Tumor fraction-guided cell-free DNA profiling in metastatic solid tumor patients

Autor: Maha Shady, Nicholas D. Socci, Julie L. Yang, Helen Won, Maria E. Arcila, Marc Ladanyi, Gopa Iyer, Michael L. Cheng, Xiaohong Jing, Hongxin Zhang, Jonathan Rosenberg, Ahmet Zehir, Pedram Razavi, Kety Huberman, Agnes Viale, Fanli Meng, Darren R. Feldman, Debyani Chakravarty, Michael F. Berger, Venkatraman E. Seshan, S. Duygu Selcuklu, Dennis Stephens, Wassim Abida, Maysun Hasan, Dana E. Rathkopf, Dean F. Bajorin, Erika Gedvilaite, Dana W.Y. Tsui, Preethi Srinivasan, Howard I. Scher, David B. Solit, Juber Patel, Samuel Funt, Ryma Benayed, Ian Johnson, Bob T. Li, Brian Houck-Loomis
Rok vydání: 2021
Předmět:
Zdroj: Genome Medicine
Genome Medicine, Vol 13, Iss 1, Pp 1-15 (2021)
ISSN: 1756-994X
Popis: BackgroundCell-free DNA (cfDNA) profiling is increasingly used to guide cancer care, yet mutations are not always identified. The ability to detect somatic mutations in plasma depends on both assay sensitivity and the fraction of circulating DNA in plasma that is tumor-derived (i.e., cfDNA tumor fraction). We hypothesized that cfDNA tumor fraction could inform the interpretation of negative cfDNA results and guide the choice of subsequent assays of greater genomic breadth or depth.MethodsPlasma samples collected from 118 metastatic cancer patients were analyzed with cf-IMPACT, a modified version of the FDA-authorized MSK-IMPACT tumor test that can detect genomic alterations in 410 cancer-associated genes. Shallow whole genome sequencing (sWGS) was also performed in the same samples to estimate cfDNA tumor fraction based on genome-wide copy number alterations usingz-score statistics. Plasma samples with no somatic alterations detected by cf-IMPACT were triaged based on sWGS-estimated tumor fraction for analysis with either a less comprehensive but more sensitive assay (MSK-ACCESS) or broader whole exome sequencing (WES).ResultscfDNA profiling using cf-IMPACT identified somatic mutations in 55/76 (72%) patients for whom MSK-IMPACT tumor profiling data were available. A significantly higher concordance of mutational profiles and tumor mutational burden (TMB) was observed between plasma and tumor profiling for plasma samples with a high tumor fraction (z-score≥5). In the 42 patients from whom tumor data was not available, cf-IMPACT identified mutations in 16/42 (38%). In total, cf-IMPACT analysis of plasma revealed mutations in 71/118 (60%) patients, with clinically actionable alterations identified in 30 (25%), including therapeutic targets of FDA-approved drugs. Of the 47 samples without alterations detected and low tumor fraction (z-scorez-score≥5) were analyzed by WES, which identified mutational signatures and alterations in potential oncogenic drivers not covered by the cf-IMPACT panel. Overall, we identified mutations in 90/118 (76%) patients in the entire cohort using the three complementary plasma profiling approaches.ConclusionscfDNA tumor fraction can inform the interpretation of negative cfDNA results and guide the selection of subsequent sequencing platforms that are most likely to identify clinically-relevant genomic alterations.
Databáze: OpenAIRE
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