Somatic acquisition and signaling of TGFBR1*6A in cancer

Boris Pasche, Thomas J. Knobloch, Yansong Bian, Junjian Liu, Sharbani Phukan, Diana Rosman, Virginia Kaklamani, Lisa Baddi, Farida S. Siddiqui, Wendy Frankel, Thomas W. Prior, David E. Schuller, Amit Agrawal, Jas Lang, M. Eileen Dolan, Everett E. Vokes, William S. Lane, Chiang Ching Huang, Trinidad Caldes, Antonio Di CristofanoHeather Hampel, Ing Marie Nilsson, Gunnar Von Heijne, Riccardo Fodde, V. V.V.S. Murty, Albert De La Chapelle, Christopher M. Weghorst

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1634-1646
Number of pages13
JournalJournal of the American Medical Association
Volume294
Issue number13
DOIs
StatePublished - Oct 5 2005
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Pasche, B., Knobloch, T. J., Bian, Y., Liu, J., Phukan, S., Rosman, D., Kaklamani, V., Baddi, L., Siddiqui, F. S., Frankel, W., Prior, T. W., Schuller, D. E., Agrawal, A., Lang, J., Dolan, M. E., Vokes, E. E., Lane, W. S., Huang, C. C., Caldes, T., ... Weghorst, C. M. (2005). Somatic acquisition and signaling of TGFBR1*6A in cancer. Journal of the American Medical Association, 294(13), 1634-1646. https://doi.org/10.1001/jama.294.13.1634