The Role of Single-Nucleotide Polymorphisms in Cholangiocarcinoma: A Systematic Review

SIMPLE SUMMARY: Cholangiocarcinoma (CCA) is the second most common primary liver cancer, associated with a dismal prognosis due to its late diagnosis and lack of effective systemic therapies. Single-nucleotide polymorphisms (SNPs) are polymorphisms of a DNA sequence caused by a single nucleotide variation at the genomic level between individuals. While original work investigating the role of SNPs in CCA has been published during the last decades, currently no systematic review has been conducted summarizing the current knowledge and thereby facilitating further research of this interesting topic. Thus, we here aimed to systemically evaluate and illustrate the association between SNPs and CCA, focusing on tumorigenesis and prognosis. We identified 43 SNPs in 32 genes associated with CCA risk, metastatic progression and overall prognosis based on 34 studies, and comprehensively describe the associated mechanisms and potential clinical implications within a variety of detailed figures and tables. Our findings indicate that multiple SNPs play different roles at various stages of CCA and might serve as biomarkers guiding treatment and allowing oncological risk assessment. ABSTRACT: Single-nucleotide polymorphisms (SNPs) play an essential role in various malignancies, but their role in cholangiocarcinoma (CCA) remains to be elucidated. Therefore, the purpose of this systematic review was to evaluate the association between SNPs and CCA, focusing on tumorigenesis and prognosis. A systematic literature search was carried out using PubMed, Embase, Web of Science and the Cochrane database for the association between SNPs and CCA, including literature published between January 2000 and April 2022. This systematic review compiles 43 SNPs in 32 genes associated with CCA risk, metastatic progression and overall prognosis based on 34 studies. Susceptibility to CCA was associated with SNPs in genes related to inflammation (PTGS2/COX2, IL6, IFNG/IFN-γ, TNF/TNF-α), DNA repair (ERCC1, MTHFR, MUTYH, XRCC1, OGG1), detoxification (NAT1, NAT2 and ABCC2), enzymes (SERPINA1, GSTO1, APOBEC3A, APOBEC3B), RNA (HOTAIR) and membrane-based proteins (EGFR, GAB1, KLRK1/NKG2D). Overall oncological prognosis was also related to SNPs in eight genes (GNB3, NFE2L2/NRF2, GALNT14, EGFR, XRCC1, EZH2, GNAS, CXCR1). Our findings indicate that multiple SNPs play different roles at various stages of CCA and might serve as biomarkers guiding treatment and allowing oncological risk assessment. Considering the differences in SNP detection methods, patient ethnicity and corresponding environmental factors, more large-scale multicentric investigations are needed to fully determine the potential of SNP analysis for CCA susceptibility prediction and prognostication.