Combined Genetic Assessment of Transforming Growth Factor-β Signaling Pathway Variants May Predict Breast Cancer Risk

Abstract

There is growing evidence that common variants of the transforming growth factor-beta (TGF-beta) signaling pathway may modify breast cancer risk. In vitro studies have shown that some variants increase TGF-beta 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-beta circulating levels. Cases and controls were of similar ethnicity and geographic location. Thirty percent of cases were identified as high or low TGF-beta 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-beta 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-beta 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.

Association between the TGFB1 -509C/T and TGFBR2 -875A/G polymorphisms and gastric cancer: a case-control study

“…Thus, it is feasible that the combination of the TGFB1 -509C/T and TGFBR2 -875A/G gene polymorphisms confer a synergistic effect on gastric cancer initiation and progression. This result confirmed the hypothesis that a combined assessment of functionally relevant common variants may aid in the characterization of cancer risk and prediction of disease aggressiveness (25).…”

TGF-β1 genotype and phenotype in breast cancer and their associations with IGFs and patient survival

“…Several genetic polymorphisms exist in the TGF-b1 gene, one of which is a T-C transition at nucleotide 29 of the coding region, resulting in a leucine to proline substitution at codon 10 (Blobe et al, 2000;Breast Cancer Association Consortium, 2006;Cox et al, 2007). This single nucleotide polymorphism (SNP) T29C, which is in strong linkage disequilibrium with another common SNP C-509T, has been studied extensively for its association with breast cancer risk and survival (Yokota et al, 2000;Goode et al, 2002;Hishida et al, 2003;Krippl et al, 2003;Ziv et al, 2003;Jin et al, 2004;Le Marchand et al, 2004;Shu et al, 2004;Kaklamani et al, 2005;Lee et al, 2005;Shin et al, 2005;Skerrett et al, 2005;Breast Cancer Association Consortium, 2006;Feigelson et al, 2006;Gonzalez-Zuloeta Ladd et al, 2007). Two studies found increased risk of breast cancer among Koreans and Dutch who carry the C allele (Lee et al, 2005;Gonzalez-Zuloeta Ladd et al, 2007), whereas two other studies showed decreased risk in relation to C genotype among Americans who were older than 65 years or Japanese who were premenopausal (Hishida et al, 2003;Ziv et al, 2003).…”

Transforming growth factor-beta: A target for cancer therapy

“…TβRI mutations occur less frequently than TβRII mutations, and have been reported most often in ovarian, pancreatic and cervical carcinomas, as well as in some lymphomas (Elliott and Blobe, 2005;Seoane, 2006). TβRI signal sequence mutations have also been reported in breast and colorectal cancers Kaklamani et al, 2005). The TβRI*6A mutation most commonly reported enables cancer cells to resist the cytostatic action of TGF-β Pasche et al, 2005).…”