Author/Editor		Silva, Ines; Salhi, Amel; Giles, Keith M.; Vogelsang, Matjaž; Won Han, Sung; Ismaili, Naima; Lui, Kevin P.; Robinson, Eric M.; Wilson, Melissa; Shapiro, Richard
Title		Identification of a novel pathogenic germline KDR variant in melanoma
Type		članek
Publication year		2015
ISSN		1078-0432 - Clinical cancer research : an official journal of the American Association for Cancer Research
Language		eng
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 non-synonymous 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 using anti-CD34 antibody. Results: Serum VEGF levels and tumor microvessel density were significantly higher in Q472H versus KDR wild-type 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. Consultion: Our data support the integration of germline analysis into personalized treatment decision-making and suggest that patients with germline KDR variant might benefit from anti-angiogenesis treatment.
Keywords		melanom nove patogene zarodne KDR variante identifikacija melanoma novel pathogenic germline KDR variant identification