Cancer Epidemiology Biomarkers & Prevention Vol. 15, 1236-1237, June 2006
© 2006 American Association for Cancer Research
Transforming Growth Factor ß Receptor Type I and Transforming Growth Factor ß1 Polymorphisms Are Not Associated with Postmenopausal Breast Cancer
Heather Spencer Feigelson,
Alpa V. Patel,
W. Ryan Diver,
Victoria L. Stevens,
Michael J. Thun and
Eugenia E. Calle
Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia
Requests for reprints: Heather Spencer Feigelson, Department of Epidemiology and Surveillance Research, American Cancer Society, 1599 Clifton Road Northeast, Atlanta, GA 30329. Phone: 404-929-6815; Fax: 404-327-6450. E-mail: heather.feigelson{at}cancer.org
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Introduction
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A polymorphic allele in transforming growth factor ß receptor 1 (TGFßR1) is hypothesized to increase risk of cancer (1). The allele, designated as TGFßR1*6A, results from the deletion of three alanines within a nine-alanine stretch in exon 1, and in vitro studies have shown that TGFßR1*6A is an impaired mediator of TGF-ß antiproliferative signals compared with wild-type (TGFßR1*9A; refs. 2, 3). Most previous studies (2, 4, 5), including a meta-analysis (6), have found an association between TGFßR1*6A and increased risk of breast cancer, but the majority of these studies were hospital based (2, 5, 6). One study (5) further suggested that TGFßR1*6A interacts with the TGFß1 T29C polymorphism. The TGFß1 29C allele leads to significantly higher serum levels of TGF-ß1 (7, 8), is hypothesized to reduce breast cancer risk (8), and has been examined in many previous breast cancer studies (5, 8-15). We used a nested case-control study within the Cancer Prevention Study II Nutrition Cohort (16) to examine whether the TGFßR1*6A allele influenced risk of postmenopausal breast cancer either alone or in combination with TGFß1 T29C.
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Materials and Methods
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This analysis includes 502 postmenopausal breast cancer cases and 505 controls drawn from a subgroup of the cohort who donated blood samples (n = 21,965 women). Controls were matched on age, race/ethnicity, and date of blood collection; cases and controls had no previous history of cancer (other than nonmelanoma skin cancer). The cohort and case control study are detailed elsewhere (16, 17).
Genotyping was done at Applied Biosystems (Foster City, CA) using DNA purified from buffy coat. The TGFß1 T29C assay was done using TaqMan as previously described (12). The TGFßR1 assay has also previously been described (1). Following PCR amplification, TGFßR1 alleles were visualized using an ABI Prism sequence analyzer. A 115-bp peak corresponded to the *9A allele and a 107-bp peak corresponded to the *6A allele. Laboratory personnel were blinded to case-control status and 10% blind duplicates were included in the assays. The concordance rate was 100% for TGFß1 and 98% for TGFßR1. Overall success rate for the genotyping assays was >96% for both loci and there were no deviations from Hardy-Weinberg equilibrium.
Unconditional logistic regression was used to examine the association between TGFß1 and TGFßR1 and breast cancer while controlling for matching factors. We examined whether the association with the variants of interest differed by stage at diagnosis using general summary stage to classify cases as in situ, localized, or regional/distant metastasis. We evaluated whether known breast cancer risk factors were confounders in the logistic models but their inclusion in the models did not appreciably change our effect estimates, and thus we did not include them in the final models.
To examine possible interactions between *6A (TGFßR1) and T29C (TGFß1) alleles, individuals were classified into low, intermediate, or high TGF-ß signalers based on previously published criteria shown in Table 1
(5).
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Table 1. ORs and 95% CIs for breast cancer by TGFßR1 and TGFß1 among all cases and controls and by stage in the Cancer Prevention Study II Nutrition Cohort
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Results
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Cases were mostly Caucasian (99%) with median age of 68 years (range, 46-83 years) at diagnosis. Table 1 shows the genotype frequencies, odds ratios (OR), and 95% confidence intervals (95% CI) for the association between breast cancer and the TGFßR1*6A and TGFß1 T29C overall and by stage. Because the TGFßR1*6A allele is uncommon (allele frequency among controls, 10.7%), we combined women homozygous and heterozygous for the *6A allele and compared them with *9A homozygotes. We found no association with breast cancer and TGFßR1*6A (OR, 0.95; 95% CI, 0.69-1.30, for 6A carriers versus 9A/9A) or with TGFß1 C/C compared with T/T (OR, 0.89; 95% CI, 0.61-1.31), and no differences in analyses stratified by stage.
Because the TGFß1 T allele is associated with lower circulating levels of TGF-ß1 than the C allele, and the TGFßR1*6A allele is a compromised form of wild-type TGFßR1, a previous study combined these variants to classify individuals as high, intermediate, or low signalers (5). We found no statistically significant differences across these groups (Ptrend = 0.70).
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Conclusions
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We found no evidence of association of breast cancer with TGFßR1*6A nor with TGFß1 T29C allele, either alone or in combination. Our study had 
80% power to detect an OR of >1.5 for allele frequencies of 11% as observed for TGFßR1*6A among our controls (
= 0.05, ß = 0.20). Previous studies have reported ORs in the range of 1.5 to 1.6 (2, 4, 5); thus, we had adequate power to observe an association of similar magnitude in our population.
A meta-analysis of TGFßR1*6A that included 1,420 cases of breast cancer reported a summary OR of 1.38 (95% CI, 1.14-1.67) among *6A carriers compared with *9A/*9A (6). However, there are important methodologic limitations in previous studies included in the meta-analysis. None were population based and most used external controls and did not account for differences in age and ethnicity between case and control groups (2, 4-6, 10).
TGFß1 and breast cancer has been studied more extensively than TGFßR1, and the results have been mixed (5, 8-15). Only one previous study (5) has looked at these two polymorphisms jointly and found increased risk of breast cancer among the group that they defined as low signalers compared with high signalers (OR, 1.69; 95% CI, 1.08-2.66). By their definition, high signalers are those with TGFß1 (C/C) and TGFßR1 (9A/9A). We did not observe an association between breast cancer and low signaling in our study (OR, 1.12; 95% CI, 0.69-1.81).
In summary, although both the variants examined in this study have been shown to affect TGF-ß signaling, we found no evidence that they are associated with postmenopausal breast cancer, either alone or in combination.
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Footnotes
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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 with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 3/ 1/06;
accepted 3/29/06.
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Introduction
Materials and Methods
