Genetic variations in the VEGF pathway as prognostic factors in metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy

• Published in: The pharmacogenomics journal Vol. 15; no. 5; pp. 397 - 404
• Main Authors: Paré-Brunet, L, Sebio, A, Salazar, J, Berenguer-Llergo, A, Río, E, Barnadas, A, Baiget, M, Páez, D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2015; Nature Publishing Group
• Subjects: 45/23; 45/77; 5-Fluorouracil; 692/53/2422; Adult; Aged; Aged, 80 and over; Angiogenesis; Biomedical and Life Sciences; Biomedicine; Cancer; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Disease-Free Survival; Drug metabolism; Female; Fluorouracil - administration & dosage; Gene Expression; Genes; Genetic aspects; Genetic Association Studies; Genetic diversity; Genetic variation; Health aspects; Human Genetics; Humans; Kisspeptins - genetics; Male; Medical prognosis; Metastases; Metastasis; Middle Aged; Neoplasm Metastasis; Oncology; Organoplatinum Compounds - administration & dosage; original-article; Oxaliplatin; Pharmacotherapy; Prognosis; Properties; Psychopharmacology; Signal Transduction; Single-nucleotide polymorphism; Solid tumors; Survival; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor Receptor-2 - genetics
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/tpj.2015.1

Angiogenesis is a significant biological mechanism in the progression and metastasis of solid tumors. Vascular endothelial growth factor (VEGF), its receptors and signaling effectors have a central role in tumor-induced angiogenesis. Genetic variation in the VEGF pathway may impact on tumor angiogenesis and, hence, on clinical cancer outcomes. This study evaluates the influence of common genetic variations within the VEGF pathway in the clinical outcomes of 172 metastatic colorectal cancer (mCRC) patients treated with first-line oxaliplatin/5-fluorouracil chemotherapy. A total of 27 single-nucleotide polymorphisms (SNPs) in 16 genes in the VEGF-dependent angionenesis process were genotyped using a dynamic array on the BioMark™ system. After assessing the
KRAS
mutational status, we found that four SNPs located in three genes (
KISS1
,
KRAS
and
VEGFR2
) were associated with progression-free survival. Five SNPs in three genes (
ITGAV
,
KRAS
and
VEGFR2
) correlated with overall survival. The gene–gene interactions identified in the survival tree analysis support the importance of
VEGFR2
rs2071559 and
KISS1
rs71745629 in modulating these outcomes. This study provides evidence that functional germline polymorphisms in the VEGF pathway may help to predict outcome in mCRC patients who undergo oxaliplatin/5-fluorouracil chemotherapy.