TY - JOUR
T1 - Somatic acquisition and signaling of TGFBR1*6A in cancer
AU - Pasche, Boris
AU - Knobloch, Thomas J.
AU - Bian, Yansong
AU - Liu, Junjian
AU - Phukan, Sharbani
AU - Rosman, Diana
AU - Kaklamani, Virginia
AU - Baddi, Lisa
AU - Siddiqui, Farida S.
AU - Frankel, Wendy
AU - Prior, Thomas W.
AU - Schuller, David E.
AU - Agrawal, Amit
AU - Lang, Jas
AU - Dolan, M. Eileen
AU - Vokes, Everett E.
AU - Lane, William S.
AU - Huang, Chiang Ching
AU - Caldes, Trinidad
AU - Di Cristofano, Antonio
AU - Hampel, Heather
AU - Nilsson, Ing Marie
AU - Von Heijne, Gunnar
AU - Fodde, Riccardo
AU - Murty, V. V.V.S.
AU - De La Chapelle, Albert
AU - Weghorst, Christopher M.
PY - 2005/10/5
Y1 - 2005/10/5
N2 - Context: TGFBR1*6A is a common polymorphis of the type I transforming growth factor β receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown. Objectives: To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3-amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells. Design, Setting, and Patients: Tumor and germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A. Main Outcome Measures: TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-β-dependent cell proliferation. Results: TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-β growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells. Conclusions: TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-β. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-β signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer.
AB - Context: TGFBR1*6A is a common polymorphis of the type I transforming growth factor β receptor (TGFBR1). Epidemiological studies suggest that TGFBR1*6A may act as a tumor susceptibility allele. How TGFBR1*6A contributes to cancer development is largely unknown. Objectives: To determine whether TGFBR1*6A is somatically acquired by primary tumors and metastases during cancer development and whether the 3-amino acid deletion that differentiates TGFBR1*6A from TGFBR1 is part of the mature receptor or part of the signal sequence and to investigate TGFBR1*6A signaling in cancer cells. Design, Setting, and Patients: Tumor and germline tissues from 531 patients with a diagnosis of head and neck, colorectal, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. In vitro translation assays, MCF-7 breast cancer cells stably transfected with TGFBR1*6A, TGFBR1, or the vector alone, DLD-1 colorectal cancer cells that endogenously carry TGFBR1*6A, and SW48 colorectal cancer cells that do not carry TGFBR1*6A. Main Outcome Measures: TGFBR1*6A somatic acquisition in cancer. Determination of the amino terminus of the mature TGFBR1*6A and TGFBR1 receptors. Determination of TGF-β-dependent cell proliferation. Results: TGFBR1*6A was somatically acquired in 13 of 44 (29.5%) colorectal cancer metastases, in 4 of 157 (2.5%) of colorectal tumors, in 4 of 226 (1.8%) head and neck primary tumors, and in none of the 104 patients with breast cancer. TGFBR1*6A somatic acquisition is not associated with loss of heterozygosity, microsatellite instability, or a mutator phenotype. The signal sequences of TGFBR1 and TGFBR1*6A are cleaved at the same site resulting in identical mature receptors. TGFBR1*6A may switch TGF-β growth inhibitory signals into growth stimulatory signals in MCF-7 breast cancer cells and in DLD-1 colorectal cancer cells. Conclusions: TGFBR1*6A is somatically acquired in 29.5% of liver metastases from colorectal cancer and may bestow cancer cells with a growth advantage in the presence of TGF-β. The functional consequences of this conversion appear to be mediated by the TGFBR1*6A signal sequence rather than by the mature receptor. The results highlight a new facet of TGF-β signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer.
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U2 - 10.1001/jama.294.13.1634
DO - 10.1001/jama.294.13.1634
M3 - Article
C2 - 16204663
AN - SCOPUS:26044435160
SN - 0098-7484
VL - 294
SP - 1634
EP - 1646
JO - JAMA - Journal of the American Medical Association
JF - JAMA - Journal of the American Medical Association
IS - 13
ER -