Genetic variants in C-type lectin genes are associated with colorectal cancer susceptibility and clinical outcome Shun Lu 1 , Melanie Bevier 1 , Stefanie Huhn 1 , Juan Sainz 1 , Jesus Lascorz 1 , Barbara Pardini 2,3 , Alessio Naccarati 2,3 , Ludmila Vodickova 2,4 , Jan Novotny 5 , Kari Hemminki 1,6 , Pavel Vodicka 2,4 and Asta F€ orsti 1,6 1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany 2 Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic 3 Human Genetics Foundation (HuGeF), Turin, Italy 4 Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic 5 Department of Oncology, General Teaching Hospital, Prague, Czech Republic 6 Center of Primary Health Care Research, Clinical Research Center, Lund University, Malm€ o, Sweden Inflammatory responses play a vital role at different stages of colorectal carcinogenesis. C-type lectins mediate inflammatory/ immune responses and participate in immune escape of pathogens and tumors. Our study aimed to evaluate the correlation between polymorphisms in three C-type lectin genes, CD209, MBL2 and REG4, and colorectal cancer (CRC) risk and clinical outcome. We genotyped 15 potentially functional single nucleotide polymorphisms (SNPs) and assessed their associations with CRC risk in a case-control study of 1353 CRC cases and 767 healthy controls from the Czech Republic. We also analyzed these SNPs in relation to overall and event-free survival in 414 patients. Two CD209 SNPs were associated with CRC risk after adjustment for multiple comparison. Minor allele carriers of the promoter SNP rs2287886 had an increased risk of CRC (OR 1.30, 95% CI 1.08–1.56), while minor allele carriers of the 3 0 UTR SNP, rs7248637, had a decreased risk (OR 0.74, 95% CI 0.60–0.91). Multivariate survival analyses, including age, gender, TNM stage and grade, showed that patients without distant metastasis at the time of diagnosis and carrying the rs2994809 T allele had a decreased overall and event-free survival (HR 2.11, 95% CI 1.20–3.72 and HR 2.00, 95% CI 1.18–3.39, respectively). We show that SNPs in CD209 may affect CRC risk, while a SNP in REG4 may be a useful marker for CRC progression. Colorectal cancer (CRC) is the most common cancer and the second leading cause of cancer-related death in Europe. 1 Inflammatory responses play a vital role at different stages of colorectal carcinogenesis, including initiation, progression and recurrence. Cancer immunology may help clinician to design better therapeutic strategies. 2 C-type lectins are a fam- ily of soluble and transmembrane proteins which recognize microbial carbohydrate moieties and sense products from dying cells and tumor cells. 3 They not only mediate inflam- matory/immune responses to pathogens, they also participate in immune escape of pathogens and tumors and have func- tions related to cell-cell adhesion and migration. 3,4 Three C-type lectins, dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN), mannose-binding lectin (MBL), and regenerating gene 4 (REG4) have been suggested to affect colorectal carcinogene- sis and prognosis. 5–15 DC-SIGN, also known as CD209, is a Type II transmembrane C-type lectin expressed by dendritic cells (DCs). It plays an important role in the induction of immune responses by interaction with numerous different pathogens, and affects many other DC functions, such as DC-T cell interaction and DC migration. 16 Several studies have suggested that DCs recognize CRC cells through bind- ing of DC-SIGN to tumor-specific glycosylation. 5–7 Tumor cells may escape immunosurveillance by suppressing DC functions through interaction with DC-SIGN. 16,17 MBL, coded by the MBL2 gene, is a C-type serum lectin produced by liver. MBL plays a key role in innate immunity. 18 It is able to bind a diverse range of microbes, and kill them through activation of the complement system or by promoting phagocytosis. Previous investigation has reported that CRC patients have increased serum MBL levels with an increased MBL complement activation pathway. 8 However, low pre-op- erative MBL levels seem to predict increased risk of post- Key words: CD209, colorectal cancer, MBL, polymorphism, REG4 Abbreviations: CI: confidence interval; CRC: colorectal cancer; DC: dendritic cell; HR: hazard ratio; LD: linkage disequilibrium; MAF: minor allele frequency; OR: odds ratio; SNP: single nucleo- tide polymorphism; UICC: International Union against Cancer; UTR: untranslated region; WGA: whole genome amplification. Additional Supporting Information may be found in the online version of this article. Grant sponsor: Grant agency of the Czech Republic (GACR), Grant numbers: CZ:GACR:GA P304/10/1286; P304/12/1585 DOI: 10.1002/ijc.28251 History: Received 20 Dec 2012; Accepted 15 Apr 2013; Online 3 May 2013 Correspondence to: Asta F€ orsti, Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany, Tel.: 149- 6221421803, Fax: 149-6221421810, E-mail: a.foersti@dkfz.de Cancer Genetics Int. J. Cancer: 133, 2325–2333 (2013) V C 2013 UICC International Journal of Cancer IJC