[CANCER RESEARCH 61, 8351 8352, November 15, 2001]

Letters to the Editor

T R-I(6A) Polymorphism Is not a Tumor Susceptibility Allele in Macedonian Colorectal Cancer Patients1 Correspondence re: B. Pasche et al. Type I T R-I(6A) Is a Candidate Tumor Susceptibility Allele. Cancer Res., 58: 27272732, 1998. Letter
In their article, Pasche et al. (1) suggested that the common polymorphism in the type 1 transforming growth factor receptor gene, T RI(6A), which results in a deletion of three of nine alanine stretch in the extracellular domain of the protein, acts as a tumor susceptibility allele that may contribute to the development of cancer, especially colon cancer. We have analyzed the frequency of T R-I(6A) allele in a group of 117 patients with colorectal cancer, 100 individuals attending the geriatric clinic without a history of malignant disease and 100 newborns, all from Macedonia. Patients, aged individuals, and newborns matched for ethnic status and gender. The mean age of the cases was slightly lower than the age of normal individuals attending the geriatric clinic (63.5 versus 75.6 years, respectively). The presence of the T R-I(6A) allele was evaluated as described by Pasche et al. (1, 2). The results obtained are presented in Table 1. the incidence of this variant among colorectal cancer patients from other southeast European populations, as well as among United States immigrants originating from this region, should clarify this issue. Ana-Marija Stefanovska Georgi D. Efremov Aleksandar J. Dimovski Macedonian Academy of Sciences and Arts Research Center for Genetic Engineering and Biotechnology 1000 Skopje, Republic of Macedonia Djingis Jasar Gjorgi Zografski Institute of Oncology and Radiotherapy Faculty of Medicine 1000 Skopje, Republic of Macedonia Toni Josifovski Milco Panovski Department of Abdominal Surgery Faculty of Medicine 1000 Skopje, Republic of Macedonia Renata Jankova Mirko Spiroski Institute of Immunology Faculty of Medicine 1000 Skopje, Republic of Macedonia References
1. Pasche, B., Kolachana, P., Nafa, K., Satagopan, J., Chen, Y-G., Lo, R. S., Brener, D., Yang, D., Kirstein, L., Oddoux, C., Ostrer, H., Vineis, P., Varesco, L., Jhanwar, S., Luzzatto, L., Massague, J., and Offit, K. Type I T R-I(6A) is a candidate tumor susceptibility allele. Cancer Res., 58: 27272732, 1998. 2. Pasche, B., Luo, Y., Rao, P. H., Nimer, S. D., Dmitrovsky, E., Caron, P., Luzzatto, L., Ofit, K., Cordon-Cardo, C., Renault, B., Satagopan, J. M., Murty, V. V. V. S., and receptor maps to 9q22 and Massague, J. Type, I. Transforming growth factor exhibits a polymorphism and a rare variant within a polyalanine tract. Cancer Res., 59: 5678 5682, 1999.

Table 1 T R-I genotypes in 117 colorectal cancer patients and 200 controls from Macedonia wt/wta Colorectal cancer patients Normal controls (geriatric clinic) Newborns
a

wt/T R-I(6A) 8 (6.8%) 11 (11.0%) 9 (9.0%)

T R-I(6A)/T R-I(6A) 1 (0.9%) 1 (1.0%)

Total 117 100 100

108 88 91

wt, wild-type allele.

One homozygote for T R-I(6A) allele was detected in both the colorectal cancer group and in the group of normal individuals (P 0.71). The one homozygote in the normal control group was a 68-year-old lady without any history of a malignant disease. A smaller proportion of heterozygotes for T R-I(6A) allele was found in the colorectal cancer group (6.8%) as compared both to newborns (9%) and to the group of aged normal controls (11%), although these differences were not statistically significant (P 0.74 and P 0.40, respectively). These results indicate that both heterozygosity (odds ratio, 0.592; 95% confidence interval, 0.231.54) and homozygosity (odds ratio, 0.08; 95% confidence interval, 0.011.97) for T R-I(6A) allele are not predisposition factors for the development of colorectal cancer in our population. However, the similar allele frequencies of the T R-I(6A) allele among normal controls from the Macedonia and New York metropolitan areas (0.055 and 0.053, respectively) and the observed differences in the allele frequencies between colorectal cancer patients from both populations (0.043 and 0.112, respectively; P 0.009) strongly suggest that certain environmental factors influence the transforming growth factor- pathway leading to promotion of colorectal cancerogenesis. This possibility is strengthened by the fact that no homozygotes for T R-I(6A) allele were observed among 65 colorectal cancer patients from northern Italy (1). A wider study of
Received 4/16/01; accepted 9/14/01. 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. 1 Supported in part by Grants 4008662/98 from the Ministry of Education and Science of the Republic of Macedonia and 11-513/1 from the Science Funds of the Macedonian Academy of Sciences and Arts (both to G. D. E.).

