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Journal of Clinical Oncology, Vol 23, No 30 (October 20), 2005: pp. 7743-7744 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.9108
Is TGFBR1*6A Really Associated With Increased Risk of Cancer?Laboratory of Medical Genetics, School of Life Sciences, Suzhou University, Suzhou, People's Republic of China
The First Affiliated Hospital, Suzhou University, Suzhou, People's Republic of China
Department of Surgery, Shanghai Hospital for Pulmonary Diseases, Shanghai, People's Republic of China To the Editor: Compelling evidence has shown that TGFBR1 could be a tumor suppressor gene, and mutation of the TGFBR1 gene was found to correlate with development of several human cancers.1,2 Moreover, polymorphisms of the TGFBR1 gene, including TGFBR1*6A and Int7G24A, were reported to correlate with increased risk of cancer.3,4 Before reading with great interest Dr Lai's comment5 on the article by Kaklamani et al6 published in Journal of Clinical Oncology, we also made the same conclusion as that described by Dr Lai, that the seven case-control studies were too different to be pooled for a meta-analysis under a fixed-effects model. Interestingly, a meta-analysis of twelve case-control studies by Pasche et al3 indicated that the Breslow-Day test for heterogeneity is marginally significant. It suggests that pooling of more negative data might be necessary for credibility of a meta-analysis and helpful for removing some publication biases. Therefore, it is needed to update the meta-analysis regarding the association between TGFBR1*6A and cancer risk, and to re-evaluate whether the TGFBR1*6A polymorphism is associated with increased cancer risk. Fortunately, following the publication of Pasche et al,3 the five corresponding articles have been published as of May 2005.7-11 These studies provide us with an opportunity for further meta-analysis. We now describe them below, respectively.1 The study by Kaklamani et al,7 published in September 2004, performed genotyping for TGFBR1*6A in 442 patients with prostate cancer and in 465 controls. Genotyping revealed that the frequency of TGFBR1*6A carriers was 13.5% among controls and 14.0% among cases (Table 1). The authors suggested that TGFBR1*6A makes no contribution to the development of prostate cancer.2 The study by Jin et al,8 published in October 2004, genotyped the TGFBR1 9A/6A polymorphism in 391 breast cancer cases and in 437 controls. The genotype distributions in controls were 81.1% (9A/9A), 16.9% (9A/6A), and 2.0% (6A/6A), and in patients, 79.4% (9A/9A), 19.7% (9A/6A), and 0.7% (6A/6A) as presented in Table 1, indicating that no significant difference between the breast cancer and healthy control groups was found for the TGFBR1 9A/6A polymorphism.3 The study by Suarez et al,9 published in March 2005, examined the association between TGFBR1*6A and prostate cancer. This study consisted of 537 cases and 488 controls. The frequencies of TGFBR1 9A/6A genotypes among controls and cases were summarized in Table 1. The data showed that there is no compelling evidence for an association of TGFBR1*6A with prostate cancer.4 In another study by Kaklamani et al.10 published in April 2005, 611 cases of breast cancer and 690 controls were genotyped in relation to TGFBR1 9A/6A polymorphism. As illustrated in Table 1, TGFBR1*6A allelic frequency was significantly higher among cases (0.082) than among controls (0.057).5 The study by Spillman et al,11 published in May 2005, was a case-control study on TGFBR1 9A/6A polymorphism and ovarian cancer with 588 cases and 614 controls (Table 1). The authors concluded that TGFBR1*6A does not appear to increase risk of ovarian cancer.
Although most of the above-mentioned studies presented negative association of TGFBR1*6A with cancer, the credibility of the meta-analysis could be improved by pooling these additional studies. Consequently, combined analysis of 17 studies indicates that allelic frequency of TGFBR1*6A in cases (0.090) is 20% higher than in controls (0.075; P < .001), which is not much lower than the 27% increment calculated previously.3 As illustrated in Figure 1, the test for heterogeneity is not significant (Q5 = 5.51; P = .36), and this means that the 17 studies are homogeneous and can be pooled, suggesting that the fixed-effects model could be used to assess odds ratio. Inclusion of five novel additional studies addresses the issue concerned by Dr Lai.5 Overall, the pooled odds ratio is 1.22 (95% CI, 1.12 to 1.34), which is statistically significant (P < .0001). The results showed that TGFBR1*6A carriers have a 22% increased risk of cancer. This meta-analysis, including 13,113 individuals, strongly supports the idea provided by Pasche et al3 and further confirms that TGFBR1*6A is associated with increased cancer risk.
Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
Acknowledgment Research supported in part by grants from China's National Natural Science Foundation (30400533) and Science and Technology Committee of Jiangsu Province (BK2004402) and Medicine Development Foundation of Suzhou University (EE120511). REFERENCES
1. Chen T, Triplett J, Dehner B, et al: Transforming growth factor-beta receptor type I gene is frequently mutated in ovarian carcinomas. Cancer Res 61:4679-4682, 2001 2. Chen T, Yan W, Wells RG: Novel inactivating mutations of transforming growth factor-ß type I receptor gene in head-and-neck cancer metastases. Int J Cancer 93:653-661, 2001[CrossRef][Medline]
3. Pasche B, Kaklamani V, Hou N, et al: TGFBR1*6A and cancer: A meta-analysis of 12 case-control studies. J Clin Oncol 22:756-758, 2004 4. Zhang HT: Int7G24A variant of the TGFBR1 gene and cancer risk: A meta-analysis of three case-control studies. Lung Cancer 49:419-420, 2005[Medline]
5. Lai R: Association between TGFBR1*6A and cancer: Is there any evidence? J Clin Oncol 22:2754, 2004
6. Kaklamani VG, Hou N, Bian Y, et al: TGFBR1*6A and cancer risk: A meta-analysis of seven case-control studies. J Clin Oncol 21:3236-3243, 2003 7. Kaklamani V, Baddi L, Rosman D, et al: No major association between TGFBR1*6A and prostate cancer. BMC Genet 5:28, 2004[CrossRef][Medline] 8. Jin Q, Hemminki K, Grzybowska E, et al: Polymorphisms and haplotype structures in genes for transforming growth factor beta1 and its receptors in familial and unselected breast cancers. Int J Cancer 112:94-99, 2004[CrossRef][Medline] 9. Suarez BK, Pal P, Jin CH, et al: TGFBR1*6A is not associated with prostate cancer in men of European ancestry. Prostate Cancer Prostatic Dis 8:50-53, 2005[Medline]
10. Kaklamani VG, Baddi L, Liu J, et al: Combined genetic assessment of transforming growth factor-beta signaling pathway variants may predict breast cancer risk. Cancer Res 65:3454-3461, 2005 11. Spillman MA, Schildkraut JM, Halabi S, et al: Transforming growth factor beta receptor I polyalanine repeat polymorphism does not increase ovarian cancer risk. Gynecol Oncol 97:543-549, 2005[CrossRef][Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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