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BDJOpen www.nature.com/bdjopen ARTICLE OPEN Variations in AXIN2 predict risk and prognosis of colorectal cancer 1 2 3 4 3 5 L. Otero , E. Lacunza , V. Vasquez , V. Arbelaez , F. Cardier and F. González OBJECTIVE: Colorectal cancer (CRC) and hypodontia are frequent and different diseases with common genes are involved in their etiology. The objective of this study was to identify the association between AXIN2 rs2240308 with hypodontia and CRC. PATIENTS AND METHODS: This study consisted of 50 individuals with hypodontia, 50 individuals with CRC, and 155 healthy individuals from Colombia. SNP genotyping assays of rs2240308 were performed and family history of cancer in individuals with hypodontia was documented. In silico analysis was implemented to deﬁne the genomic proﬁle of the AXIN2 gene associated with CRC. Multivariate analysis, chi square, odd ratio tests, and R software were used for statistical analysis. RESULTS: AXIN2 rs2240308 showed association with CRC (OR = 5.4 CI: 2.7–10.4; p < 0.001) and with other familial cancer in individuals with hypodontia (p < 0.005 OR = 1.75, 95% CI: 1.22–6.91). In silico analysis showed that variations in AXIN2 found in CRC patients, were more frequently in earlier stages of tumor and patients who carry variations in the AXIN2 gene have a worse prognosis (p < 0.05). The association between AXIN2 rs2240308 with hypodontia was not signiﬁcant. CONCLUSIONS: These results suggest that AXIN2 rs2240308 polymorphism is associated with CRC and AXIN2 could be a risk marker for predisposition and prognosis of CRC. BDJ Open (2019) 5:13 ; https://doi.org/10.1038/s41405-019-0022-z INTRODUCTION 3β (GSK3β), and disheveled (DLV) protein. Hence, molecules Dental agenesis is one of the most common congenital anomalies such as WNT (WNT4, WNT6, and WNT10) and AXIN2 play an in human dentition. Hypodontia occurs when there are one to ﬁve important role during the embryonic development that involves missing teeth and its prevalence reaches 2.6–11.3% depending dental formation. the ethnic group. Although the etiology of dental agenesis The association between AXIN2 and CRC involves defects in the involved genetic and environmental factors, the genes more canonical WNT signaling pathway, which regulates and coordi- frequently associated with hypodontia in different populations are nates the AXIN complex for the degradation of β-catenin under 2,3 AXIN2, MSX1, PAX9, EDA, and WNT10. normal conditions. In addition, AXIN2 expression can be elevated From the study of Lamni et al., many investigations relating in CRC as a result of APC mutations. However, and in an dental agenesis with predisposition to cancer, primarily Colorectal independent way, alterations in AXIN2 (loss-of-function, dosage 5–7 cancer (CRC), have arisen. This association is supported by the dependent, or even gain-of-function mutations) can contribute to molecular events that keep homeostasis of morphogenesis and development of gastric cancer. tissue regeneration. CRC is the fourth most common cause of The genetic connection between alterations in embryonic cancer-related deaths in the world and it has been reported that development of dental organs and predisposition to cancer is colorectal carcinogenesis is associated with alterations in Wnt understandable; particularly the ﬁnding that AXIN2 mutations signaling. Some CRC, like adenomatous polyposis and hereditary could lead to an inefﬁcient block of the WNT signaling pathway. nonpolyposis CRC syndrome (Lynch syndrome), involve mutations Somatic mutations in the AXIN-complex proteins associated with in germline or in repair genes. Developmental homeostasis degradation of β-catenin or mutations in β-catenin have been involves the wingless/integration (WNT) signaling pathway con- found in different tissues with carcinoma, including skin, gastro- 10 4,14 trolling cell proliferation, differentiation, and cell death. When intestinal, hepatocellular, and ovarian epithelial cancer. In cells receive the WNT signal, β-catenin is stabilized and joins the addition, AXIN2 has also been independently associated with DNA-bound T-cell