Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic
Despite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n = 176) and those without (n = 82)...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-01-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396414000498 |
| _version_ | 1818152333303873536 |
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| author | Samantha B. Foley Jonathan J. Rios Victoria E. Mgbemena Linda S. Robinson Heather L. Hampel Amanda E. Toland Leslie Durham Theodora S. Ross |
| author_facet | Samantha B. Foley Jonathan J. Rios Victoria E. Mgbemena Linda S. Robinson Heather L. Hampel Amanda E. Toland Leslie Durham Theodora S. Ross |
| author_sort | Samantha B. Foley |
| collection | DOAJ |
| description | Despite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n = 176) and those without (n = 82). Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency < 1% in ESP6500) in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks. |
| first_indexed | 2024-12-11T13:53:03Z |
| format | Article |
| id | doaj.art-1f198127c83440ceb15c422f19f3476a |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-11T13:53:03Z |
| publishDate | 2015-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-1f198127c83440ceb15c422f19f3476a2022-12-22T01:04:10ZengElsevierEBioMedicine2352-39642015-01-0121748110.1016/j.ebiom.2014.12.003Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics ClinicSamantha B. Foley0Jonathan J. Rios1Victoria E. Mgbemena2Linda S. Robinson3Heather L. Hampel4Amanda E. Toland5Leslie Durham6Theodora S. Ross7Department of Internal Medicine, UT Southwestern Medical Center, Dallas TX, 75390, USASarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas 75219, USADepartment of Internal Medicine, UT Southwestern Medical Center, Dallas TX, 75390, USADepartment of Cancer Genetics, UT Southwestern Medical Center, Dallas, TX, 75390, USADepartment of Human Genetics, Ohio State University, Columbus, OH, 43210, USADepartment of Human Genetics, Ohio State University, Columbus, OH, 43210, USADepartment of Internal Medicine, UT Southwestern Medical Center, Dallas TX, 75390, USADepartment of Internal Medicine, UT Southwestern Medical Center, Dallas TX, 75390, USADespite the potential of whole-genome sequencing (WGS) to improve patient diagnosis and care, the empirical value of WGS in the cancer genetics clinic is unknown. We performed WGS on members of two cohorts of cancer genetics patients: those with BRCA1/2 mutations (n = 176) and those without (n = 82). Initial analysis of potentially pathogenic variants (PPVs, defined as nonsynonymous variants with allele frequency < 1% in ESP6500) in 163 clinically-relevant genes suggested that WGS will provide useful clinical results. This is despite the fact that a majority of PPVs were novel missense variants likely to be classified as variants of unknown significance (VUS). Furthermore, previously reported pathogenic missense variants did not always associate with their predicted diseases in our patients. This suggests that the clinical use of WGS will require large-scale efforts to consolidate WGS and patient data to improve accuracy of interpretation of rare variants. While loss-of-function (LoF) variants represented only a small fraction of PPVs, WGS identified additional cancer risk LoF PPVs in patients with known BRCA1/2 mutations and led to cancer risk diagnoses in 21% of non-BRCA cancer genetics patients after expanding our analysis to 3209 ClinVar genes. These data illustrate how WGS can be used to improve our ability to discover patients' cancer genetic risks.http://www.sciencedirect.com/science/article/pii/S2352396414000498Cancer geneticsBRCA1/2Whole-genome sequenceClinVarPathogenic variantsSingle nucleotide variant |
| spellingShingle | Samantha B. Foley Jonathan J. Rios Victoria E. Mgbemena Linda S. Robinson Heather L. Hampel Amanda E. Toland Leslie Durham Theodora S. Ross Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic EBioMedicine Cancer genetics BRCA1/2 Whole-genome sequence ClinVar Pathogenic variants Single nucleotide variant |
| title | Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic |
| title_full | Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic |
| title_fullStr | Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic |
| title_full_unstemmed | Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic |
| title_short | Use of Whole Genome Sequencing for Diagnosis and Discovery in the Cancer Genetics Clinic |
| title_sort | use of whole genome sequencing for diagnosis and discovery in the cancer genetics clinic |
| topic | Cancer genetics BRCA1/2 Whole-genome sequence ClinVar Pathogenic variants Single nucleotide variant |
| url | http://www.sciencedirect.com/science/article/pii/S2352396414000498 |
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