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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

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

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


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