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

Isabella Lurje; Zoltan Czigany; Jan Bednarsch; Nadine Therese Gaisa; Edgar Dahl; Ruth Knüchel; Hannah Miller; Tom Florian Ulmer; Pavel Strnad; Christian Trautwein; Frank Tacke; Ulf Peter Neumann; Georg Lurje

doi:10.1159/000521613

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

Liver Cancer. 2022 Jan 25;11(2):162-173. doi: 10.1159/000521613. eCollection 2022 Apr.

Authors

Isabella Lurje^{1

2}, Zoltan Czigany², Jan Bednarsch², Nadine Therese Gaisa³, Edgar Dahl³, Ruth Knüchel³, Hannah Miller^{1

4}, Tom Florian Ulmer², Pavel Strnad⁵, Christian Trautwein⁵, Frank Tacke^{1

5}, Ulf Peter Neumann^{2

6}, Georg Lurje^{2

4}

Affiliations

¹ Department of Hepatology and Gastroenterology, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany.
² Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.
³ Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
⁴ Department of Surgery, Campus Charité Mitte, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁵ Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
⁶ Department of Surgery, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands.

Abstract

Background: 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 (VEGF, EGF, EGFR, IL-1b, IL-6, CXCL8 (IL-8), IL-10, CXCR1, HIF1A, and COX2 genes) for their prediction of tumor recurrence and survival in pCCA patients undergoing surgery in a curative intent.

Methods: 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.

Results: Out of the assessed variants, only the CXCR1 (also: interleukin-8-receptor alpha - IL-8RA) +860C>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 p = 0.007; median CSS 31 months, log-rank p = 0.007; and median OS 6 months, log-rank p = 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>G remained an independent prognostic factor for DFS (adjusted p = 0.008), CSS (adjusted p = 0.001), and OS (adjusted p = 0.001).

Conclusion: Genetic variant of CXCR1 +860C>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.

Keywords: CXCR1; IL-8; Perihilar cholangiocarcinoma; Single-nucleotide polymorphism.