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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Identification of a Novel Pathogenic Germline KDR Variant in Melanoma
Ines P Silva1, Amel Salhi1, Keith M Giles1
1The Ronald O. Perelman Department of Dermatology, New York, New York. The Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York, New York.
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. Clin Cancer Res; 22(10); 2377-85. ©2015 AACR.
Insights
Germline variants like KDR Q472H in melanoma patients impact tumor growth and angiogenesis. Patients with this variant may benefit from antiangiogenesis therapy, highlighting the importance of germline analysis for personalized cancer treatment.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Pan-cancer next-generation sequencing identifies somatic mutations and enables basket trials for solid tumors.
- Germline variants, often overlooked, can impact cancer prognostication and treatment response.
Purpose of the Study:
- To investigate the clinical relevance of nonsynonymous germline variants in melanoma.
- To assess the impact of the KDR Q472H germline variant on melanoma biology and response to therapy.
Main Methods:
- Analysis of matched tumor and normal DNA from 34 melanoma patients using a cancer-associated gene panel.
- Assessment of proliferation, invasion, VEGF levels, and tumor microvessel density (MVD) in patient-derived cell lines and human samples.
- Evaluation of treatment response using a VEGFR2 antibody in KDR Q472H and wild-type cells.
Main Results:
- The KDR Q472H germline variant was identified in 35% of melanoma patients.
- Patients with the KDR Q472H variant exhibited higher serum VEGF levels and tumor MVD.
- Melanoma cells with the KDR variant showed increased proliferation and invasion, and sensitivity to VEGFR2 inhibition.
Conclusions:
- Germline analysis should be integrated into personalized treatment decision-making for cancer patients.
- Patients with the germline KDR variant may benefit from antiangiogenesis treatments targeting VEGFR2.
