Lack of an Association between the TGFBR 1 * 6 AVariant and Colorectal Cancer

Purpose: Recently a common variant of theTGFBR1 gene,TGFBR1*6A, has been proposed to act as a low-penetrance tumor susceptibility allele for colorectal cancer, but data from published studies with individually low statistical power are conflicting. To further evaluate the relationship betweenTGFBR1*6A and colorectal cancer risk, we have conducted a large case-control study and a meta-analysis of previously published studies. Experimental Design: A total of 1,042 colorectal cancer cases and 856 population controls were genotyped for theTGFBR1*6A polymorphism. Previously published case-control studies of the relationship betweenTGFBR1*6A and colorectal cancer were identified, and a metaanalysis was conducted. Results:We found no evidence that homozygosity, heterozygosity or carrier status for the TGFBR1*6A allele confers an increased risk of colorectal cancer; respective odds ratios (OR) were 1.05 [95% confidence interval (95% CI), 0.83-1.32], 0.82 (95% CI, 0.34-1.99), and 0.92 (95% CI, 0.74-1.15), respectively. A meta-analysis of our case-control study and seven other studies that provided data on 2,627 colorectal cancer cases and 3,387 controls also yielded no evidence that possessionof theTGFBR1*6A allele is associatedwith an elevated riskof colorectal cancer; pooled estimate of the OR were 1.20 (95% CI, 0.64-2.24) for homozygosity, 1.11 (95% CI, 0.96-1.29) for heterozygosity, and1.13 (95% CI, 0.98-1.30) for carriers ofTGFBR1*6A. Conclusion: Current data provide limited support for the hypothesis that sequence variation in TGFBR1defined by theTGFBR1*6A allele confers an elevated risk of colorectal cancer. Colorectal cancer is the third most common cause of cancerrelated mortality in the Western world, and in the United States, it represents the secondmost common cause of cancer death (1). A recent twin study indicates that about 35% of all colorectal cancers can be ascribed to an inherited susceptibility (2). Mendelian predisposition syndromes associated with mutations in known genes (such as APC , DNA mismatch repair genes, MYH, SMAD4, BMPR1A/ALK3 , and STK11/LKB1), however, together account for onlyf5% of the overall incidence (3). The nature of the remaining heritability is at present undefined, but a model in which high-risk alleles account for all of the excess inherited risk seems improbable. An attractive hypothesis concerning the allelic architecture of colorectal cancer susceptibility proposes that part of the inherited risk is conferred by common, low-penetrance alleles. Transforming growth factor h (TGF-h) is a potent inhibitor of cell growth influencing the behavior of a number of cancers (4). TGF-h mediates its action through a heteromeric cell-surface complex of two types of transmembrane serine/threonine kinases; TGF-h receptor type 1 (TGFBR1) and type 2 (TGFBR2 ; refs. 5, 6). Unrestricted cell growth due to lack of growth inhibitory activity seems to be the most important result of a defect in the TGF-h signaling pathway. A common variant of TGFBR1, TGFBR1*6A, generated by a deletion of three GCG triplets coding for alanine within a nine alanine (*9A) repeat sequence of exon 1 of the gene apparently encodes for TGFBR1 with reduced TGF-h growth inhibitory signaling activity. The TGFBR1*6A allele has been proposed to act as a low-penetrance susceptibility allele for a number of malignancies (7). Although some studies have suggested that the TGFBR1*6A allele confers an elevated risk of colorectal cancer, findings have been inconsistent (8, 9). Cancer Prevention Author’s Affiliations: Department ofMolecularMedicine and Surgery, Karolinska Institutet; Department of Surgery, St. Go« rans Hospital; Department of Surgery, Karolinska University Hospital, Solna; Department of Clinical Science, Division of Surgery, Karolinska Institutet at Danderyd Hospital; Centre of Gastrointestinal Disease, Ersta Hospital; Department of Medical & Surgical Gastroenterology, Karolinska University Hospital, Huddinge; Department of Surgery, South Stockholm General Hospital; Department of Pathology, Dalian Medical University, Dalian, China; Department of Surgery, So« derta« lje Hospital, So« derta« lje, Sweden; La« nssjukhuset Ga« vle-Sandviken, Ga« vle, Sweden; Norrta« lje Hospital, Norrta« lje, Sweden; Department of Surgery, Uppsala University Hospital, Uppsala, Sweden; Department of Surgery, O« rebroUniversity Hospital, O« rebro, Sweden; Department of Surgery, Colorectal Unit, Central Hospital,Va« ster/s, Sweden; Department of Surgery, Central Hospital, Karlstad, Sweden; and Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, United Kingdom Received12/4/06; revised 3/12/07; accepted 3/29/07. Grant support: Cancer and Allergy Foundation, the Gustav, the 5th Jubilee¤ Foundation, the Nilson-Ehle Foundation, the FoU Foundation, the Swedish Research Council, and the Swedish Cancer Society. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Annika Lindblom, Department of Molecular Medicine and Surgery, Karolinska Institutet, CMML8:02 S-17176 Stockholm, Sweden. E-mail: Annika.Lindblom@ki.se. F2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-06-2865 www.aacrjournals. org Clin Cancer Res 2007;13(12) June15, 2007 3748 Research. on April 10, 2017. © 2007 American Association for Cancer clincancerres.aacrjournals. org Downloaded from To clarify the effect of variation within TGFBR1 defined by the TGFBR1*6A variant on risk of colorectal cancer, we have conducted a large case-control study and meta-analysis of published studies. Materials andMethods