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

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Vascular Endothelial Growth Factor A
Angiogenic Proteins
Neoplasms
Colorectal Neoplasms
Pancreatic Neoplasms
Single Nucleotide Polymorphism
Genotype
Vascular Endothelial Growth Factor C
Vascular Endothelial Growth Factor Receptor
Proteins
Transcription Factors
Enzyme-Linked Immunosorbent Assay
Alleles
Ligands

All Science Journal Classification (ASJC) codes

  • General

Cite this

Innocenti, F., Jiang, C., Sibley, A. B., Etheridge, A. S., Hatch, A. J., Denning, S., ... 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
Innocenti, Federico ; Jiang, Chen ; Sibley, Alexander B. ; Etheridge, Amy S. ; Hatch, Ace J. ; Denning, Stefanie ; Niedzwiecki, Donna ; Shterev, Ivo D. ; Lin, Jiaxing ; Furukawa, Yoichi ; Kubo, Michiaki ; Kindler, Hedy L. ; Auman, J. Todd ; Venook, Alan P. ; Hurwitz, Herbert I. ; McLeod, Howard L. ; Ratain, Mark J. ; Gordan, Raluca ; Nixon, Andrew B. ; Owzar, Kouros. / Genetic variation determines VEGF-A plasma levels in cancer patients. In: Scientific reports. 2018 ; Vol. 8, No. 1.
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title = "Genetic variation determines VEGF-A plasma levels in cancer patients",
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.",
author = "Federico Innocenti and Chen Jiang and Sibley, {Alexander B.} and Etheridge, {Amy S.} and Hatch, {Ace J.} and Stefanie Denning and Donna Niedzwiecki and Shterev, {Ivo D.} and Jiaxing Lin and Yoichi Furukawa and Michiaki Kubo and Kindler, {Hedy L.} and Auman, {J. Todd} and Venook, {Alan P.} and Hurwitz, {Herbert I.} and McLeod, {Howard L.} and Ratain, {Mark J.} and Raluca Gordan and Nixon, {Andrew B.} and Kouros Owzar",
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Innocenti, F, Jiang, C, Sibley, AB, Etheridge, AS, Hatch, AJ, Denning, S, Niedzwiecki, D, Shterev, ID, Lin, J, Furukawa, Y, Kubo, M, Kindler, HL, Auman, JT, Venook, AP, Hurwitz, HI, McLeod, HL, Ratain, MJ, Gordan, R, Nixon, AB & Owzar, K 2018, 'Genetic variation determines VEGF-A plasma levels in cancer patients', Scientific reports, vol. 8, no. 1, 16332. https://doi.org/10.1038/s41598-018-34506-4

Genetic variation determines VEGF-A plasma levels in cancer patients. / Innocenti, Federico; Jiang, Chen; Sibley, Alexander B.; Etheridge, Amy S.; Hatch, Ace J.; Denning, Stefanie; Niedzwiecki, Donna; Shterev, Ivo D.; Lin, Jiaxing; Furukawa, Yoichi; Kubo, Michiaki; Kindler, Hedy L.; Auman, J. Todd; Venook, Alan P.; Hurwitz, Herbert I.; McLeod, Howard L.; Ratain, Mark J.; Gordan, Raluca; Nixon, Andrew B.; Owzar, Kouros.

In: Scientific reports, Vol. 8, No. 1, 16332, 01.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic variation determines VEGF-A plasma levels in cancer patients

AU - Innocenti, Federico

AU - Jiang, Chen

AU - Sibley, Alexander B.

AU - Etheridge, Amy S.

AU - Hatch, Ace J.

AU - Denning, Stefanie

AU - Niedzwiecki, Donna

AU - Shterev, Ivo D.

AU - Lin, Jiaxing

AU - Furukawa, Yoichi

AU - Kubo, Michiaki

AU - Kindler, Hedy L.

AU - Auman, J. Todd

AU - Venook, Alan P.

AU - Hurwitz, Herbert I.

AU - McLeod, Howard L.

AU - Ratain, Mark J.

AU - Gordan, Raluca

AU - Nixon, Andrew B.

AU - Owzar, Kouros

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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Innocenti F, Jiang C, Sibley AB, Etheridge AS, Hatch AJ, Denning S et al. Genetic variation determines VEGF-A plasma levels in cancer patients. Scientific reports. 2018 Dec 1;8(1). 16332. https://doi.org/10.1038/s41598-018-34506-4