Resequencing of the vascular endothelial growth factor promoter reveals haplotype structure and functional diversity

Milan Radovich, Bradley A. Hancock, Nawal Kassem, Deming Mi, Todd Skaar, Bryan Schneider

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Our group has previously reported that SNPs in the VEGF promoter are strongly associated with efficacy and toxicity to the anti-VEGF antibody bevacizumab in breast cancer. In order to better understand the biologic mechanism for our previously reported biomarkers, we embarked on a comprehensive evaluation of genetic variation in the VEGF promoter coupled with a study of its intrinsic function. We resequenced 48 Caucasians and 48 African-Americans for the VEGF promoter to identify SNPs and elucidate its haplotype structure. We further cloned the haplotypes into reporter constructs and assessed the role of SNPs on promoter function in breast cancer cell lines. SNPs that were identified included twenty previously reported SNPs/insertions/deletions, one novel SNP, and one novel deletion. Among these variants, we identified five SNPs that tag six haplotypes capturing 74% of the genetic variation of the promoter. Subsequently, assessment of the haplotypes in reporter constructs demonstrates significant variation in promoter induced expression among the haplotypes. In particular, two haplotypes had higher expression and one haplotype had lower expression across cell lines. Haplotypes containing SNPs previously reported to be associated with increased survival with the use of bevacizumab are high-expressing haplotypes, thus lending putative functional evidence to the prior clinical finding.

Original languageEnglish
Pages (from-to)211-218
Number of pages8
JournalAngiogenesis
Volume13
Issue number3
DOIs
StatePublished - Sep 2010

Fingerprint

Haplotypes
Vascular Endothelial Growth Factor A
Single Nucleotide Polymorphism
Cells
Biomarkers
Toxicity
Breast Neoplasms
Antibodies
Cell Line
Genetic Promoter Regions
African Americans
Anti-Idiotypic Antibodies
Bevacizumab

Keywords

  • Haplotype
  • Promoter
  • Resequencing
  • SNP
  • VEGF

ASJC Scopus subject areas

  • Cancer Research
  • Physiology
  • Clinical Biochemistry

Cite this

Resequencing of the vascular endothelial growth factor promoter reveals haplotype structure and functional diversity. / Radovich, Milan; Hancock, Bradley A.; Kassem, Nawal; Mi, Deming; Skaar, Todd; Schneider, Bryan.

In: Angiogenesis, Vol. 13, No. 3, 09.2010, p. 211-218.

Research output: Contribution to journalArticle

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