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Epidemiology and Prevention |
1 Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine and 2 Department of Preventive Medicine, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois; 3 Human Genetics Program, Department of Pediatrics, New York University Medical Center; 4 Department of Medicine and 5 Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center; 6 Department of Epidemiology, Mailman School of Public Health and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York
Requests for reprints: Boris Pasche, Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 676 North St. Clair Street, Suite 880, Chicago, IL 60611. Phone: 312-695-0320; Fax: 312-695-0318; E-mail: b-pasche{at}northwestern.edu.
There is growing evidence that common variants of the transforming growth factor-ß (TGF-ß) signaling pathway may modify breast cancer risk. In vitro studies have shown that some variants increase TGF-ß signaling, whereas others have an opposite effect. We tested the hypothesis that a combined genetic assessment of two well-characterized variants may predict breast cancer risk. Consecutive patients (n = 660) with breast cancer from the Memorial Sloan-Kettering Cancer Center (New York, NY) and healthy females (n = 880) from New York City were genotyped for the hypomorphic TGFBR1*6A allele and for the TGFB1 T29C variant that results in increased TGF-ß circulating levels. Cases and controls were of similar ethnicity and geographic location. Thirty percent of cases were identified as high or low TGF-ß signalers based on TGFB1 and TGFBR1 genotypes. There was a significantly higher proportion of high signalers (TGFBR1/TGFBR1 and TGFB1*CC) among controls (21.6%) than cases (15.7%; P = 0.003). The odds ratio [OR; 95% confidence interval (95% CI)] for individuals with the lowest expected TGF-ß signaling level (TGFB1*TT or TGFB1*TC and TGFBR1*6A) was 1.69 (1.08-2.66) when compared with individuals with the highest expected TGF-signaling levels. Breast cancer risk incurred by low signalers was most pronounced among women after age 50 years (OR, 2.05; 95% CI, 1.01-4.16). TGFBR1*6A was associated with a significantly increased risk for breast cancer (OR, 1.46; 95% CI, 1.04-2.06), but the TGFB1*CC genotype was not associated with any appreciable risk (OR, 0.89; 95% CI, 0.63-1.21). TGFBR1*6A effect was most pronounced among women diagnosed after age 50 years (OR, 2.20; 95% CI, 1.25-3.87). This is the first study assessing the TGF-ß signaling pathway through two common and functionally relevant TGFBR1 and TGFB1 variants. This approach may predict breast cancer risk in a large subset of the population.
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B. Pasche, V. Kaklamani, A. Rademaker, N. Hou, H. Ahsan, and Y. Chen In Reply J. Clin. Oncol., October 20, 2005; 23(30): 7744 - 7746. [Full Text] [PDF]
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