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Carcinogenesis Advance Access originally published online on July 5, 2007
Carcinogenesis 2007 28(9):1965-1970; doi:10.1093/carcin/bgm155
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Published by Oxford University Press 2007.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Transforming growth factor beta 1 (TGFB1) gene polymorphisms and risk of advanced colorectal adenoma

Sonja I. Berndt1,*, Wen-Yi Huang1, Nilanjan Chatterjee1, Meredith Yeager1,2, Robert Welch1,2, Stephen J. Chanock1, Joel L. Weissfeld3, Robert E. Schoen3,4 and Richard B. Hayes1

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
2 SAIC-Frederick, NCI-FCRDC, Frederick, MD 20877, USA
3 Department of Epidemiology and the University of Pittsburgh Cancer Institute
4 Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA

* To whom correspondence should be addressed. Tel: +301 594 7898; Fax: +301 402 1819; Email: berndts{at}mail.nih.gov


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 
Transforming growth factor beta 1 (TGFB1) is a multifunctional cytokine that has been implicated in the pathogenesis of colorectal neoplasia. To investigate the association between genetic variants in TGFB1 and the risk of colorectal adenoma, we conducted a case–control study of 754 advanced adenoma cases and 769 controls from the baseline screening exam of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Cases included participants diagnosed with advanced left-sided adenoma (≥1 cm, high-grade dysplasia or villous characteristics), and controls were subjects without evidence of a left-sided polyp by sigmoidoscopy. DNA was extracted from blood specimens, and five single-nucleotide polymorphisms in TGFB1 of known or suggested functional significance (–800G>A, –509C>T, Leu10Pro, Arg25Pro and Thr263Ile) were genotyped. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between each polymorphism and adenoma. The high TGFB1 producer genotypes, –509TT and 10Pro/Pro, were associated with an increased risk of colorectal adenoma compared with other genotypes (OR = 1.51, 95% CI: 1.04–2.20 and OR = 1.37, 95% CI: 1.02–1.86, respectively). These increased risks, particularly for –509TT, were greater for persons with multiple adenomas (OR = 1.89, 95% CI: 1.16–3.09, P = 0.01) and individuals with rectal adenoma (OR = 2.95, 95% CI: 1.66–5.26, P = 0.0002). Haplotype analysis revealed similar findings under a recessive model. No associations were observed for polymorphisms at codons 25 and 263. In conclusion, variants that enhance TGFB1 production may be associated with an increased risk of advanced colorectal adenoma.

Abbreviations: 95% CI, 95% confidence interval; OR, odds ratio; TGFB1, transforming growth factor beta 1; TGFBRII, transforming growth factor beta receptor type II


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Funding
 References
 
Transforming growth factor beta 1 (TGFB1) is a multifunctional cytokine that inhibits the proliferation of normal intestinal epithelial cells but promotes the growth of malignant colorectal cancer cells (1). Adenomas have been shown to display lower TGFB1 mRNA and protein levels compared with colorectal cancers (2), and loss of the growth inhibitory effects of TGFB1 is reported to accompany the transformation of colorectal adenoma to cancer (3,4). Increased levels of TGFB1 are thought to confer a survival advantage to tumor cells. Serum levels of TGFB1 are higher among patients with colorectal cancer compared with healthy controls (5–7), and elevated TGFB1 levels have been positively associated with advanced tumor stage (5–7) and metastasis after surgical resection (8). Similarly, increased TGFB1 expression at protein levels in colorectal tumor tissues have been associated with advanced stage (9,10), disease recurrence (11) and shorter survival (9).

Several common polymorphisms in the TGFB1 gene with possible functional significance have been reported. The –800G>A polymorphism is situated within a partial putative cAMP-response element binding protein (CREB) consensus site and may alter transcription (12). The –509C>T polymorphism is located within a YY1 consensus binding site, and although not all studies have been consistent (13), one study demonstrated that transfection with the construct containing the T allele enhanced YY1 binding and increased promoter activity compared with the C allele (14). The –509T allele has been associated with increased TGFB1 plasma levels (12) and reduced T-cell proliferation (15), and a study of twins estimated that the –509C>T polymorphism explained ~8% of the genetic variation in TGFB1 plasma levels (12). The Leu10Pro and Arg25Pro polymorphisms encode non-synonymous amino acid substitutions within the signal peptide sequence of the TGFB1 precursor. Transfection with constructs containing either the 10Leu or 10Pro alleles revealed that the 10Pro variant leads to a greater increase of TGFB1 secretion compared with the 10Leu allele (16). Although not all studies have been consistent (17), the 10Pro allele has been associated with elevated TGFB1 serum levels (18,19). Similarly, the 25Arg allele has been associated with increased TGFB1 production upon stimulation in vitro (20). The Thr263Ile polymorphism is located within the cleaved part of the TGFB1 proprotein, but it may affect the activation of TGFB1 (21).

