EGFR pathway polymorphisms and bladder cancer susceptibility and prognosis

Abstract

The epidermal growth factor receptor (EGFR) pathway has recently been appreciated as a central mediator of tumorigenesis and an important drug target; however, the influence of genetic variation in this pathway on bladder cancer is not understood. Pathway activation leads to cell proliferation, angiogenesis and is antiapoptotic. We sought to test the hypothesis that bladder cancer susceptibility and survival are modified by inherited variations in the sequence of the EGFR and its pathway members. We tested associations using a population-based study of 857 bladder cancer cases and 1191 controls from New Hampshire. Multifactor dimensionality reduction software was used to predict gene-gene interactions. We detected an increased risk of bladder cancer associated with variant genotypes for the single nucleotide polymorphisms EGFR_03 [adjusted odds ratio (OR) 1.7 (95% confidence interval (CI) 1.0-2.8)] and EGFR_05 [adjusted OR 1.5 (95% CI 1.0-2.1)] compared with wild-type. EGFR variants experienced longer survival than those with wild-type alleles [e.g. adjusted hazard ratio EGFR_1808 0.3 (95% CI 0.1-0.9)]. In contrast, the variant form of the ligand, EGF_04, had worse survival [adjusted hazard ratio 1.5 (95% CI 1.0-2.3)] compared with wild-type. Our findings suggest modified bladder cancer risk and survival associated with genetic variation in the EGFR pathway. Understanding these genetic influences on increased bladder cancer susceptibility and survival may help in cancer prevention, drug development and choice of therapeutic regimen.

Germline prognostic markers for urinary bladder cancer: Obstacles and opportunities

“…These pathways can affect cell proliferation, differentiation, apoptosis, tumor metastasis, angiogenesis, and immune response. In a large case-control study of 857 UBC cases and 1191 controls from New Hampshire, Mason et al found genetic variants of EGFR were associated with increased UBC risk [40]. Moreover, several of the variants also correlated with overall survival in the cases.…”

“…One of the EGFR SNPs (R521K; rs11543848) is a known functional SNP that alters ligand binding and transmembrane signaling [39]. The variant allele of this SNP decreases receptor tyrosine kinase activation and was associated with increased UBC survival [40]. In another large case-control study of 1157 UBC cases and 1157 matched controls, Castillejo et al examined the association of three SNPs in TGFB1 and three SNPs and one insertion/deletion polymorphism of TGFBR1 with UBC risk and clinical outcome(tumor relapse, progression, and survival) [41].…”

Emerging antibody-based therapeutic strategies for bladder cancer: A systematic review

“…Blocking of EGFR-EGF interaction has been demonstrated to arrest bladder cancer cells growth, resulting in tumor cell death, and limit apoptosis in vitro [31,32]. Several activating mutations of the kinase domain or truncating mutations of the extracellular domain have been described in bladder cancer but few are expected to modulate response profile to EGFR blocking [33,34]. Thus, antibody-based therapeutic blockade of EGFR or its ligands represents a new and exciting option for bladder cancer therapy.…”

Alterações na expressão de genes para citocinas, fatores de crescimento e seus receptores estão associadas com as neoplasias epiteliais ovarianas

“…Os ligantes vinculam-se ao EGFR ativando a transdução de sinal que regula para cima os fatores de transcrição, levando ao estímulo do crescimento celular. 23 Outra característica peculiar do EGF é sua potente ação mitogênica no mesotélio ovariano 24 , local onde há uma significativa expressão desse fator de crescimento e de seu receptor. 25 Dependendo do tipo de célula, a ligação do EGF ao EGFR induz várias cascatas ativadoras que podem resultar em várias respostas celulares que incluem mitose, secreção de proteínas, diferenciação e aquisição de motilidade.…”