Transcriptomic silencing as a potential mechanism of treatment resistance

被引:24
作者
Adashek, Jacob J. [1 ]
Kato, Shumei [2 ,3 ]
Parulkar, Rahul [4 ]
Szeto, Christopher W. [4 ]
Sanborn, J. Zachary [4 ]
Vaske, Charles J. [4 ]
Benz, Stephen C. [4 ]
Reddy, Sandeep K. [5 ]
Kurzrock, Razelle [2 ,3 ]
机构
[1] Univ S Florida, Dept Internal Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33620 USA
[2] Univ Calif San Diego, Ctr Personalized Canc Therapy, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, Div Hematol & Oncol, Dept Med, La Jolla, CA 92093 USA
[4] Nantomics, Santa Cruz, CA USA
[5] NantHlth, Culver City, CA USA
关键词
DRUG-RESISTANCE; CANCER;
D O I
10.1172/jci.insight.134824
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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, PET, 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.
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页数:9
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