To examine the association between these five TGFB1 polymorphisms and the risk of advanced colorectal adenoma, we conducted a case–control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Funding
 References
 
Study population
The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial is a randomized trial to evaluate screening methods for the early detection of prostate, lung, colorectal and ovarian cancer (22,23). From 1993 to 2001, 154 952 men and women aged 55–74 years were recruited from 10 centers in the USA (Birmingham, AL; Denver, CO; Detroit, MI; Honolulu, HI; Marshfield, WI; Minneapolis, MN; Pittsburgh, PA; Salt Lake City, UT; St. Louis, MO and Washington, DC). Participants randomized to the screening arm of the trial underwent a 60 cm flexible sigmoidoscopy at baseline. Those found to have polyps or suspicious lesions on sigmoidoscopy were referred to their primary physician for further evaluation, and most subsequently received colonoscopy (24). Information regarding the diagnosis was abstracted from medical and pathologic reports by trained personnel. All participants provided written informed consent, and the study protocol was approved by institutional review boards at the 10 screening centers and the National Cancer Institute.

Identification of cases and controls
For this investigation, cases and controls were selected from among participants randomized to the screening arm, who underwent a successful sigmoidoscopic examination (defined as insertion to at least 50 cm with ≥90% of mucosa visible or suspicious lesion discovered) at baseline, provided a blood specimen, completed a risk factor questionnaire and consented to participate in etiologic studies of cancer or related diseases. Participants with a self-reported history of colorectal polyps or polyposis syndrome (e.g. familial adenomatous polyposis), inflammatory bowel disease or cancer (except basal cell or squamous cell skin cancer) were excluded. Cases were randomly selected from among subjects diagnosed with left-sided (descending, sigmoid colon or rectum) advanced adenoma (≥1 cm in size, exhibiting high-grade dysplasia, carcinoma in situ or villous characteristics) at baseline. Controls were selected from among subjects without evidence of a polyp or suspicious lesion on sigmoidoscopic examination and were frequency matched to cases on race and sex.

Of the 772 cases and 777 controls selected for this study, 18 cases and eight controls (1.7%) had insufficient DNA or discrepancies on repeated DNA fingerprint analyses and were excluded from analysis, leaving 754 cases and 769 controls for this study. Approximately 32% of cases had multiple adenomatous polyps, at least one of which was advanced, 64% had at least one adenoma considered to be histologically aggressive (villous characteristics, high-grade dysplasia or carcinoma in situ) and 74% had at least one large adenoma (≥1 cm).

Genotype analysis
DNA was extracted from whole-blood or buffy coat samples and five common single-nucleotide polymorphisms in TGFB1 [–800G>A (rs1800468), –509C>T (rs1800469), Ex1–327T>C (rs1982073), Ex1–282G>C (rs1800471), Ex5–73C>T (rs1800472)] were genotyped using TaqMan® or MGB EclipseTM assays at the National Cancer Institute Core Genotyping Facility (25). Laboratory personnel were blinded to case–control status. Depending on the assay, 1–7% of participants had insufficient DNA for genotyping. Of those remaining, genotyping was successfully completed for >97%, and replicate samples (33–46 subjects assayed two to seven times per polymorphism) interspersed in the plates displayed 100% concordance for all polymorphisms.

When stratified by race, the genotype frequencies among controls were consistent with Hardy–Weinberg proportions (P > 0.05) for all polymorphisms, except TGFB1 –509C>T (P = 0.003 for Caucasians) and TGFB1 Leu10Pro (P = 0.009 for Caucasians). No problems were observed with the assays and replicate samples showed 100% concordance, suggesting that the small deviations from Hardy–Weinberg proportions for these highly linked polymorphisms (r2 = 0.7) were probably due to chance.

