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Carcinogenesis Advance Access originally published online on April 9, 2007
Carcinogenesis 2007 28(9):1914-1917; doi:10.1093/carcin/bgm077
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The functional genetic variant Arg324Gly of frizzled-related protein is associated with colorectal cancer risk

Kalai S. Shanmugam1,2,*, Hermann Brenner3, Michael Hoffmeister3, Jenny Chang-Claude4 and Barbara Burwinkel1,2

1 Helmholtz-University Group Molecular Epidemiology
2 Division of Molecular Genetic Epidemiology
3 Division of Clinical Epidemiology and Aging Research
4 Division of Cancer Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany

* To whom correspondence should be addressed. Tel: +49 6221 421811; Fax: +49 6221 421810; Email: k.shanmugam{at}dkfz.de


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
The Wnt–ß-catenin pathway plays a central role in colorectal tumorigenesis. Frizzled-related protein (FRZB, also termed secreted frizzled-related protein 3, sFRP3) antagonizes the signaling of wingless (Wnt) ligands through the frizzled membrane-bound receptors, resulting in ß-catenin destabilization thereby suppressing the expression of target genes. Recently, the FRZB Gly324 variant has been shown to have an attenuated ability to antagonize Wnt signaling and to be associated with an increased osteoarthritis risk. Here, we investigated, for the first time, the role of Arg324Gly (970C>G) along with Arg200Trp (598C>T) on colorectal cancer (CRC) risk by analyzing 659 patients and 607 control individuals drawn from the German DACHS (Darmkrebs: Chancen der Verhütung durch Screening) study. Although Arg200Trp showed no effect on CRC risk, we found homozygous carriers of Gly324 more frequent in cases than in controls, leading to a significantly increased risk for CRC [odds ratio (OR) = 5.1, 95% confidence interval (95% CI) = 1.74–14.71, P < 0.001]. The association was stronger in rectal cancer (OR = 7.52, 95% CI = 2.40–23.25, P < 0.0001) than in colon cancer (OR = 3.66, 95% CI = 1.14–11.76, P < 0.05). Since modified Wnt signaling and down-regulation of frizzled-related proteins have been observed in many human cancers, this variant may also affect the susceptibility to other cancers.

Abbreviations: 95% CI, 95% confidence interval; CRC, colorectal cancer; OR, odds ratio; sFRP, secreted frizzled-related protein; SNP, single-nucleotide polymorphism


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Colorectal cancer (CRC) is one of the most common cancers in the developed countries (1). About 5% of familial CRC can be ascribed to germ line mutations in the high-penetrance genes adenomatosis polyposis coli (APC) causing colon cancer with adenomatous polyposis coli, and to the mismatch repair genes MLH1 and MSH2 leading to hereditary non-polyposis CRC. The identification of new predisposing gene variants and gene variant combinations will contribute to the further understanding of the genetic basis of CRC (2–5).

The Wnt signaling pathway plays a central role in colorectal carcinogenesis (6,7). In the canonical Wnt–ß-catenin pathway, Wnt ligands form a complex with a receptor of the frizzled family and the low-density lipoprotein receptor-related proteins 5 and 6. In the absence of Wnt ligands, ß-catenin is recruited to the ‘destruction complex’ that contains Axin and adenomatosis polyposis coli. The complex facilitates the phosphorylation of ß-catenin by casein kinase 1 (CSNK1A1L) and glycogen synthase kinase-3 beta, leading to the ubiquitylation and proteasomal degradation of ß-catenin, thus repressing the transcription of the target genes in the nucleus. In the presence of a Wnt ligand, ß-catenin is uncoupled from the ‘degradation complex’, which results in cytoplasmic ß-catenin stabilization and translocation to the nucleus. There, it binds lymphoid enhancer factor and T-cell factor family transcription factors, promoting the expression of target genes like c-MYC, c-JUN, CCND1, PTGS2, MMP-7, PLAUR and CD44 that play major roles in the development and progression of colorectal carcinoma (8–11).

FRZB (also termed secreted frizzled-related protein 3, sFRP3), containing a cysteine-rich domain, highly homologous to the extracellular, ligand-binding domain of frizzled receptors (12), antagonizes the signaling of Wnt ligands through competing with frizzled membrane-bound receptors (13). Human FRZB has been mapped to human chromosome 2q31–33 (14), a genomic region where allelic loss has been observed in patients with colorectal, prostate, gastric, papillary bladder, head and neck cancer, and non-small cell lung carcinomas and neuroblastomas (15–20). Down-regulation of secreted frizzled-related proteins (sFRPs) by gene deletion or promoter hypermethylation has been shown in many human cancers including CRC (21–26). Furthermore, a recent study has demonstrated tumor-suppressing activities of FRZB in prostate cancer cells (27). Taken together, these data indicate that FRZB act as tumor suppressor.

