Identification of a Novel Pathogenic Germline KDR Variant in Melanoma

Ines P. Silva, Amel Salhi, Keith M. Giles, Matjaz Vogelsang, Sung Won Han, Naima Ismaili, Kevin P. Lui, Eric M. Robinson, Melissa A. Wilson, Richard L. Shapiro, Anna Pavlick, Judy Zhong, Tomas Kirchhoff, Iman Osman

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)2377-2385
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number10
DOIs
Publication statusPublished - 2016 May 15
Externally publishedYes

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Vascular Endothelial Growth Factor Receptor-2
Melanoma
Neoplasms
Microvessels
Vascular Endothelial Growth Factor A
Neoplasm Genes
Mutation Rate
Therapeutics
Anti-Idiotypic Antibodies
Decision Making
Research Design
Ions
Cell Line
Antibodies
DNA
Serum

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Silva, I. P., Salhi, A., Giles, K. M., Vogelsang, M., Han, S. W., Ismaili, N., ... Osman, I. (2016). Identification of a Novel Pathogenic Germline KDR Variant in Melanoma. Clinical Cancer Research, 22(10), 2377-2385. https://doi.org/10.1158/1078-0432.CCR-15-1811

Identification of a Novel Pathogenic Germline KDR Variant in Melanoma. / Silva, Ines P.; Salhi, Amel; Giles, Keith M.; Vogelsang, Matjaz; Han, Sung Won; Ismaili, Naima; Lui, Kevin P.; Robinson, Eric M.; Wilson, Melissa A.; Shapiro, Richard L.; Pavlick, Anna; Zhong, Judy; Kirchhoff, Tomas; Osman, Iman.

In: Clinical Cancer Research, Vol. 22, No. 10, 15.05.2016, p. 2377-2385.

Research output: Contribution to journalArticle

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 2016, 'Identification of a Novel Pathogenic Germline KDR Variant in Melanoma', Clinical Cancer Research, vol. 22, no. 10, pp. 2377-2385. https://doi.org/10.1158/1078-0432.CCR-15-1811
Silva, Ines P. ; Salhi, Amel ; Giles, Keith M. ; Vogelsang, Matjaz ; Han, Sung Won ; Ismaili, Naima ; Lui, Kevin P. ; Robinson, Eric M. ; Wilson, Melissa A. ; Shapiro, Richard L. ; Pavlick, Anna ; Zhong, Judy ; Kirchhoff, Tomas ; Osman, Iman. / Identification of a Novel Pathogenic Germline KDR Variant in Melanoma. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 10. pp. 2377-2385.
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AU - Han, Sung Won

AU - Ismaili, Naima

AU - Lui, Kevin P.

AU - Robinson, Eric M.

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