Abstract A06: The added value of examining germline variants in a precision cancer therapy study
Authors: Schienda Jaclyn , Clinton Catherine M. , Corson Laura B. , Imamovic-Tuco Alma , Pinto Navin , Maese Luke , Laetsch Theodore W. , Kim AeRang , Vear Susan I. , Macy Margaret E. , Applebaum Mark A. , Bagatell Rochelle , Sabnis Amit J. , Weiser Daniel A. , Glade-Bender Julia L. , Volchenboum Samuel L. , Kang Wenjun , Manning Danielle , Nowak Jonathan , Schiffman Joshua , Lindeman Neal I. , Church Alanna J. , Janeway Katherine A. , Crompton Brian D. , Kamihara Junne 
Published: August 2020

Abstract
Introduction: Tumor profiling is becoming a more routine part of clinical care. Many academic centers and commercial entities offer tumor sequencing of cancer-related genes without matched germline profiling. We hypothesize that tumor-only sequencing may limit full clinical interpretation and have decreased sensitivity to identify significant germline variants.
Methods: The Genomic Assessment Improves Novel Therapy (GAIN) Consortium is a clinical cancer genomics study for patients with high-risk solid malignancies. Patients in this study were selected for subanalysis if panel sequencing of 447 genes was performed on a tumor and interpreted by an expert panel prior to the availability of matched germline sequencing. Interpretation of tumor sequencing included both therapeutic recommendations and a curation of cancer-related variants of potential clinical significance if present in the germline. Germline sequencing was separately performed targeting 147 genes (a subset of the somatic panel) and analyzed with a germline-specific pipeline to identify and filter variants. We examined clinical recommendations in the somatic reports that were based on single-nucleotide variants identified from the 147 overlapping genes. We compared these interpretations with results from the matched germline data.
Results: We identified 159 participants with somatic and germline sequencing reports meeting the eligibility criteria. Germline sequencing identified 38 pathogenic or likely pathogenic (P/LP) germline variants in 35 of 159 patients (22%). Of those 35 patients, 17 (49%) had a P/LP variant in an autosomal dominant cancer predisposition gene, 19 (54%) in an autosomal recessive gene, and 1 (2.9%) in a noncancer gene. Of the 38 total variants, 21 (55%) were identified by the analytic pipeline used for somatic sequencing and noted as potential germline variants in the somatic reports. Forty treatment recommendations were made from the somatic data within the overlapping genes. Ten (25%) treatment recommendations were based on variants that were later determined to be germline. These included variants in TP53, SDHA, SMARCA4, TSC2, FAM175A, CHEK2, and AKT1, many of which were noted in the somatic reports to be variants of uncertain significance or possibly germline.
Conclusions: In this study, we found that clinically actionable germline variants were under-reported when relying on analytical pipelines and clinical interpretations developed for the analysis of tumor samples. In the absence of germline sequencing, we also found that cancer treatment recommendations can be made based on mutations identified from tumor sequencing that are germline variants. In many cases, these recommendations remain appropriate (e.g., PARP inhibitors for BRCA1/2) while in other cases germline data facilitated a more nuanced interpretation of actionability. These findings support the use of germline genetic testing and paired tumor-germline analysis in precision cancer medicine studies.
Citation Format: Jaclyn Schienda, Catherine M. Clinton, Laura B. Corson, Alma Imamovic-Tuco, Navin Pinto, Luke Maese, Theodore W. Laetsch, AeRang Kim, Susan I. Vear, Margaret E. Macy, Mark A. Applebaum, Rochelle Bagatell, Amit J. Sabnis, Daniel A. Weiser, Julia L. Glade-Bender, Samuel L. Volchenboum, Wenjun Kang, Danielle Manning, Jonathan Nowak, Joshua Schiffman, Neal I. Lindeman, Alanna J. Church, Katherine A. Janeway, Brian D. Crompton, Junne Kamihara. The added value of examining germline variants in a precision cancer therapy study [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A06.