factor family of transcription proteins for tooth agenesis and non-syndromic cleft lip palate (NSCLP). regulating the expression of target genes. In the absence of AXIN2 SNP rs2240308 has been mapped at human chromosome WNT, β-catenin protein is degraded by the proteasome via action 17q23-q24. This polymorphism (rs2240308, c.148 G > A) results in of a multiprotein complex. This complex is composed of the tumor an amino acid change from proline to a serine. Although, suppressor adenomatous polyposis coli gene product (APC) and rs2240308 has been associated with hypodontia and cancer in 16,17 AXIN1 (axis inhibition protein 1) or its homologous protein, AXIN2. different populations, in Iranian subjects, this polymorphism They formed a structure with β-catenin, glycogen synthase kinase was related with decreased risk for CRC. The inconsistent results 1 2 Dentistry and Sciences Faculties, Center of Dental Research, Pontiﬁcia Universidad Javeriana, Carrera 7 No. 40-62, Bogotá, Colombia; Medicine Faculty, Centro de Investigaciones Inmunológicas Básicas y Aplicadas (CINIBA), Universidad Nacional de La Plata, Calle 60 y 120, CP:1900 La Plata, Argentina; Dentistry Faculty, Pontiﬁcia 4 5 Universidad Javeriana, Carrera 7 No. 40-62, Bogotá, Colombia; Gastroenterology, Centro Médico Almirante Colón, Carrera 16. No. 84A-09, Bogotá, Colombia and Dentistry Faculty, Universidad de Cartagena, Cra. 6 #36-100, Cartagena, Bolívar, Colombia Correspondence: L Otero (firstname.lastname@example.org) Received: 7 March 2019 Revised: 18 July 2019 Accepted: 24 July 2019 © The Author(s) 2019 1234567890();,: Variations in AXIN2 predict risk and prognosis of colorectal cancer L. Otero et al. reported in literature are explained by racial differences. In associated with AXIN2 to appear, at least in the study of Cell Latino populations, genetic studies relating hypodontia and CRC Reports 2016. The same procedure was applied to each study, we are scarce, although AXIN2 rs2240308 was recently associated with set the lower threshold in order to obtain altered genes related CRC in Mexican population. Therefore, identifying and analyzing with AXIN2. To get the overlapping genes between the networks, genetic mutations in CRC and hypodontia can provide relevant Euler Diagram was used. APC was the most redundant gene. For information about the biological behavior of both diseases. The gene network association and functional enrichment analysis, we aim of this study was to identify the association between AXIN2 employed the web resources GeneMania (https://genemania.org/) rs2240308 with hypodontia and CRC. and Enrichr (http://amp.pharm.mssm.edu/Enrichr/), respectively. Statistical analysis MATERIALS AND METHODS The Chi-square, Fisher’s Exact and Odds Ratio (ORs) tests were Population sample calculated to assess associations between variations in AXIN2 The population consisted of individuals who assisted to Dentistry rs2240308 with hypodontia and CRC. Multivariate analysis was faculties at Pontiﬁcia Universidad Javeriana and Universidad de employed to identify relationship between familial cancer history Cartagena and adults who underwent surgery for CRC at in patients with hypodontia and AXIN2 variations. P < 0.05 was gastroenterology private clinic in Bogotá, and Hospital Universi- considered statistically signiﬁcant. These statistical analyses were tario del Caribe in Cartagena, Colombia. Subjects were selected performed with and SPSS version 22.0 (software license Pontiﬁcia randomly from these institutions and population sample was Universidad Javeriana) and in silico analysis was performed with R divided into three groups according to their pathology. A group of software (https://www.r-project.org/). 