<i>RET</i> Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients

Abstract

<b>Purpose:</b> 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 of <i>RET</i> aberrations across multiple cancers may facilitate clinical trial development targeting <i>RET</i><b>Experimental Design:</b> We interrogated the molecular portfolio of 4,871 patients with diverse malignancies for the presence of <i>RET</i> aberrations using Clinical Laboratory Improvement Amendments-certified targeted next-generation sequencing of 182 or 236 gene panels.<b>Results:</b> Among diverse cancers, <i>RET</i> aberrations 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 novel <i>SQSTM1-RET</i>] and amplifications [25% (22/88)]. Most patients had coexisting aberrations in addition to <i>RET</i> anomalies [81.8% (72/88)], with the most common being in <i>TP53</i>-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)]. <i>RET</i> fusions 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 (<i>KIF5B-RET</i>) and medullary thyroid carcinoma (<i>RET</i> M918T) that responded to a vandetanib (multikinase RET inhibitor)-containing regimen are shown.<b>Conclusions:</b><i>RET</i> aberrations 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 with <i>RET</i> anomalies will require customized combination strategies. <i>Clin Cancer Res; 23(8); 1988-97. ©2016 AACR</i>.