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|Ref Type||Journal Article|
|Authors||Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R|
|Title||RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2017 Apr 15|
|Abstract Text||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 of RET aberrations across multiple cancers may facilitate clinical trial development targeting RETExperimental Design: We interrogated the molecular portfolio of 4,871 patients with diverse malignancies for the presence of RET aberrations using Clinical Laboratory Improvement Amendments-certified targeted next-generation sequencing of 182 or 236 gene panels.Results: Among diverse cancers, RET 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 SQSTM1-RET] and amplifications [25% (22/88)]. Most patients had coexisting aberrations in addition to RET anomalies [81.8% (72/88)], with the most common being in TP53-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)]. RET 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 (KIF5B-RET) and medullary thyroid carcinoma (RET M918T) that responded to a vandetanib (multikinase RET inhibitor)-containing regimen are shown.Conclusions:RET 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 RET anomalies will require customized combination strategies. Clin Cancer Res; 23(8); 1988-97. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|KDR||G1145E||missense||unknown||KDR (VEGFR2) G1145E lies within the protein kinase domain of the Kdr (Vegfr2) protein (UniProt.org). G1145E has been identified in sequencing studies (PMID: 29399405, PMID: 27683183, PMID: 25314059), but has not been biochemically characterized and therefore, its effect on Kdr (Vegfr2) protein function is unknown (PubMed, Apr 2020).|
|NOTCH1||S2329fs||frameshift||unknown||NOTCH1 S2329fs results in a change in the amino acid sequence of the Notch1 protein beginning at aa 2329 of 2555, likely resulting in premature truncation of the functional protein (UniProt.org). S2329fs has been identified in sequencing studies (PMID: 27683183), but has not been biochemically characterized and therefore, its effect on Notch1 protein function is unknown (PubMed, Aug 2020).|
|RET||A756V||missense||unknown||RET A756V lies within the protein kinase domain of the Ret protein (UniProt.org). A756V has been identified in sequencing studies (PMID: 27683183), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jul 2020).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ATM L804fs ATM S978fs RET M918T||thyroid gland medullary carcinoma||predicted - sensitive||Everolimus + Vandetanib||Case Reports/Case Series||Actionable||In a clinical case study, addition of Afinitor (everolimus) to Caprelsa (vandetanib) treatment resulted in significant tumor reduction in a medullary thyroid carcinoma patient harboring ATM L804fs*4, ATM S978fs*12, and RET M918T, that achieved prolonged stable disease on Caprelsa (vandetanib) treatment alone (PMID: 27683183).||27683183|