50 subjects with hypodontia, a group of 50 subjects with CRC, and a control group of 155 healthy individuals from both cities in Colombia. This observational analytical cross-sectional study was RESULTS approved by the Ethical Committees of Dentistry faculty of Genotyping Pontiﬁcia Universidad Javeriana (CIEFOUJ 201108-7539). Informed The demographic data for the study participants are described in consent was obtained from all subjects participating. Table 1. Familial cancer history was higher in patients with Patients with hypodontia and healthy individuals were exam- hypodontia compared with the control group showing a statistical ined at the same clinic by two dentists and patients with CRC were signiﬁcant difference for AXIN2 rs2240308 (p < 0.005 OR = 1.75, operated by the single professional. Hypodontia-affected indivi- 95% CI: 1.22–6.91). However, Gastric cancer was the most frequent duals were in the age range of 18–28 years. Hypodontia diagnosis cancer in relatives of patients with hypodontia. In contrast, only was conﬁrmed through complete intraoral examination, panora- 10% of patients with CRC reported family history of hypodontia mic radiographies, and clinical records. Subjects with an uncertain (Table 2). hypodontia diagnosis, syndromes associated with hypodontia, The observed genotype distribution for the Axin2 rs2240308 trauma history, or agenesis of third molars were excluded from the polymorphism in all groups, controls, hypodontia, and CRC was in study. Subjects with CRC were in the age range of 32–64 years. agreement with the Hardy–Weinberg equilibrium. Statistical CRC in all patients was histopathologically conﬁrmed. There was signiﬁcant association was observed for CRC with AXIN2 no restriction on sex, age, or histopathological classiﬁcation and rs2240308 (OR = 5.4, 95% CI: 2.7–10.4; p < 0.001). The most states for selection of CRC patients. The control group included frequent type and stage of CRC in this sample was adenocarci- age, sex, and ethnic background matched selected from healthy noma (68%) and Dukes'B colon cancer (63.4%). individuals in the same area during the same time period as the Regarding to hypodontia, there was no signiﬁcant association case study. The ethnic background was determined by skin with AXIN2 rs2240308 (p < 0.31). The most frequent tooth agenesis pigmentation and origin of the participants. Subjects with was observed in upper lateral incisors (40%) followed by syndromes, hypodontia, trauma, or any type of cancer were mandibular second premolars (24%). Other teeth with agenesis excluded. were lower lateral incisors, maxillary ﬁrst premolars, and lower central incisors (36%). Genotyping Self-reported family history of cancer and hypodontia was collected through questionnaire in all participants (control hypodontia and CRC groups). DNA was obtained from saliva samples through Oragene DNA kit (DNA Genonek Inc, Canada). Table 1. Phenotype for the study participants AXIN2 rs2240308 PCR products were obtained from the samples of Phenotype CRC group Hypodontia Control group all the individuals enrolled in the study and sent for genotyping to (%) n = 50 group (%) n = 50 (%) n = 155 the Molecular Cloning Laboratories (MCLAB, San Francisco, CA). Age (years) 32–64 18–28 18–64 In silico analysis Sex With the aim of deﬁning the genomic proﬁle of AXIN2 in CRC, we Male 37 23 77 performed an in silico analysis on data obtained from the web resource cBioPortal. Three comprehensive studies and one Female 13 27 78 TCGA Provisional study were considered: DFCI, Cell Reports 2016 Ethnic 13 African, 9 African, 19 African, (n = 619), Genentech, Nature 2012 (n = 276), TCGA, Provisional background 29 American, 29 American, 109 American, (Raw data at the NCI, n = 633), and MSK, Cancer Cell 2018 (n = colombia (Latin 8 European 12 European 27 European 20–22 America) 1134). The tools provided by cBioportal and R packages from Bioconductor were employed for data integrative analysis and Origin (place of 25 Cartagena 25 Cartagena 65 Cartagena visualization. birth and (Caribbean) (Caribbean) (Caribbean) residence) 25 Bogotá 25 Bogotá 90 Bogotá For each study, we obtained a network of the most frequently (Central) (Central) (Central) altered neighboring genes of AXIN2. The number of genes was ﬁltered according to the percentage of alteration of the neighbor Cartagena is located at Caribbean region and Bogotá is located in central genes, with a set threshold >2.6%. This threshold was established zone of Colombia in 2.6 because it is the minimum threshold for some altered gene BDJ Open (2019) 5:13 Variations in AXIN2 predict