Prognostic tumor sequencing panels frequently identify germ line variants associated with hereditary hematopoietic malignancies.
Michael W Drazer, Sabah Kadri, Madina Sukhanova, Sushant A Patil, Allison H West, Simone Feurstein, Dalein A Calderon, Matthew F Jones, Caroline M Weipert, Christopher K Daugherty, Adrián A Ceballos-López, Gordana Raca, Mark W Lingen, Zejuan Li, Jeremy P Segal, Jane E Churpek, Lucy A Godley
Author Information
Michael W Drazer: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Center. ORCID
Sabah Kadri: Department of Pathology, The University of Chicago, Chicago, IL; and.
Madina Sukhanova: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Center.
Sushant A Patil: Department of Pathology, The University of Chicago, Chicago, IL; and.
Allison H West: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Center.
Simone Feurstein: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Center.
Dalein A Calderon: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Center.
Matthew F Jones: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Center.
Caroline M Weipert: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Center.
Christopher K Daugherty: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Center.
Adrián A Ceballos-López: Section of Hematology, Department of Internal Medicine, Clinica de Mérida, Mérida, Mexico.
Gordana Raca: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Center.
Mark W Lingen: Department of Pathology, The University of Chicago, Chicago, IL; and.
Zejuan Li: Department of Human Genetics, and.
Jeremy P Segal: Department of Pathology, The University of Chicago, Chicago, IL; and.
Jane E Churpek: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Center.
Lucy A Godley: Section of Hematology/Oncology, Department of Medicine, The University of Chicago Comprehensive Cancer Center.
Next-generation sequencing (NGS)-based targeted gene capture panels are used to profile hematopoietic malignancies to guide prognostication and treatment decisions. Because these panels include genes associated with hereditary hematopoietic malignancies (HHMs), we hypothesized that these panels could identify pathogenic germ line variants in malignant cells, thereby identifying patients at risk for HHMs. In total, pathogenic or likely pathogenic variants in , , , , , , or were identified in 74 (21%) of 360 patients. Germ line tissue was available for 24 patients with 25 pathogenic or likely pathogenic variants with variant allele frequencies >0.4. Six (24%) of these 25 variants were of germ line origin. Three variants, 2 variants, and a variant previously implicated in Li-Fraumeni syndrome were of germ line origin. No likely pathogenic/pathogenic germ line variants possessed variant allele frequencies <0.4. This study demonstrates that NGS-based prognostic panels may identify individuals at risk for HHMs despite not being designed for this purpose. Furthermore, variants known to cause Li-Fraumeni syndrome as well as known pathogenic variants in genes such as and are especially likely to be of germ line origin. Thus, tumor-based panels may augment, but should not replace, comprehensive germ line-based testing and counseling.
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