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Supplemental Table 1 from Discrimination of Germline EGFR T790M Mutations in Plasma Cell-Free DNA Allows Study of Prevalence Across 31,414 Cancer Patients

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posted on 2023-03-31, 20:03 authored by Yuebi Hu, Ryan S. Alden, Justin I. Odegaard, Stephen R. Fairclough, Ruthia Chen, Jennifer Heng, Nora Feeney, Rebecca J. Nagy, Jayshree Shah, Bryan Ulrich, Martin Gutierrez, Richard B. Lanman, Judy E. Garber, Cloud P. Paweletz, Geoffrey R. Oxnard

Alterations detectable by Guardant360 gene panel

Funding

Damon Runyon Cancer Research Foundation

Anna Fuller Fund

Conquer Cancer Foundation of ASCO

Bonnie J. Addario Lung Cancer Foundation

National Cancer Institute (NCI)

United States Department of Health and Human Services

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NCI Cancer Clinical Investigator Team Leadership Award

Stading-Younger Cancer Research Foundation Thoracic Oncology Fund

History

ARTICLE ABSTRACT

Purpose: Plasma cell-free DNA (cfDNA) analysis is increasingly used clinically for cancer genotyping, but may lead to incidental identification of germline-risk alleles. We studied EGFR T790M mutations in non–small cell lung cancer (NSCLC) toward the aim of discriminating germline and cancer-derived variants within cfDNA.Experimental Design: Patients with EGFR-mutant NSCLC, some with known germline EGFR T790M, underwent plasma genotyping. Separately, deidentified genomic data and buffy coat specimens from a clinical plasma next-generation sequencing (NGS) laboratory were reviewed and tested.Results: In patients with germline T790M mutations, the T790M allelic fraction (AF) in cfDNA approximates 50%, higher than that of EGFR driver mutations. Review of plasma NGS results reveals three groups of variants: a low-AF tumor group, a heterozygous group (∼50% AF), and a homozygous group (∼100% AF). As the EGFR driver mutation AF increases, the distribution of the heterozygous group changes, suggesting increased copy number variation from increased tumor content. Excluding cases with high copy number variation, mutations can be differentiated into somatic variants and incidentally identified germline variants. We then developed a bioinformatic algorithm to distinguish germline and somatic mutations; blinded validation in 21 cases confirmed a 100% positive predictive value for predicting germline T790M. Querying a database of 31,414 patients with plasma NGS, we identified 48 with germline T790M, 43 with nonsquamous NSCLC (P < 0.0001).Conclusions: With appropriate bioinformatics, plasma genotyping can accurately predict the presence of incidentally detected germline risk alleles. This finding in patients indicates a need for genetic counseling and confirmatory germline testing. Clin Cancer Res; 23(23); 7351–9. ©2017 AACR.

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