Statistical analysis
Conditional logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between each polymorphism and colorectal adenoma, adjusting for age at screening (55–59, 60–64, 65–69 or 70+). Additional adjustment for smoking status, body mass index and regular aspirin or ibuprofen use did not significantly alter the results, and the results were similar when the analysis was restricted to Caucasians (data not shown). Interactions between the polymorphisms and other covariates were examined by including the main effect and cross-product terms in logistic regression models, and the statistical significance of the interaction was evaluated by comparing nested models with and without the cross-product terms using a likelihood ratio test. Polytomous logistic regression models were used to estimate ORs (and 95% CIs) for different adenoma subtypes (e.g. small or large), adjusting for matching variables and age. To examine the heterogeneity in risk between subtypes, a two-stage polytomous logistic regression model (26) in MATLAB was used to estimate the OR (and 95% CI) for the case–case comparison for each characteristic (e.g. large versus small) controlling for the other three characteristics (e.g. histological aggressiveness, multiplicity and tumor location) as well as age, sex and race.

As linkage disequilibrium patterns vary by race, haplotype analyses were limited to Caucasian subjects (94%). Pairwise linkage disequilibrium (D' and r2) was estimated using Haploview (http://www.broad.mit.edu/mpg/haploview/index.php). Haplotypes were estimated using an expectation–maximization algorithm, and the generalized linear model implemented in HaploStats (http://mayoresearch.mayo.edu/mayo/research/schaid_lab/software.cfm) was used to estimate risks for individual haplotypes. Unless otherwise indicated, statistical analyses were conducted using STATA 7.0 (College Station, TX).


   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Funding
 References
 
Cases and controls were similar with regard to matching factors (i.e. race and sex), but cases were more likely to be older (OR = 1.05; 95% CI: 1.03–1.07 per 1 year increase), have ever smoked (OR = 1.35; 95% CI: 1.09–1.67) and reported a family history of colorectal cancer (OR = 1.44, 95% CI: 1.04–1.99) compared with controls (Table I).


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  		Table I. Baseline characteristics of the colorectal adenoma cases and controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

 
The high TGFB1 producer genotypes, –509TT and 10Pro/Pro, were associated with an increased risk of advanced colorectal adenoma compared with the other genotypes, which was consistent with a recessive genetic model of inheritance (Table II). A positive association was observed with heterozygotes at –800G>A compared with GG homozygotes, but no association was observed for the AA homozygotes or the combined grouping of GA and AA genotypes compared with GG carriers (Table II). All the TGFB1 polymorphisms were in strong linkage disequilibrium (D' = 0.99–1.0). Most of the polymorphisms were weakly correlated with each other (r2 = 0.002–0.13), except –509C>T and Leu10Pro which were highly correlated with each other (r2 = 0.71). The strong correlation between the –509C>T and Leu10Pro polymorphisms made it impossible to differentiate the effects of one polymorphism from the other statistically, as mutual adjustment attenuated the effects of both polymorphisms. Adjustment for the other TGFB1 polymorphisms had little effect on the OR for the recessive models for –509C>T (OR range: 1.49–1.62) or Leu10Pro (OR range: 1.36–1.47).


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  		Table II. Risk of advanced colorectal adenoma associated with TGFB1 gene polymorphisms in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

 
Consistent with the single-locus analysis, the haplotype analysis suggested that the TGFB1 association followed a recessive genetic model (Table III). Under the recessive model, the haplotype containing the variant alleles at both –509C>T and Leu10Pro was associated with a statistically significant increased risk of adenoma. But the OR for the less common haplotype containing the variant at Leu10Pro and wild type at –509C>T was also elevated (even if not statistically significant), making it difficult to rule out the variant at either locus as the risk-causing allele.


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  		Table III. Risk of advanced colorectal adenoma associated with TGFB1 haplotypes among Caucasians in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

 
As adenomas vary in their propensity to progress and undergo malignant transformation, we explored the associations of the –509C>T and Leu10Pro polymorphisms with selected adenoma characteristics. For both variants, the associations were stronger among those with multiple adenomas compared with single adenoma and rectal adenoma compared with distal adenoma (Table IV). The OR for –509TT homozygotes was 1.89 (95% CI: 1.16–3.09) for multiple adenomas compared with 1.34 (95% CI: 0.88–2.04) for single adenoma, and 2.95 (95% CI: 1.66–5.26) for rectal adenoma compared with 1.46 (95%CI: 0.93–2.29) for distal adenoma. A case–case comparison confirmed that the positive association with –509TT homozygotes was stronger for multiple adenoma compared with single adenoma (P = 0.008) and for rectal adenoma compared with distal adenoma (P = 0.005) (Table V).


