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


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.

  • Authors: Tyler Landrith; Bing Li; 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
  • Collaborators: Advocate Medical Group; Aurora St. Luke's Medical Center; Cedar Sinai Medical Center; Community Health Network; Dana Farber Cancer Institute; Huntsman Cancer Institute; Kaiser Permanente San Jose Medical Center; Massachusetts General Hospital; Medical College of Wisconsin; Ohio Health; Ohio State University Comprehensive Cancer Center; Smilow Cancer Hospital at Yale New Haven Health; Texas Oncology; University of Alabama at Birmingham; University of California, Irvine; University of Michigan; University of Pennsylvania; University of Texas Southwestern Medical Center
  • Journal: Precision Oncology
  • Date: 2020 - Feb

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