|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 23, No 30 (October 20), 2005: pp. 7744-7746 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.0197
In ReplyCancer Genetics Program, Division of Hematology/Oncology, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL
Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL
Division of Epidemiology of Mailman School of Public Health and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY We appreciate the efforts of Dr Zhang and collaborators to further investigate the association between TGFBR1*6A and cancer risk. Despite the fact that most studies to date have not shown an association between TGFBR1*6A and cancer, their meta-analysis of 17 studies confirm the data from our two previous meta-analyses.1,2 The results lend further support to the role of TGFBR1*6A as a high-frequency (14.1% of controls carry at least one copy of the gene), low-penetrance (overall cancer risk is increased by 22%) tumor susceptibility gene. Our own analysis of these studies shows that the previously observed TGFBR1*6A allelic dosing effect is confirmed: cancer risk incurred by TGFBR1*6A homozygotes (odds ratio [OR], 2.04; 95% CI, 1.49 to 2.78) is more than twice higher than cancer risk incurred by TGFBR1*6A heterozygotes (OR, 1.13; 95% CI, 1.03 to 1.24). The additional studies published since our last meta-analysis also help ascertain more precisely the role of TGFBR1*6A in several common forms of cancer. The study by Spillman et al3 provides new primary data for the analysis of TGFBR1*6A in ovarian cancer and combined analysis of four studies2-5 further strengthens the association between TGFBR1*6A homozygosity and ovarian cancer (Table 1). Two additional studies provide new primary data for the analysis of TGFBR1*6A in prostate cancer.6,7 We have combined the data from these two studies with the data presented in our original report.4 As presented in Table 1, TGFBR1*6A homozygosity is associated with a 200% increased prostate cancer risk. Given the strong genetic evidence of prostate cancer familial clustering, large case control studies of TGFBR1*6A are warranted to validate these new exciting findings. The additional breast cancer study by Jin et al8 further strengthens the association of TGFBR1*6A with breast cancer. This association is the strongest of all tumor types studied so far. Both TGFBR1*6A heterozygosity and homozygosity are associated with increased breast cancer risk (Table 1).
The results of this third meta-analysis further highlight the need for large, adequately powered studies to assess the impact of high-frequency, low-penetrance candidate tumor susceptibility genes such as TGFBR1*6A. The data show that epidemiological studies of inadequate numbers of well-matched cases and controls are inappropriate for the study of alleles such as TGFBR1*6A. Indeed, estimates based on TGFBR1*6A allelic frequency and OR indicate that a minimum of 5,000 cases and 5,000 controls are needed to detect TGFBR1*6A effects with respect to cancer susceptibility, defined as a control frequency of 14.1% and an OR of 1.17 for TGFBR1/TGFBR1*6A effects, and a control frequency of 0.5% and an OR of 2.00 for TGFBR1*6A/TGFBR1*6A effects. These numbers provide some estimates for future studies and suggest that TGFBR1*6A homozygosity is associated with a substantial increase in risk of breast, colon, prostate, and ovarian cancers. Most studies included in this meta-analysis include consecutive patients with a diagnosis of cancer, and therefore attempted to assess an association between sporadic cancer and TGFBR1*6A. Whether TGFBR1*6A may account for a proportion of familial breast and colorectal cancer cases is unknown. A recent report by Bian et al suggests that TGFBR1*6A may act as a potent modifier of colorectal cancer risk among patients with a strong family history of colorectal cancer.9 Indeed, in this case-case study of 208 patients with the Lynch syndrome (hereditary nonpolyposis colorectal cancer), TGFBR1*6A homozygotes had a more than 10-fold higher risk of colorectal cancer among noncarriers of mismatch repair gene mutations than among carriers (case-case interaction OR, 10.70; 95% CI, 1.16 to 98.4). Another recent report highlights the fact that a combined assessment of TGFBR1*6A and TGFB1 T29C, another functionally relevant TGF-ß signaling pathway variant, may help predict breast cancer risk in up to 30% of the general population.10 This exemplifies the fact that TGFBR1*6A penetrance may depend on other, yet unknown, gene-gene interactions. While the data on the association between TGFBR1*6A and cancer are more robust now than they were two years ago, several important questions remain unanswered. First, TGFBR1*6A mechanism of action needs to be better understood in light of the allelic dosing effect observed in this meta-analysis. Second, could TGFBR1*6A account for a proportion of the hypothetical breast/colon cancer syndrome? Third, does TGFBR1*6A act as a modifier of known high- penetrance tumor susceptibility genes such as BRCA1 and BRCA2? Fourth, how should the current data be applied in clinical practice? Additional, appropriately powered studies are needed to expand our knowledge of TGFBR1*6A and help define its future role in cancer risk assessment. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. 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
2. Pasche B, Kaklamani VG, Hou N, et al: TGFBR1*6A and Cancer: A meta-analysis of 12 case-control studies. J Clin Oncol 22:756-758, 2004 3. 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]
4. Pasche B, Kolachana P, Nafa K, et al: T beta R-I(6A) is a candidate tumor susceptibility allele. Cancer Res 59:5678-5682, 1999
5. Baxter SW, Choong DY, Eccles DM, et al: Transforming growth factor beta receptor 1 polyalanine polymorphism and exon 5 mutation analysis in breast and ovarian cancer. Cancer Epidemiol Biomarkers Prev 11:211-214, 2002 6. 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, 2004 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. Bian Y, Caldes T, Wijnen J, et al: TGFBR1*6A may contribute to hereditary colorectal cancer. J Clin Oncol 23:3074-3078, 2005
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 Related Correspondence
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