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  		Table IV. Risk of advanced colorectal adenoma associated with TGFB1 –509C>T and Leu10Pro polymorphisms by select adenoma characteristicsa

 


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  		Table V. Case–case comparison of the risk of select adenoma characteristics associated with TGFB1 –509C>T and Leu10Pro polymorphismsa

 
No significant differences in risk were observed by smoking status, age at screening or sex for any of the TGFB1 polymorphisms. Use of ibuprofen or aspirin did not modify the association between colorectal adenoma risk and any polymorphism, except TGFB1 Thr263Ile (Pinteraction = 0.004). The 263Ile variant was associated with an increased risk of adenoma among persons not taking aspirin or ibuprofen regularly (OR = 3.30, 95% CI: 1.45–7.49), but no association was observed among regular users (OR = 0.72, 95% CI: 0.35–1.45).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Funding
 References
 
TGFB1 is a multifunctional cytokine that plays an important role in modulating cell growth. TGFB1 signals the target cell by binding to a heterodimeric complex of two transmembrane receptors, transforming growth factor beta receptor type I and transforming growth factor beta receptor type II (TGFBRII) [reviewed in ref. 1]. The binding triggers the phosphorylation of the type I receptor by the type II receptor, activating the type I receptor kinase, which in turn stimulates the phosphorylation of downstream proteins and the formation of the Smad4 complex. The Smad4 complex then translocates to the nucleus, interacting with promoters of transcription factors to influence expression of select genes.

Alteration in the response to TGFB1 is thought to be a key factor in cancer cell behavior and carcinogenesis (1). Although TGFB1 inhibits the growth of normal epithelial cells, it promotes the proliferation of malignant cancer cells and loss of the growth inhibitory effects of TGFB1 accompanies the transformation of colorectal adenoma to cancer (3,4). The mechanism by which the loss of growth inhibition occurs is unclear. Inactivating somatic mutations in the TGFBRII gene have been observed in colorectal cancers, especially microsatellite unstable tumors (27,28). Evidence suggests that mutations in TGFBRII promote TGFB1-induced cell proliferation (29); however, TGFBRII alterations are rare in sporadic adenomas (30,31). Some colorectal cancer cell lines with TGFBRII mutations are inhibited from growing by TGFB1 (32), and other cell lines are unresponsive to the growth inhibitory effects of TGFB1 even though they do not harbor TGFBRII mutations (33). This suggests that there are other mechanisms by which TGFB1 resistance occurs in the adenoma–carcinoma sequence. Somatic mutations in the downstream Smad4 gene have also been observed in colorectal cancers (34), particularly microsatellite stable tumors (35); however, some Smad4-deficient cell lines are inhibited from growing by TGFB1 (36), and Smad4 mutations are rarely seen in colorectal adenoma (37), suggesting that Smad4 mutations occur later in the adenoma–carcinoma sequence and probably do not explain early loss of TGFB1 growth inhibitory effects. Some evidence suggests that Ras activation may play a role in the altered response to TGFB1 seen in cancer cells. Ras-transformed cells are often resistant to the growth inhibitory effects of TGFB1 (38,39) and may be more prone to invasiveness (40,41). K-ras mutations correlate with the progression of colorectal neoplasia (42), occurring in ~10–35% of small adenomas and 40–60% of large adenomas (31,42). Although K-ras mutations may not confer a high level of TGFB1 resistance in colorectal cells (4), there is some evidence that mutations in K-ras and Smad4 may act jointly to disrupt TGFB1-mediated growth inhibition (43).

In our study, we found that TGFB1 –509TT and 10Pro/Pro genotypes were associated with an increased risk of advanced colorectal adenoma. Although the association with the –509T variant was slightly stronger than that for the 10Pro variant, the strong correlation between these polymorphisms made it impossible to conclusively determine which variant was primarily driving the increased risk. Both variants are associated with increased TGFB1 serum levels (12,18,19), which would be expected to promote cell proliferation in cells that have lost their growth inhibitory response to TGFB1. Like our study, the Breast Cancer Association Consortium recently found that the TGFB1 10Pro variant was associated with an increased risk of breast cancer (44), suggesting a broader role for TGFB1 variants in cancer susceptibility; however, other smaller studies of TGFB1 polymorphisms and colorectal neoplasia have yielded mixed results (45–48). No association was observed between adenoma risk and –509C>T or Leu10Pro in smaller studies of adenoma (45,47); however, these studies were not restricted to cases with advanced adenoma, and the inclusion of cases with early adenoma may have attenuated the associations. Studies of colorectal cancer and the –509T allele have yielded inconsistent results (46–48), but these studies were limited in statistical power due to their small sample sizes, making inferences difficult.

