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Boris Pasche, MD, PhD; Thomas J. Knobloch, PhD^*; Yansong Bian, MD, PHD^*; Junjian Liu, PhD^*; Sharbani Phukan, MD^*; Diana Rosman, BA^*; Virginia Kaklamani, MD; Lisa Baddi, DO; Farida S. Siddiqui, PhD; Wendy Frankel, MD; Thomas W. Prior, PhD; David E. Schuller, MD; Amit Agrawal, MD; Jas Lang, PhD; M. Eileen Dolan, PhD; Everett E. Vokes, MD; William S. Lane, BA; Chiang-Ching Huang, PhD; Trinidad Caldes, PhD; Antonio Di Cristofano, PhD; Heather Hampel, MS; IngMarie Nilsson, PhD; Gunnar von Heijne, PhD; Riccardo Fodde, PhD; V. V. V. S. Murty, PhD; Albert de la Chapelle, MD, PhD; Christopher M. Weghorst, PhD

JAMA. 2005;294:1634-1646.

Context  TGFBR1*6A is a common polymorphism 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.

Author Affiliations: Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine (Drs Pasche, Bian, Liu, Phukan, Kaklamani, Baddi, and Siddiqui and Ms Rosman), Robert H. Lurie Comprehensive Cancer Center (Drs Pasche, Bian, Liu, Phukan, Kaklamani, Baddi, Siddiqui, and Huang and Ms Rosman), and Department of Preventive Medicine (Dr Huang), The Feinberg School of Medicine, Northwestern, University, Chicago, Ill; Division of Environmental Health Sciences, School of Public Health (Drs Knobloch and Weghorst), Department of Pathology (Drs Frankel and Prior), Comprehensive Cancer Center (Drs Frankel, Prior, Schuller, Agrawal, Lang, de la Chapelle, and Weghorst and Ms Hampel), and Department of Otolaryngology (Drs Schuller and Agrawal), and Human Cancer Genetics Program (Ms Hampel and Dr de la Chapelle), Ohio State University, Columbus; Section of Hematology/Oncology, Department of Medicine and Cancer Research Center, University of Chicago, Chicago, Ill (Drs Dolan and Vokes); Microchemistry and Proteomics Analysis Facility, Harvard University, Cambridge, Mass (Mr Lane); Molecular Oncology Laboratory, Hospital Clínico San Carlos, Martin Lagos, Madrid, Spain (Dr Caldes); Human Genetics Program, Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pa (Dr Di Cristofano); Department of Biochemistry and Biophysics, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden (Drs Nilsson and von Heijne); Department of Pathology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, the Netherlands (Dr Fodde); and Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, NY (Dr Murty).
*These authors contributed equally to this work.

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