ABSTRACT:
BACKGROUND:
Angiogenesis plays an essential role in tumor growth and metastasis, and is a
major target in cancer therapy. VEGFR and PDGFR are key players involved in
this process. The purpose of this study was to assess the incidence of genetic
variants in these receptors and its potential clinical implications in
colorectal cancer (CRC).
METHODS:
VEGFR2,
PDGFRalpha and PDGFRbeta mutations were evaluated by sequencing their tyrosine
kinase domains in 8 CRC cell lines and in 92 samples of patients with CRC.
Correlations with clinicopathological features and survival were analyzed.
RESULTS:
Four SNPs
were identified, three in PDGFRalpha [exon 12 (A12): c.1701A>G; exon 13
(A13): c.1809G>A; and exon 17 (A17): c.2439+58C>A] and one in PDGFRbeta
[exon 19 (B19): c.2601A>G]. SNP B19, identified in 58% of tumor samples and
in 4 cell lines (LS174T, LS180, SW48, COLO205), was associated with higher
PDGFR and pPDGFR protein levels. Consistent with this observation, 5-year
survival was greater for patients with PDGFR B19 wild type tumors (AA) than for
those harboring the G-allele genotype (GA or GG) (51% vs 17%; p=0.073). Multivariate
analysis confirmed SNP B19 (p=0.029) was a significant prognostic factor for
survival, independent of age (p=0.060) or TNM stage (p<0.001).
CONCLUSIONS:
PDGFRbeta
exon 19 c.2601A>G SNP is commonly encountered in CRC patients and is
associated with increased pathway activation and poorer survival. Implications
regarding its potential influence in response to PDGFR-targeted agents remain
to be elucidated.
Source:
PDGFRalpha/beta and VEGFR2 polymorphisms in colorectal cancer: incidence
and implications in clinical outcome. Estevez-Garcia P, Castaño A, Martin AC,
Lopez-Rios F, Iglesias J, Muñoz-Galván S, Lopez-Calderero I, Molina-Pinelo S,
Pastor MD, Carnero A, Paz-Ares L, Garcia-Carbonero R (rgcarbonero@hotmail.com). BMC Cancer.
2012 Nov 12;12(1):514.
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