In this study, we analyzed, for the first time, the effects of non-conservative amino acid exchanging polymorphisms in FRZB, Arg200Trp and Arg324Gly, on cancer risk.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Study population
CRC cases and controls were drawn from the German DACHS (Darmkrebs: Chancen der Verhütung durch Screening) study, a population-based case–control study carried out in the Rhine-Neckar-Odenwald and Heilbronn region in the south-west of Germany (28). The analysis comprised 659 unrelated male and female patients (33–91 years of age; median 68) with incident invasive CRC diagnosed between January 2003 and March 2005, residing in the study region. The controls consisted of 607 unrelated male and female individuals (34–94 years of age; median 67) without a history of CRC randomly selected from lists of residents from the counties within the study region and matched to cases by 5-year age groups, sex and county of residence. Cases and controls were included if they were at least 30 years of age, German-speaking, and mentally and physically able to participate in a personal interview of ~1 h. All participants gave written informed consent. Data collection procedures for the DACHS study are reported elsewhere (28–30), and a detailed description of the study population is given in Table I).


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  		Table I. Characteristics of the study population

 
The study was approved by the Ethics Committees of the University of Heidelberg (Germany) and the State Medical Boards of Baden-Wuerttemberg and Rhineland-Palatinate (Germany).

Single-nucleotide polymorphism genotyping
The FRZB single-nucleotide polymorphisms (SNPs) Arg200Trp (598C>T) and Arg324Gly (970C>G) were analyzed by TaqMan allelic discrimination. TaqMan probes were designed using the assay-by-design service (Applied Biosystems, Foster City, CA, Table II). The samples were analyzed with the ABI Prism 7900HT detection system using the SDS 2.2 software (Applied Biosystems). To ensure the accuracy and to exclude genotyping error, at least 10% of all genotyping results were confirmed by re-genotyping with a concordance rate of 100%.


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  		Table II. Sequences of TaqMan primers and probes for allelic discrimination

 
Statistical analysis
Genotype-specific odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were computed by means of unconditional logistic regression applying a tool offered by the Institute of Human Genetics, TU Munich (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl). Hardy–Weinberg equilibrium test was undertaken using Pearson's goodness-of-fit chi-square test with one degree of freedom. Adjustment for sex and age and the two-sided Cochran-Armitage test for trend were done with the Statistical Analysis System software (version 9.1; SAS Institute, Cary, NC). The Cochran-Armitage test was also used to determine correlations between increasing stage and CRC risk.

Haplotype analysis
Haplotypes for FRZB Arg200Trp (598C>T) and Arg324Gly (970C>G) were determined using the SNPHAP 1.3 software by David Clayton (http://archimedes.well.ox.ac.uk/pise/snphap-simple.html). Each individual was assumed to carry the most likely pair of haplotypes and the haplotype distributions were estimated based on the controls. ORs and corresponding 95% CIs were calculated by comparing the distribution of each haplotype with the most frequent haplotype among cases and controls. Linkage disequilibrium between the SNPs was calculated using the Haploview (version 3.0) programe by Mark Daly (http://www.broad.mit.edu/mpg/haploview/documentation.php).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
According to our genotyping results, the two SNPs analyzed (FRZB Arg200Trp and Arg324Gly) were not in linkage disequilibrium (r2 = 0.01, D' = 0.1). Both were in agreement with the Hardy–Weinberg equilibrium in controls. Regarding Arg200Trp, the genotype distribution was similar among cases and controls, indicating no association with CRC risk (Table III). Analysis by subsite showed no effect either. A borderline significant association of FRZB Arg200Trp was identified with CRC stage II (Table IV).


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  		Table III. Genotype frequencies of FRZB Arg200Trp (598C>T) and FRZB Arg324Gly (970C>G) in CRC cases and controls, ORs with 95% CIs and respective P values

 


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  		Table IV. Genotype frequencies of FRZB Arg200Trp (598C>T) and FRZB Arg324Gly (970C>G) in CRC cases and controls, ORs with 95% CIs and respective P values

 
Regarding Arg324Gly, however, homozygous carriers of FRZB Gly324 were more frequent in cases than in controls, leading to a significantly increased risk of CRC (OR = 5.1, 95% CI = 1.74–14.71, P < 0.001, Table III). The association observed for rectal cancer (OR = 7.52, 95% CI = 2.40–23.25, P < 0.0001, Table IV) was stronger than in colon cancer (OR = 3.66, 95% CI = 1.14–11.76, P < 0.05, Table IV). FRZB Gly324 was associated with an increased CRC risk in all stages, but did not show a trend for association with stage (Ptrend = 0.63, Table IV).

Age adjustment did not change the respective ORs (data not shown). There was no appreciable difference in the genotype distribution of both SNPs in patients with and without a family history of CRC (data not shown), and haplotype analysis showed a similar haplotype distribution between cases and controls as well (Table V).


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  		Table V. Haplotype distributions of Arg200Trp (598C>T) and Arg324Gly (970C>G) in CRC patients and control individuals, ORs with 95% CIs and corresponding P values

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The Wnt signaling pathway plays a crucial role in colorectal carcinogenesis (7). FRZB/sFRP3 is a secreted Wnt antagonist and acts as a tumor suppressor (27). Assuming that genetic variations in FRZB might affect the individual CRC risk, we analyzed the FRZB Arg200Trp and Arg324Gly polymorphisms. To evaluate the putative impact of these SNPs on CRC risk, we performed a case–control study using the German DACHS study population.

