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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 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.

SUBMITTER: Landrith T 

PROVIDER: S-EPMC7039900 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes.

Landrith Tyler T   Li Bing B   Cass Ashley A AA   Conner Blair R BR   LaDuca Holly H   McKenna Danielle B DB   Maxwell Kara N KN   Domchek Susan S   Morman Nichole A NA   Heinlen Christopher C   Wham Deborah D   Koptiuch Cathryn C   Vagher Jennie J   Rivera Ragene R   Bunnell Ann A   Patel Gayle G   Geurts Jennifer L JL   Depas Morgan M MM   Gaonkar Shraddha S   Pirzadeh-Miller Sara S   Krukenberg Rebekah R   Seidel Meredith M   Pilarski Robert R   Farmer Meagan M   Pyrtel Khateriaa K   Milliron Kara K   Lee John J   Hoodfar Elizabeth E   Nathan Deepika D   Ganzak Amanda C AC   Wu Sitao S   Vuong Huy H   Xu Dong D   Arulmoli Aarani A   Parra Melissa M   Hoang Lily L   Molparia Bhuvan B   Fennessy Michele M   Fox Susanne S   Charpentier Sinead S   Burdette Julia J   Pesaran Tina T   Profato Jessica J   Smith Brandon B   Haynes Ginger G   Dalton Emily E   Crandall Joy Rae-Radecki JR   Baxter Ruth R   Lu Hsiao-Mei HM   Tippin-Davis Brigette B   Elliott Aaron A   Chao Elizabeth E   Karam Rachid R  

NPJ precision oncology 20200224


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 (<i>APC</i>, <i>ATM</i>, <i>BRCA1</i>, <i>BRCA2</i>, <i>BRIP1</i>, <i>CDH  ...[more]

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