine A. Bates Kylee E. Bates Spencer A. Boris Colin Wessman David Stone Justin Bryan Mary F. Davis Matthew H. Bailey |
| author_facet | Blaine A. Bates Kylee E. Bates Spencer A. Boris Colin Wessman David Stone Justin Bryan Mary F. Davis Matthew H. Bailey |
| author_sort | Blaine A. Bates |
| collection | DOAJ |
| description | Summary: Using rare cancer predisposition alleles derived from The Cancer Genome Atlas (TCGA) and high cancer prevalence (14% of participants) in All of Us (version 6), we assessed the impact of these rare alleles on cancer occurrence in six broad groups of genetic similarity provided by All of Us: African/African American (AFR), Admixed American/Latino (AMR), East Asian (EAS), European (EUR), Middle Eastern (MID), or South Asian (SAS). We observed that germline susceptibility to cancer consistently replicates in EUR-like participants but less so in other participants. We found that All of Us participants from the EUR (p = 1.8 × 10−7), AFR (p = 0.018), and MID (p = 0.0083) genetic similarity groups who carry a rare pathogenic mutation are more likely to have cancer than those without a rare pathogenic mutation. With the advent of combining medical records and genetic mutations, we also performed a phenome-wide association study (PheWAS) to assess the effect of pathogenic variants on additional phenotypes. This analysis again showed several associations between predisposition variants and cancer in EUR-like participants, but fewer in those of the other genetic similarity groups. As All of Us grows to 1 million participants, our projections suggest sufficient power (>99%) to detect cancer-associated variants that are common, but limited power (∼28%) to detect rare mutations when using the entire cohort. This study provides preliminary insights into genetic predispositions to cancer across a diverse cohort and demonstrates the value of All of Us as a resource for cancer research. |
| format | Article |
| id | doaj-art-d7a48ece878c49a0b03e96dbf5f9978a |
| institution | Kabale University |
| issn | 2666-2477 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
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| series | HGG Advances |
| spelling | doaj-art-d7a48ece878c49a0b03e96dbf5f9978a2025-01-31T05:12:28ZengElsevierHGG Advances2666-24772025-04-0162100405Intersection of rare pathogenic variants from TCGA in the All of Us Research Program v6Blaine A. Bates0Kylee E. Bates1Spencer A. Boris2Colin Wessman3David Stone4Justin Bryan5Mary F. Davis6Matthew H. Bailey7Department of Biology, Brigham Young University, Provo, UT 84061, USA; Department of Chemical Engineering, Brigham Young University, Provo, UT 84602, USADepartment of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USADepartment of Biology, Brigham Young University, Provo, UT 84061, USADepartment of Biology, Brigham Young University, Provo, UT 84061, USADepartment of Biology, Brigham Young University, Provo, UT 84061, USADepartment of Biology, Brigham Young University, Provo, UT 84061, USADepartment of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA; Department of Biomedical Informatics, Vanderbilt University, Nashville, TN 37203, USADepartment of Biology, Brigham Young University, Provo, UT 84061, USA; Simmons Center for Cancer Research, Brigham Young University, Provo, UT 84602, USA; Corresponding authorSummary: Using rare cancer predisposition alleles derived from The Cancer Genome Atlas (TCGA) and high cancer prevalence (14% of participants) in All of Us (version 6), we assessed the impact of these rare alleles on cancer occurrence in six broad groups of genetic similarity provided by All of Us: African/African American (AFR), Admixed American/Latino (AMR), East Asian (EAS), European (EUR), Middle Eastern (MID), or South Asian (SAS). We observed that germline susceptibility to cancer consistently replicates in EUR-like participants but less so in other participants. We found that All of Us participants from the EUR (p = 1.8 × 10−7), AFR (p = 0.018), and MID (p = 0.0083) genetic similarity groups who carry a rare pathogenic mutation are more likely to have cancer than those without a rare pathogenic mutation. With the advent of combining medical records and genetic mutations, we also performed a phenome-wide association study (PheWAS) to assess the effect of pathogenic variants on additional phenotypes. This analysis again showed several associations between predisposition variants and cancer in EUR-like participants, but fewer in those of the other genetic similarity groups. As All of Us grows to 1 million participants, our projections suggest sufficient power (>99%) to detect cancer-associated variants that are common, but limited power (∼28%) to detect rare mutations when using the entire cohort. This study provides preliminary insights into genetic predispositions to cancer across a diverse cohort and demonstrates the value of All of Us as a resource for cancer research.http://www.sciencedirect.com/science/article/pii/S2666247725000089MeSHneoplasmsgenetic predisposition to diseasediverse geneticsgenotype-phenotype associationphenome-wide association study |
| spellingShingle | Blaine A. Bates Kylee E. Bates Spencer A. Boris Colin Wessman David Stone Justin Bryan Mary F. Davis Matthew H. Bailey Intersection of rare pathogenic variants from TCGA in the All of Us Research Program v6 HGG Advances MeSH neoplasms genetic predisposition to disease diverse genetics genotype-phenotype association phenome-wide association study |
| title | Intersection of rare pathogenic variants from TCGA in the All of Us Research Program v6 |
| title_full | Intersection of rare pathogenic variants from TCGA in the All of Us Research Program v6 |
| title_fullStr | Intersection of rare pathogenic variants from TCGA in the All of Us Research Program v6 |
| title_full_unstemmed | Intersection of rare pathogenic variants from TCGA in the All of Us Research Program v6 |
| title_short | Intersection of rare pathogenic variants from TCGA in the All of Us Research Program v6 |
| title_sort | intersection of rare pathogenic variants from tcga in the all of us research program v6 |
| topic | MeSH neoplasms genetic predisposition to disease diverse genetics genotype-phenotype association phenome-wide association study |
| url | http://www.sciencedirect.com/science/article/pii/S2666247725000089 |
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