Genetic Variant of CXCR1 (rs2234671) Associates with Clinical Outcome in Perihilar Cholangiocarcinoma

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.