T R-I(6A) Association with Colorectal Cancer: A New Twist?1

Reply We have recently genotyped an additional cohort of 107 patients with stage III colorectal patients diagnosed at Memorial Sloan-Kettering Cancer Center using the previously described method (1). Eighteen of
Received 8/6/01; accepted 9/19/01. 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. 1 Supported by CA76156-02 and The Lymphoma Foundation.

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LETTER TO EDITOR

Table 1 wt/wt Stage III colorectal cancer patients 89 wt/6A T R-I(6A) 6A/6A Others Total allelic frequency 0 107 0.084

18 (16.8%) 0

Previously studied 90 colorectal cancer patients All New York patients 179 with colorectal cancer All Italian/Macedonian 165 colorectal cancer patients New York normal 654 controls
a b

17 (15.2%) 4 (3.6%)

112

0.116 0.100a 0.050b

of the control group (0.050) and significantly lower than that of the New York colorectal patients (P 0.007; Table 1). Stefanovska et al. raise the interesting hypothesis that environmental factors may have an impact on the transforming growth factor signaling pathway contribution to colorectal carcinogenesis. This hypothesis is supported by our common findings and warrants validation studies. Boris Pasche Yansong Bian Jennifer Reich Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois Alfred Rademaker Department of Preventive Medicine, Northwestern University Medical School and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois Prema Kolachana Kenneth Offit 2 Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York

35 (16.0%) 4 (1.8%)

219

16 (8.8%)

182

78 (10.6%) 0

735

0.053

P 0.004 when compared with all New York normal controls (two-tailed 2 test). P 0.007 when compared with all New York cancer patients with colorectal cancer (two-tailed 2 test).

these patients were T R-I(6A) homozygotes. Using a 2 test, we find that T R-I(6A) allelic frequency is significantly higher among 219 New York patients with a diagnosis of colorectal cancer than among 735 New York healthy controls (P 0.0004; Table 1). This data confirm our earlier findings of T R-I(6A) association with colorectal cancer (2). The recent finding that T R-I(6A) allelic frequency is elevated in ovarian cancer indicates that T R-I(6A) may be associated with a variety of cancers (3). This is in agreement with a meta-analysis of studies on T R-I(6A) published before 2001. There were 11 T R-I(6A) homozygotes among 1264 patients with a diagnosis of cancer and none among 853 healthy controls (P 0.004). Furthermore, T R-I(6A) heterozygote frequency was significantly higher in the cancer group (14.6%) than among controls (11.2%; P 0.037; Ref. 4). The data provided by Stefanovska et al. add useful information to the understanding of T R-I(6A) role in colorectal cancer. The identical T R-I(6A) allelic frequency in their (0.055) and our (0.053) New York control groups rules out a geographically related difference. We found eight T R-I(6A) heterozygotes and no homozygotes in our previously published group of 65 Italian patients with a diagnosis of colorectal cancer. This results in an allelic frequency of 0.061, which was not significantly different from the control group. As seen in Table 1, combined analysis of the Italian and Macedonian colorectal patients shows a T R-I(6A) allelic frequency (0.053) identical to that

References
1. Pasche, B., Luo, Y., Rao, P. H., Nimer, S. D., Dmitrovsky, E., Caron, P., Luzzatto, L., Offit, K., Cordoncardo, C., Renault, B., Satagopan, J. M., Murty, V. S., and Massague, J. Type I transforming growth factor receptor maps to 9q22 and exhibits a polymorphism and a rare variant within a polyalanine tract. Cancer Res., 58: 27272732, 1998. 2. Pasche, B., Kolachana, P., Nafa, K., Satagopan, J., Chen, Y. G., Lo, R. S., Brener, D., Yang, D., Kirstein, L., Oddoux, C., Ostrer, H., Vineis, P., Varesco, L., Jhanwar, S., Luzzatto, L., Massague, J., and Offit, K. T R-I(6A) is a candidate tumor susceptibility allele. Cancer Res., 59: 5678 5682, 1999. 3. Chen, T., Triplett, J., Dehner, B., Hurst, B., Colligan, B., Pemberton, J., Graff, J. R., and Carter, J. H. Transforming growth factor- receptor type i gene is frequently mutated in ovarian carcinomas. Cancer Res., 61: 4679 4682, 2001. 4. Pasche, B. Role of transforming growth factor in cancer. J. Cell. Physiol., 186: 153168, 2001.
2 To whom requests for reprints should be addressed, at Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021. Phone: (212) 434-5152; Fax: (212) 434-5166.

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