Transcriptomic silencing as a potential mechanism of treatment resistance. JCI Insight 2020 Jun 04;5(11)
Date
06/05/2020Pubmed ID
32493840Pubmed Central ID
PMC7308055DOI
10.1172/jci.insight.134824Scopus ID
2-s2.0-85086008367 (requires institutional sign-in at Scopus site) 22 CitationsAbstract
Next-generation sequencing (NGS) has not revealed all the mechanisms underlying resistance to genomically matched drugs. Here, we performed in 1417 tumors whole-exome tumor (somatic)/normal (germline) NGS and whole-transcriptome sequencing, the latter focusing on a clinically oriented 50-gene panel in order to examine transcriptomic silencing of putative driver alterations. In this large-scale study, approximately 13% of the somatic single nucleotide variants (SNVs) were unexpectedly not expressed as RNA; 23% of patients had ≥1 nonexpressed SNV. SNV-bearing genes consistently transcribed were TP53, PIK3CA, and KRAS; those with lower transcription rates were ALK, CSF1R, ERBB4, FLT3, GNAS, HNF1A, KDR, PDGFRA, RET, and SMO. We also determined the frequency of tumor mutations being germline, rather than somatic, in these and an additional 462 tumors with tumor/normal exomes; 33.8% of germline SNVs within the gene panel were rare (not found after filtering through variant information domains) and at risk of being falsely reported as somatic. Both the frequency of silenced variant transcription and the risk of falsely identifying germline mutations as somatic/tumor related are important phenomena. Therefore, transcriptomics is a critical adjunct to genomics when interrogating patient tumors for actionable alterations, because, without expression of the target aberrations, there will likely be therapeutic resistance.
Author List
Adashek JJ, Kato S, Parulkar R, Szeto CW, Sanborn JZ, Vaske CJ, Benz SC, Reddy SK, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
FemaleGene Silencing
Germ-Line Mutation
High-Throughput Nucleotide Sequencing
Humans
Male
Middle Aged
Neoplasms
Polymorphism, Single Nucleotide
Transcriptome
