title: Combined genetic assessment of transforming growth factor-beta 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.
authors.affiliation: 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, Chicago, IL 60611, USA.
authors.forename: Virginia G
authors.initials: VG
authors.lastname: Kaklamani
authors.forename: Lisa
authors.initials: L
authors.lastname: Baddi
authors.forename: Junjian
authors.initials: J
authors.lastname: Liu
authors.forename: Diana
authors.initials: D
authors.lastname: Rosman
authors.forename: Sharbani
authors.initials: S
authors.lastname: Phukan
authors.forename: Ciarán
authors.initials: C
authors.lastname: Bradley
authors.forename: Chris
authors.initials: C
authors.lastname: Hegarty
authors.forename: Bree
authors.initials: B
authors.lastname: McDaniel
authors.forename: Alfred
authors.initials: A
authors.lastname: Rademaker
authors.forename: Carole
authors.initials: C
authors.lastname: Oddoux
authors.forename: Harry
authors.initials: H
authors.lastname: Ostrer
authors.forename: Loren S
authors.initials: LS
authors.lastname: Michel
authors.forename: Helen
authors.initials: H
authors.lastname: Huang
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Habibul
authors.initials: H
authors.lastname: Ahsan
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: Boris
authors.initials: B
authors.lastname: Pasche
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics; D000328:Adult; D000368:Aged; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics*
chemical_list: D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human