The increased risk observed with the TGFB1 –509TT and 10Pro/Pro high producer genotypes was stronger for multiple adenomas and rectal adenoma. Assuming that elevated TGFB1 serum levels promote cell growth and expansion, the stronger association for multiple adenomas compared with single adenoma is consistent with what would be expected. Several studies have reported that K-ras mutations are more common in rectal than colon adenoma (49–52). If K-ras mutations confer resistance to the growth inhibitory effects of TGFB1, then it is reasonable to hypothesize that TGFB1 polymorphisms that increase TGFB1 serum levels may have a greater effect on advanced adenoma in the rectum as opposed to the colon. However, additional studies are needed to confirm these findings.

We also observed a significant interaction between the TGFB1 Thr263Ile polymorphism and regular use of aspirin or ibuprofen with the 263Ile variant displaying an increased risk among non-users. Non-steroidal anti-inflammatory drugs, such as aspirin and ibuprofen, have been shown to protect against the risk of colorectal neoplasia [reviewed in ref. 53]. Although the mechanism is not completely understood, aspirin and ibuprofen inhibit cyclooxygenase 2 expression, which is up-regulated in ~45% of colorectal adenomas and 85% of colorectal cancers (54) and thought to be an important component in colorectal carcinogenesis. In contrast, TGFB1 has been shown to induce cyclooxygenase 2 expression (55). Thus, in theory, TGFB1 genetic variants that lead to increased cyclooxygenase 2 expression may have a greater effect in individuals who do not regularly take non-steroidal anti-inflammatory drugs. However, caution should be exercised in interpreting the interaction we observed in this study. Although the finding is intriguing, the functional significance of the 263Ile variant is uncertain and the number of cases (n = 26) and controls (n = 8) with the variant was small in the subgroup of non-users.

Our study had a few limitations. By not selecting haplotype tagging single-nucleotide polymorphisms or tag single-nucleotide polymorphisms, we may not have captured all common genetic variation in TGFB1 in this study. However, we genotyped variants that are likely to have a functional impact on the expression or activation of TGFB1 and, thus, may be more important for adenoma risk. In addition, as our study population consisted primarily of Caucasians, our results may not be generalizable to other ethnic populations with different environmental exposures. Our analyses were confined to the risk of distal adenoma and may not be generalizable to proximal adenoma risk. In addition, it is possible, since our cases consist of persons with adenoma detected at the baseline screen and are essentially prevalent cases, that we over-sampled slow growing polyps. However, by restricting our cases to advanced adenoma, we should capture adenomas more likely to transform. Finally, our statistical power to detect associations within subgroups and interactions with environmental factors was limited, so additional studies are needed to replicate these findings.

In conclusion, we found that the high TGFB1 producer genotypes, –509TT and 10Pro/Pro, were associated with an increased risk of advanced colorectal adenoma. This study gives additional support to the important role of TGFB1 in the adenoma–carcinoma sequence and suggests that common genetic variation in the TGFB pathway may modulate risk.


   Funding
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
References
 
Intramural Research Program of the National Cancer Institute, National Institutes of Health.


   Acknowledgments
 
We thank Zeynep Kalaylioglu for conducting the two-stage polytomous regression analysis. We also would like to thank the participants of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial for making this study possible as well as Dr Christine Berg, Dr Philip Prorok, all the Prostate, Lung, Colorectal and Ovarian investigators and staff at the screening centers for their commitment to this trial.

Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 

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Received April 30, 2007; revised June 13, 2007; accepted June 26, 2007.


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B. S. Saltzman, J. F. Yamamoto, R. Decker, L. Yokochi, A. G. Theriault, T. M. Vogt, and L. Le Marchand
Association of Genetic Variation in the Transforming Growth Factor {beta}-1 Gene with Serum Levels and Risk of Colorectal Neoplasia
Cancer Res., February 15, 2008; 68(4): 1236 - 1244.
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