risk and prognosis of colorectal cancer L. Otero et al. Table 2. Percentage of family history of cancer or hypodontia in all groups (CRC, hypodontia, and control) Family history of cancer and hypodontia CRC group (%) Hypodontia group (%) Control group (%) n = 50 n = 50 n = 155 CRC 14 10 1.93 Gastric cancer 8 18 3.22 None 46 38 73.55 Other types of cancer (breast, liver, ovarian, 32 34 21.29 oral, liver, prostatic, lung, brain, kidney) Hypodontia 10 18 2.58 Fig. 1 Genomic proﬁle of AXIN2 in colorectal cancer. a The percentage and number of samples with gene alterations in AXIN2 are shown across the different datasets included in the analysis. b Gene network analysis of AXIN2 associated genes that are also altered in CRC in at least 2.6 % of cases. This percentage—at the bottom of each network—represents the minimum alteration frequency of the genes that integrate the network; below this threshold there are no genes altered associated to AXIN2. c Euler diagram of common genes between the different lists of genes obtained from the network analysis In silico analysis metastatic CRC. However, patients who harbor mutations in The genomic proﬁle of AXIN2 in CRC patients indicates that the AXIN2 were found to be associated with a worse prognosis. frequency of alteration/mutation of the gene is usually not higher Along with AXIN2 those patients also showed mutations in WNT than 10% of the patients. It is commonly associated with the pathway related genes such as APC, RNF43, PIK3CA,among alteration of other genes related with the WNT pathway, such as others. Mutations in these genes, as well the activation of the APC and CTNBB1. Genomic proﬁle for AXIN2 in CRC is shown in WNT pathway, have been primarily associated with Instability Figs. 1 and 2. Also, there was an association with the tumor Microsatellite (MSI) molecular subtyperight-sideCRC tumors.It location, being AXIN2 gene more frequently mutated in tumor is possible that AXIN2 mutation can be a passenger of these samples derived from the right colon than those derived from the driver genes in MSS tumors, but in turn it could be considered a left. Staging and sample type were also evaluated and the group driver gene in MSI right-side tumors. The association of AXIN2 of AXIN2 mutated showed an association with earlier stages mutation with poor prognosis and its appearance in early compared with the other group. Interestingly, overall survival stages, position it as a prognostic and predictive marker in the analysis indicated that patients who carry variations in the AXIN2 deﬁned molecular subtype of right-side colorectal tumors with gene have a worse prognosis (p < 0.05). MSI. In summary, by data mining analysis we have deﬁned the genomic proﬁle of AXIN2 gene in CRC. It is altered in 5–10% of CRC patients, it would be associated with the MSI molecular DISCUSSION subtype and right-side tumors. Moreover, AXIN2 was found more The association between AXIN2 and CRC has been demonstrated frequently altered in early-stage tumors compared with in different populations, but the association between rs2240308 BDJ Open (2019) 5:13 Variations in AXIN2 predict risk and prognosis of colorectal cancer L. Otero et al. and CRC in Latino American population, it has been previously rs2240308 polymorphism has been mainly associated with reported only in Mexican population. The present study showed prostate and lung cancer, but its association with ovarian a statistically signiﬁcant association between AXIN2 rs2240308 and cancer, head and neck cancer, astrocytoma, and CRC did not CRC (OR = 5.4 CI: 2.7–10.4; p < 0.001). Latin America has a history show similar results. Liu et al. reported that AXIN2 is of large admixture between Africans, Europeans, and Native overexpressed in CRC in patients with DNA mismatch repair, Americans, for this reason, this region has a high physical and butinthisstudy,theydid notreportthe associationwith genetic ancestry variation. The Asian ancestry in Colombia and rs2240308. In addition, several studies propose that hypodon- Mexico is <1%. Signiﬁcant differences have been reported in the tia associated with AXIN2 variations could be a risk marker