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 language | English |
|---|---|
| Pages (from-to) | 2377-2385 |
| Number of pages | 9 |
| Journal | Clinical Cancer Research |
| Volume | 22 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2016 May 15 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
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 journal › Article
}
TY - JOUR
T1 - Identification of a Novel Pathogenic Germline KDR Variant in Melanoma
AU - Silva, Ines P.
AU - Salhi, Amel
AU - Giles, Keith M.
AU - Vogelsang, Matjaz
AU - Han, Sung Won
AU - Ismaili, Naima
AU - Lui, Kevin P.
AU - Robinson, Eric M.
AU - Wilson, Melissa A.
AU - Shapiro, Richard L.
AU - Pavlick, Anna
AU - Zhong, Judy
AU - Kirchhoff, Tomas
AU - Osman, Iman
PY - 2016/5/15
Y1 - 2016/5/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84968830552&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84968830552&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-15-1811
DO - 10.1158/1078-0432.CCR-15-1811
M3 - Article
C2 - 26631613
AN - SCOPUS:84968830552
VL - 22
SP - 2377
EP - 2385
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 10
ER -