RETAberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients.
Purpose:Aberrations in genetic sequences encoding the tyrosine kinase receptor RET lead to oncogenic signaling that is targetable with anti-RET multikinase inhibitors. Understanding the comprehensive genomic landscape ofRETaberrations across multiple cancers may facilitate clinical trial development targetingRETExperimental Design:We interrogated the molecular portfolio of 4,871 patients with diverse malignancies for the presence ofRETaberrations using Clinical Laboratory Improvement Amendments-certified targeted next-generation sequencing of 182 or 236 gene panels.Results:Among diverse cancers,RETaberrations were identified in 88 cases [1.8% (88/4, 871)], with mutations being the most common alteration [38.6% (34/88)], followed by fusions [30.7% (27/88), including a novelSQSTM1-RET] and amplifications [25% (22/88)]. Most patients had coexisting aberrations in addition toRETanomalies [81.8% (72/88)], with the most common being inTP53-associated genes [59.1% (52/88)], cell cycle-associated genes [39.8% (35/88)], the PI3K signaling pathway [30.7% (27/88)], MAPK effectors [22.7% (20/88)], or other tyrosine kinase families [21.6% (19/88)].RETfusions were mutually exclusive with MAPK signaling pathway alterations. All 72 patients harboring coaberrations had distinct genomic portfolios, and most [98.6% (71/72)] had potentially targetable coaberrations with either an FDA-approved or an investigational agent. Two cases with lung (KIF5B-RET) and medullary thyroid carcinoma (RETM918T) that responded to a vandetanib (multikinase RET inhibitor)-containing regimen are shown.Conclusions:RETaberrations were seen in 1.8% of diverse cancers, with most cases harboring actionable, albeit distinct, coexisting alterations. The current report suggests that optimal targeting of patients withRETanomalies will require customized combination strategies.Clin Cancer Res; 23(8); 1988-97. ©2016 AACR.
Department of Medicine, Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, San Diego, Moores Cancer Center, San Diego, California. smkato@ucsd.edu.
Shumei
S
Kato
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Vivek
V
Subbiah
N-of-One, Inc., Lexington, Massachusetts.
Erica
E
Marchlik
N-of-One, Inc., Lexington, Massachusetts.
Sheryl K
SK
Elkin
N-of-One, Inc., Lexington, Massachusetts.
Jennifer L
JL
Carter
Department of Medicine, Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, San Diego, Moores Cancer Center, San Diego, California.
Razelle
R
Kurzrock
D002869:Chromosome Aberrations; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D000070584:Tripartite Motif Proteins
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C064419:TRIM27 protein, human; D000070584:Tripartite Motif Proteins