Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes
Abstract Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remai...
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Nature Portfolio
2020
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oai:doaj.org-article:50f2e0c212b24359a87e5f0fd59980ac2021-12-02T14:18:12ZSplicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes10.1038/s41698-020-0109-y2397-768Xhttps://doaj.org/article/50f2e0c212b24359a87e5f0fd59980ac2020-02-01T00:00:00Zhttps://doi.org/10.1038/s41698-020-0109-yhttps://doaj.org/toc/2397-768XAbstract Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remaining without a molecular diagnosis. To address this, we used capture RNA-sequencing (RNA-seq) to generate a splicing profile of 18 TSGs (APC, ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53) in 345 whole-blood samples from healthy donors. We subsequently demonstrated that this approach can detect mis-splicing by comparing splicing profiles from the control dataset to profiles generated from whole blood of individuals previously identified with pathogenic germline splicing variants in these genes. To assess the utility of our TSG splicing profile to prospectively identify pathogenic splicing variants, we performed concurrent capture DNA and RNA-seq in a cohort of 1000 patients with suspected hereditary cancer syndromes. This approach improved the diagnostic yield in this cohort, resulting in a 9.1% relative increase in the detection of pathogenic variants, demonstrating the utility of performing simultaneous DNA and RNA genetic testing in a clinical context.Tyler LandrithBing LiAshley A. CassBlair R. ConnerHolly LaDucaDanielle B. McKennaKara N. MaxwellSusan DomchekNichole A. MormanChristopher HeinlenDeborah WhamCathryn KoptiuchJennie VagherRagene RiveraAnn BunnellGayle PatelJennifer L. GeurtsMorgan M. DepasShraddha GaonkarSara Pirzadeh-MillerRebekah KrukenbergMeredith SeidelRobert PilarskiMeagan FarmerKhateriaa PyrtelKara MillironJohn LeeElizabeth HoodfarDeepika NathanAmanda C. GanzakSitao WuHuy VuongDong XuAarani ArulmoliMelissa ParraLily HoangBhuvan MolpariaMichele FennessySusanne FoxSinead CharpentierJulia BurdetteTina PesaranJessica ProfatoBrandon SmithGinger HaynesEmily DaltonJoy Rae-Radecki CrandallRuth BaxterHsiao-Mei LuBrigette Tippin-DavisAaron ElliottElizabeth ChaoRachid KaramNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 4, Iss 1, Pp 1-9 (2020) |
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DOAJ |
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| topic |
Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Tyler Landrith Bing Li Ashley A. Cass Blair R. Conner Holly LaDuca Danielle B. McKenna Kara N. Maxwell Susan Domchek Nichole A. Morman Christopher Heinlen Deborah Wham Cathryn Koptiuch Jennie Vagher Ragene Rivera Ann Bunnell Gayle Patel Jennifer L. Geurts Morgan M. Depas Shraddha Gaonkar Sara Pirzadeh-Miller Rebekah Krukenberg Meredith Seidel Robert Pilarski Meagan Farmer Khateriaa Pyrtel Kara Milliron John Lee Elizabeth Hoodfar Deepika Nathan Amanda C. Ganzak Sitao Wu Huy Vuong Dong Xu Aarani Arulmoli Melissa Parra Lily Hoang Bhuvan Molparia Michele Fennessy Susanne Fox Sinead Charpentier Julia Burdette Tina Pesaran Jessica Profato Brandon Smith Ginger Haynes Emily Dalton Joy Rae-Radecki Crandall Ruth Baxter Hsiao-Mei Lu Brigette Tippin-Davis Aaron Elliott Elizabeth Chao Rachid Karam Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes |
| description |
Abstract Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remaining without a molecular diagnosis. To address this, we used capture RNA-sequencing (RNA-seq) to generate a splicing profile of 18 TSGs (APC, ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53) in 345 whole-blood samples from healthy donors. We subsequently demonstrated that this approach can detect mis-splicing by comparing splicing profiles from the control dataset to profiles generated from whole blood of individuals previously identified with pathogenic germline splicing variants in these genes. To assess the utility of our TSG splicing profile to prospectively identify pathogenic splicing variants, we performed concurrent capture DNA and RNA-seq in a cohort of 1000 patients with suspected hereditary cancer syndromes. This approach improved the diagnostic yield in this cohort, resulting in a 9.1% relative increase in the detection of pathogenic variants, demonstrating the utility of performing simultaneous DNA and RNA genetic testing in a clinical context. |
| format |
article |
| author |
Tyler Landrith Bing Li Ashley A. Cass Blair R. Conner Holly LaDuca Danielle B. McKenna Kara N. Maxwell Susan Domchek Nichole A. Morman Christopher Heinlen Deborah Wham Cathryn Koptiuch Jennie Vagher Ragene Rivera Ann Bunnell Gayle Patel Jennifer L. Geurts Morgan M. Depas Shraddha Gaonkar Sara Pirzadeh-Miller Rebekah Krukenberg Meredith Seidel Robert Pilarski Meagan Farmer Khateriaa Pyrtel Kara Milliron John Lee Elizabeth Hoodfar Deepika Nathan Amanda C. Ganzak Sitao Wu Huy Vuong Dong Xu Aarani Arulmoli Melissa Parra Lily Hoang Bhuvan Molparia Michele Fennessy Susanne Fox Sinead Charpentier Julia Burdette Tina Pesaran Jessica Profato Brandon Smith Ginger Haynes Emily Dalton Joy Rae-Radecki Crandall Ruth Baxter Hsiao-Mei Lu Brigette Tippin-Davis Aaron Elliott Elizabeth Chao Rachid Karam |
| author_facet |
Tyler Landrith Bing Li Ashley A. Cass Blair R. Conner Holly LaDuca Danielle B. McKenna Kara N. Maxwell Susan Domchek Nichole A. Morman Christopher Heinlen Deborah Wham Cathryn Koptiuch Jennie Vagher Ragene Rivera Ann Bunnell Gayle Patel Jennifer L. Geurts Morgan M. Depas Shraddha Gaonkar Sara Pirzadeh-Miller Rebekah Krukenberg Meredith Seidel Robert Pilarski Meagan Farmer Khateriaa Pyrtel Kara Milliron John Lee Elizabeth Hoodfar Deepika Nathan Amanda C. Ganzak Sitao Wu Huy Vuong Dong Xu Aarani Arulmoli Melissa Parra Lily Hoang Bhuvan Molparia Michele Fennessy Susanne Fox Sinead Charpentier Julia Burdette Tina Pesaran Jessica Profato Brandon Smith Ginger Haynes Emily Dalton Joy Rae-Radecki Crandall Ruth Baxter Hsiao-Mei Lu Brigette Tippin-Davis Aaron Elliott Elizabeth Chao Rachid Karam |
| author_sort |
Tyler Landrith |
| title |
Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes |
| title_short |
Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes |
| title_full |
Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes |
| title_fullStr |
Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes |
| title_full_unstemmed |
Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes |
| title_sort |
splicing profile by capture rna-seq identifies pathogenic germline variants in tumor suppressor genes |
| publisher |
Nature Portfolio |
| publishDate |
2020 |
| url |
https://doaj.org/article/50f2e0c212b24359a87e5f0fd59980ac |
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