for 27,28 association between rs2240308 and the risk of cancer for type of CRC. In contrast, other studies propose Axin2 rs2240308 as a 17 29 cancer and ethnic group. Then, while it has been reported that potential therapeutic target for preventing tumor growth. The rs2240308 increased the risk of lung cancer especially in Asian possible explanations for these inconsistencies are related with 5 26,30–32 population, a recent analysis indicated that AXIN2 148 C > T racial differences observed in these associations or, with (rs2240308) variant may be associated with decrease lung risk in other gene interactions and gene pathways involved in CRC and 25 33 Asian and Caucasian populations. Therefore, further studies in in tooth development. Latin American population should be conducted to explain the Other possible explanation could be related with the results association between AXIN2 polymorphisms and CRC. shown in silico analysis. This analysis demonstrated that the Literature about the association of AXIN2 rs2240308 poly- mutation of AXIN2 observed in CRC is usually not higher than morphism with cancer show inconsistent results. AXIN2 10% of the patients and it is commonly associated with the Fig. 2 Comprehensive analysis of AXIN2 genomic proﬁle on data from the study of Yaeger et al. a AXIN2 mutated samples in the study of Cancer Cell 2018, a total of 53 out of the 1099 patients harbored at least one mutation in AXIN2 gene. b Association of clinical variables and AXIN2 mutated samples. c Kaplan Meier of the overall survival of patients with AXIN2 mutation. d Mutational proﬁle of the most mutated genes in the AXIN2 mutated patients BDJ Open (2019) 5:13 Variations in AXIN2 predict risk and prognosis of colorectal cancer L. Otero et al. alteration of other genes related with the WNT pathway. 2. Wang, J. et al. DNA methylation is critical for tooth agenesis: implications for sporadic non-syndromic anodontia and hypodontia. Sci. Rep. 6, 19162 Nonetheless, the most frequently activated signaling in meta- (2016). static CRC is the WNT pathway. For this reason, we performed 3. Yuan, Q. et al. Role of WNT10A in failure of tooth development in humans and additional in silico analysis. This analysis showed that mutations zebraﬁsh. Mol. Genet. Genom. Med. 5, 730–741 (2017). in AXIN2 found in CRC patients were more frequently in earlier 4. Lammi, L. et al. Mutations in AXIN2 cause familial tooth agenesis and predispose stages of tumor samples derived from the right colon than those to colorectal cancer. Am. J. Hum. Genet. 74, 1043–1050 (2004). derived from the left. Furthermore, patients who carry mutations 5. Wu, Z. et al. AXIN2 rs2240308 polymorphism contributes to increased cancer risk: in the AXIN2 gene have a worse prognosis (p < 0.05). This fact, evidence based on a meta-analysis. Cancer Cell Int. 15, 68 (2015). remark the importance to identify biomarkers for CRC in 6. Lindor, N. M. et al. Colorectal cancer and self-reported tooth agenesis. Hered. population, such as AXIN2 variations in patients with Hypodon- Cancer Clin. Pract. Hered. Cancer Clin. 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Commun. 9, This work was supported by Pontiﬁcia Universidad Javeriana; Universidad de 5388 (2018). Cartagena; Johnson & Johnson [Grant number: 4325]. 25. Xu, B. et al. New insights into the association between AXIN2 148 C/T, 1365 C/T, and rs4791171 A/G variants and cancer risk. Cancer Cell Int. 19, 119 (2019). 26. Liu, D. et al. The Axin2rs2240308 polymorphism and susceptibility to lung cancer AUTHOR CONTRIBUTIONS in a Chinese population. Tumour Biol. 35, 10987–10991 (2014). Conception and design: L.O. Administrative support: F.G. and L.O. Provision of study 27. Paranjyothi, M. V. et al. Tooth agenesis: a susceptible indicator for colorectal materials or patients: V.V., F.C., and L.O. Collection and assembly of data: F.G., E.L., V.Á., cancer? J. Cancer Res. Ther. 14, 527–531 (2018). and L.O. Data analysis and interpretation: E. L. and L.O. Manuscript writing: All 28. Hlouskova, A. et al. Mutations in AXIN2 gene as a risk factor for tooth agenesis authors. 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