Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors.

Abstract

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and downstream clinical use (clinicaltrials.gov NCT01775072). Germline pathogenic and likely pathogenic (P/LP) variants were reported. One or more P/LP variants were found in 18% (138/751) of individuals when including variants in low, moderate, and high penetrance dominant or recessive genes, or 13% (99/751) in moderate and high penetrance dominant genes. 34% of high or moderate penetrance variants were unexpected based on the patient's diagnosis and previous history. 76% of patients with positive results completed a clinical genetics visit, and 21% had at least one relative undergo cascade testing as a result of this testing. Clinical actionability additionally included screening, risk reduction in relatives, reproductive use, and use of targeted therapies. Germline testing should be considered for all children with cancer.

• Authors: Elise M Fiala, Gowtham Jayakumaran, Audrey Mauguen, Jennifer A Kennedy, Nancy Bouvier, Yelena Kemel, Megan Harlan Fleischut, Anna Maio, Erin E Salo-Mullen, Margaret Sheehan, Angela G Arnold, Alicia Latham, Maria I Carlo, Karen Cadoo, Semanti Murkherjee, Emily K Slotkin, Tanya Trippett, Julia Glade Bender, Paul A Meyers, Leonard Wexler, Filemon S Dela Cruz, Nai-Kong Cheung, Ellen Basu, Alex Kentsis, Michael Ortiz, Jasmine H Francis, Ira J Dunkel, Yasmin Khakoo, Stephen Gilheeney, Sameer Farouk Sait, Christopher J Forlenza, Maria Sulis, Matthias Karajannis, Shakeel Modak, Justin T Gerstle, Todd E Heaton, Stephen Roberts, Ciyu Yang, Sowmya Jairam, Joseph Vijai, Sabine Topka, Danielle N Friedman, Zsofia K Stadler, Mark Robson, Michael F Berger, Nikolaus Schultz, Marc Ladanyi, Richard J O'Reilly, David H Abramson, Ozge Ceyhan-Birsoy, Liying Zhang, Diana Mandelker, Neerav N Shukla, Andrew L Kung, Kenneth Offit, Ahmet Zehir, Michael F Walsh
• Journal: Nature cancer (Nat Cancer) Vol. 2 Pg. 357-365 (03 2021) ISSN: 2662-1347 [Electronic] England
• PMID: 34308366 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Topics

• Child
• Genetic Predisposition to Disease
• Germ Cells
• Germ-Line Mutation (genetics)
• Humans
• Neoplasms (diagnosis)
• Prospective Studies