title: Identification of a Novel Pathogenic Germline KDR Variant in Melanoma.
abstract: 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.
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York, New York. The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York.
authors.forename: Ines P
authors.initials: IP
authors.lastname: Silva
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York, New York. The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York.
authors.forename: Amel
authors.initials: A
authors.lastname: Salhi
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York, New York. The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Giles
authors.affiliation: The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York. Departments of Population Health and Environmental Medicine, New York, New York.
authors.forename: Matjaz
authors.initials: M
authors.lastname: Vogelsang
authors.affiliation: The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York. NYU Center for Health Informatics and Bioinformatics, New York, New York.
authors.forename: Sung W
authors.initials: SW
authors.lastname: Han
authors.affiliation: Department of Pathology, New York, New York.
authors.forename: Naima
authors.initials: N
authors.lastname: Ismaili
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York, New York. The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Lui
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York, New York. The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Robinson
authors.affiliation: The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York. Department of Medicine, New York, New York.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Wilson
authors.affiliation: The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York. Department of Surgery, New York, New York.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Shapiro
authors.affiliation: The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York. Department of Medicine, New York, New York.
authors.forename: Anna
authors.initials: A
authors.lastname: Pavlick
authors.affiliation: The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York. NYU Center for Health Informatics and Bioinformatics, New York, New York.
authors.forename: Judy
authors.initials: J
authors.lastname: Zhong
authors.affiliation: The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York. Departments of Population Health and Environmental Medicine, New York, New York.
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhoff
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York, New York. The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York. Iman.Osman@nyumc.org.
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005854:Germ Cells / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics; D010865:Pilot Projects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2