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Pasche B , Knobloch TJ , Bian Y , Liu J , Phukan S , Rosman D , Kaklamani V , Baddi L , Siddiqui FS , Frankel W , Prior TW , Schuller DE , Agrawal A , Lang J , Dolan ME , Vokes EE , Lane WS , Huang CC , Caldes T , Di Cristofano A , Hampel H , Nilsson I , Von Heijne G , Fodde R , Murty VVVS , De La Chapelle A , Weghorst CM
Somatic acquisition and signaling of TGFBR1*6A in cancer
Journal of the American Medical Association. 2005 ;294(13) :1634-1646
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Context: TGFBR1*6A is a common polymorphis of the type I transforming growth factor ? 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-?-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-? 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-?. 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-? signaling in cancer and suggest that TGFBR1*6A may represent a potential therapeutic target in cancer. ©2005 American Medical Association. All rights reserved.
00987484 (ISSN) Cited By: 3; Export Date: 25 May 2006; Source: Scopus CODEN: JAMAA Language of Original Document: English Correspondence Address: Pasche, B.; Department of Medicine; Robert H. 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