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Ref Type Journal Article
PMID (26631613)
Authors Silva IP, Salhi A, Giles KM, Vogelsang M, Han SW, Ismaili N, Lui KP, Robinson EM, Wilson MA, Shapiro RL, Pavlick A, Zhong J, Kirchhoff T, Osman I
Title Identification of a Novel Pathogenic Germline KDR Variant in Melanoma.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 10
Date 2016 May 15
Abstract Text The application of pan-cancer next-generation sequencing panels in the clinical setting has facilitated the identification of low frequency somatic mutations and the testing of new therapies in solid tumors using the "basket trial" scheme. However, little consideration has been given to the relevance of nonsynonymous germline variants, which are likely to be uncovered in tumors and germline and which may be relevant to prognostication and prediction of treatment response.We analyzed matched tumor and normal DNA from 34 melanoma patients using an Ion Torrent cancer-associated gene panel. We elected to study the germline variant Q472H in the kinase insert domain receptor (KDR), which was identified in 35% of melanoma patients in both a pilot and an independent 1,223 patient cohort. Using patient-derived melanoma cell lines and human samples, we assessed proliferation, invasion, VEGF levels, and angiogenesis by analyzing tumor microvessel density (MVD) using anti-CD34 antibody.Serum VEGF levels and tumor MVD were significantly higher in Q472H versus KDR wild-type (WD) patients. Primary cultures derived from melanomas harboring the KDR variant were more proliferative and invasive than KDR wild type. Finally, using a VEGFR2 antibody, we showed that KDR Q472H cells were sensitive to targeted inhibition of VEGFR2, an effect that was not observed in KDR WT cells.Our data support the integration of germline analysis into personalized treatment decision-making and suggest that patients with germline KDR variant might benefit from antiangiogenesis treatment. Clin Cancer Res; 22(10); 2377-85. ©2015 AACR.


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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 Q472H missense gain of function KDR (VEGFR2) Q472H does not lie within any known functional domains of the Kdr (Vegfr2) protein ( Q472H confers a gain of function to the Kdr (Vegfr2) protein, resulting in increased phosphorylation of Kdr (Vegfr2) in cell culture, increased serum VEGF levels, and increased microvessel density in tumor samples (PMID: 21712447, PMID: 26631613).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KDR Q472H melanoma sensitive unspecified VEGFR2 antibody Preclinical Actionable In a preclinical study, human melanoma cells harboring KDR (VEGFR2) Q472H demonstrated increased sensitivity to treatment with a VEGFR2 (KDR) function-blocking antibody compared to cells with wild-type KDR (VEGFR), resulting in decreased proliferation and invasion in culture (PMID: 26631613). 26631613