Genetic variation determines VEGF-A plasma levels in cancer patients

Federico Innocenti, Chen Jiang, Alexander B. Sibley, Amy S. Etheridge, Ace J. Hatch, Stefanie Denning, Donna Niedzwiecki, Ivo D. Shterev, Jiaxing Lin, Yoichi Furukawa, Michiaki Kubo, Hedy L. Kindler, J. Todd Auman, Alan P. Venook, Herbert I. Hurwitz, Howard L. McLeod, Mark J. Ratain, Raluca Gordan, Andrew B. Nixon, Kouros Owzar

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Abstract

Angiogenesis is essential in tumor biology and is regulated by vascular endothelial growth factor (VEGF) ligands and receptors. Here we aimed to discover genetic variants associated with levels of circulating angiogenic proteins in cancer patients. Plasma was collected at baseline in 216 pancreatic and 114 colorectal cancer patients. Thirty-one angiogenic proteins were measured by ELISA. 484,523 Single Nucleotide Polymorphisms (SNP) were tested for association with plasma levels for each protein in pancreatic cancer patients. Three top-ranked hits were then genotyped in colorectal cancer patients, where associations with the same proteins were measured. The results demonstrated rs2284284 and MCP1 (P-value = 6.7e–08), rs7504372 and VEGF-C (P-value = 9.8e–09), and rs7767396 and VEGF-A (P-value = 5.8e–09) were SNP-protein pairs identified in pancreatic cancer patients. In colorectal cancer patients, only rs7767396 (A > G) and VEGF-A was validated (P-value = 5.18e–05). The AA genotype of rs7767396 exhibited 2.04–2.3 and 2.7–3.4-fold higher VEGF-A levels than those with AG and GG genotypes. The G allele of rs7767396 reduces binding of the NF-AT1 transcription factor. In conclusion, a common genetic variant predicts the plasma levels of VEGF-A in cancer patients through altered binding of NF-AT1.

Original languageEnglish
Article number16332
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - 01-12-2018

All Science Journal Classification (ASJC) codes

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    Innocenti, F., Jiang, C., Sibley, A. B., Etheridge, A. S., Hatch, A. J., Denning, S., Niedzwiecki, D., Shterev, I. D., Lin, J., Furukawa, Y., Kubo, M., Kindler, H. L., Auman, J. T., Venook, A. P., Hurwitz, H. I., McLeod, H. L., Ratain, M. J., Gordan, R., Nixon, A. B., & Owzar, K. (2018). Genetic variation determines VEGF-A plasma levels in cancer patients. Scientific reports, 8(1), [16332]. https://doi.org/10.1038/s41598-018-34506-4