Genetic Variant of CXCR1 (rs2234671) Associates with Clinical Outcome in Perihilar Cholangiocarcinoma
Isabella Lurje, Zoltán Czigány, Jan Bednarsch, Nadine T. Gaisa, Edgar Dahl, Ruth Knüchel, Hannah Miller, Tom Florian Ulmer, Pavel Strnad, Christian Trautwein, Frank Tacke, Ulf P. Neumann, Georg Lurje
Abstract
<b><i>Background:</i></b> Perihilar cholangiocarcinoma (pCCA) is a rare primary liver malignancy. Even in patients amenable to surgery, outcomes are often dismal. Here, we aimed to identify prognostic markers for patient outcomes by analyzing functionally relevant single-nucleotide polymorphisms (SNPs) in genes with a role in tumor inflammation and angiogenesis. We analyzed 11 polymorphisms in the inflammation-angiogenesis axis (<i>VEGF, EGF, EGFR, IL-1b, IL-6, CXCL8 (IL-8), IL-10, CXCR1, HIF1A</i>, and <i>COX2</i> genes) for their prediction of tumor recurrence and survival in pCCA patients undergoing surgery in a curative intent. <b><i>Methods:</i></b> Samples were obtained from 111 patients with pCCA undergoing liver resection in curative intent. DNA was extracted and analyzed using polymerase chain reaction-restriction fragment length polymorphism protocols and correlated with patients’ outcomes. <b><i>Results:</i></b> Out of the assessed variants, only the <i>CXCR1</i> (also: interleukin-8-receptor alpha – <i>IL-8RA</i>) +860C&#x3e;G heterozygous polymorphism (rs2234671) was associated with decreased disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) (18/111 (16.2%), median DFS 14 months, log-rank <i>p</i> = 0.007; median CSS 31 months, log-rank <i>p</i> = 0.007; and median OS 6 months, log-rank <i>p</i> = 0.002), compared to the GG genotype (92/111 (82.9%), median DFS 55 months, median CSS 63 months, and median OS 33 months). In the multivariate analysis, +860C&#x3e;G remained an independent prognostic factor for DFS (adjusted <i>p</i> = 0.008), CSS (adjusted <i>p</i> = 0.001), and OS (adjusted <i>p</i> = 0.001). <b><i>Conclusion:</i></b> Genetic variant of <i>CXCR1</i> +860C&#x3e;G may serve as a molecular marker for DFS, CSS, and OS in patients undergoing curative-intent surgery for pCCA, indicating that the analysis of SNPs in genes involved in immune-mediated angiogenesis may help to identify patient subgroups at high risk for dismal oncological and overall outcome.