According to in silico analyses, both amino acid substitutions were predicted to be ‘probably damaging’ (PolyPhen report; http://genetics.bwh.harvard.edu/pph/). Both arginine residues are highly conserved among the species. Codon 200 (598C>T) and codon 324 (970C>G) are located at the C-terminal end of FRZB/sFRP3. The binding of sFRPs by Wnt is believed to be mediated by the N-terminal frizzled cysteine-rich domain. However, a study has shown that the direct binding between sFRP1 and its ligand Wnt was strongly influenced by heparin, and it should be noted that the C-terminus shows heparin-binding activity (31,32). Some truncated sFRP forms that retain Wnt binding were not able to antagonize Wnt signaling, suggesting that both N- and C-terminal domains are necessary for optimal function (31–33).

A recent study has shown the FRZB Gly324 variant to be associated with an increased osteoarthritis risk in females (34). In addition, the FRZB Arg324 variant can inhibit ß-catenin nuclear translocation and T-cell factor/lymphoid enhancer factor-dependent transcriptional activation in vitro, whereas the FRZB Gly324 has a diminished ability to antagonize Wnt signaling (34). In line with these findings, we found FRZB Gly324 to be a risk factor for CRC (OR = 5.1, 95% CI = 1.74–14.71, P < 0.001, Table III). However, we did not observe an association of the rare Trp200-Gly324 haplotype (598T–970G) with CRC risk (Table V) as it has been observed for osteoarthritis (34).

The frequency of the G allele of the FRZB codon 324 SNP in the cases was 0.10 and 0.08 in the controls, similar to the reports by Loughlin et al. (34) (0.10 in female cases and 0.07 in controls respectively). Whereas the genotype frequencies showed a significant difference between cases and controls (GG versus CC + CG: OR = 5.10, C.I. = 1.74–14.71, P < 0.001), the allele frequencies showed no significant association (OR = 1.26, CI = 0.96–1.67, P = 0.09), because the G allele acts in a recessive manner (Table III).

Thus, only homozygosity for the risk allele (Gly/Gly) showed an association. In contrast, often in association studies an allele dose-dependent effect is observed (35–37). But this is not necessarily the case. The reason can be that in heterozygous Gly324 carriers, potential dysfunction of the altered protein can be compensated by the second allele and systemic influences, whereas in homozygous Gly324 carriers a certain critical threshold is exceeded where compensation is difficult to achieve, leading to an increased CRC risk. This threshold can be different regarding the susceptibility to different diseases (e.g. cancer and osteoarthritis). However, an undisclosed bias cannot be ruled out. Further association studies and functional investigations will be necessary to clarify this issue.

Patients had to be alive in order to complete a personal interview; therefore, we may have missed a small number of patients who died before recruitment. Patients who were not able to participate in an interview were also not recruited into the study. However, the proportion of patients with stages III–IV was high (45%). As the association of the FRZB Gly324 variant with CRC risk did not show a trend on the stage stratification (Table IV), a bias in overall association of this variant with CRC risk due to case selection appears to be unlikely.

Analyses according to subsite and stages showed no association of FRZB Arg200Trp. However, a borderline significant association of FRZB Arg200Trp was identified with CRC stage II, which most likely is a chance finding as no significant trend for CRC stage was observed (Tables III and IV). In addition, the borderline significance disappeared after the Bonferroni correction.

The FRZB codon 200 and codon 324 SNPs were in linkage equilibrium (r2 = 0.01, D' = 0.1). The same linkage equilibrium (r2 = 0.01, D' = 0.1) has been observed in a previous study regarding osteoarthritis (34).

Wnt–ß-catenin signaling seems to be involved not just in tumor initiation but also in cancer progression (38,39). Data from one study indicate that small molecule inhibitors of activated ß-catenin will be effective anticancer therapeutics in a subset of malignant colon cancers (40). Therefore, Wnt–ß-catenin signaling inhibitors are under consideration and development for cancer treatment (41). Hence, it may be interesting to investigate whether FRZB Gly324 influences the therapeutic outcome.

The strengths of the present study include the relatively large size of an ethnically homogeneous population-based case–control study and the hypothesis driven approach strengthen this study. A limitation of this study is that only one population has been studied. Therefore, further studies are necessary to confirm our results.

In summary, this is the first study to reveal a significant association between the FRZB Arg324Gly variant and an increased risk for developing CRC. This variant has been shown to attenuate the ability of FRZB/sFRP3 to antagonize Wnt signaling. Since down-regulation of sFRPs has been observed in many human cancers, this variant may affect the susceptibility to other cancers as well.


   Acknowledgments
 
We thank Kari Hemminki and Bernd Frank for support. We also thank all patients and control individuals who participated in the study.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received January 29, 2007; revised March 23, 2007; accepted March 28, 2007.


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