Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients.

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 aberrations across multiple cancers may facilitate clinical trial development targeting We interrogated the molecular portfolio of 4,871 patients with diverse malignancies for the presence of aberrations using Clinical Laboratory Improvement Amendments-certified targeted next-generation sequencing of 182 or 236 gene panels. Among diverse cancers, 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 ] and amplifications [25% (22/88)]. Most patients had coexisting aberrations in addition to anomalies [81.8% (72/88)], with the most common being in -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)]. 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 () and medullary thyroid carcinoma ( M918T) that responded to a vandetanib (multikinase RET inhibitor)-containing regimen are shown. 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 anomalies will require customized combination strategies. .