Somatic acquisition of TGFBR1*6A by epithelial and stromal cells during head and neck and colon cancer development.

Abstract

TGFBR1*6A is a common hypomorphic variant of the type I transforming growth factor (TGF)-beta receptor (TGFBR1), which transduces TGF-beta growth inhibitory signals less effectively than TGFBR1. Recent studies suggest that TGFBR1*6A confers a selective growth advantage to both normal appearing and cancerous epithelial cells in the presence of TGF-beta. We have previously shown that TGFBR1*6A is somatically acquired in head and neck and colon cancer (10). Using microdissected tissues, we show that TGFBR1*6A is somatically acquired by stromal and epithelial cells adjacent to colorectal and head and neck tumors. Somatic acquisition of the TGFBR1*6A allele is not accompanied by acquisition of other tumor-specific mutations. Furthermore, lymphocytes located within the stroma or the normal appearing epithelium do not have evidence of TGFBR1*6A acquisition. The highest TGFBR1*6A/TGFBR1 allelic ratio is observed at the tumor's edge, and traces of TGFBR1*6A are detected as far as 2 cm away from the tumor, which is suggestive of centrifugal spread of cells that harbor TGFBR1*6A. Assessment of CDH1 and CDH2 expression does not indicate epithelial-mesenchymal transformation. The results suggest that TGFBR1*6A somatic acquisition is a critical event in the early stages of cancer development that is associated with field cancerization. They also represent the first human report of somatically acquired altered stromal TGF-beta signaling during oncogenesis and the first report of a concordant mutation in the stromal and epithelial compartments in colon cancer.

• Authors: Yansong Bian, Thomas J Knobloch, Maureen Sadim, Virginia Kaklamani, Adekunle Raji, Guang-Yu Yang, Christopher M Weghorst, Boris Pasche
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 16 Issue 24 Pg. 3128-35 (Dec 15 2007) ISSN: 0964-6906 [Print] England
• PMID: 17890272 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Transforming Growth Factor beta
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I
• TGFBR1 protein, human

Topics

• Base Sequence
• Cell Transformation, Neoplastic (genetics)
• Colonic Neoplasms (genetics, pathology)
• DNA Mutational Analysis
• Epithelial Cells (metabolism, pathology)
• Head and Neck Neoplasms (genetics, pathology)
• Humans
• Molecular Sequence Data
• Polymorphism, Single Nucleotide
• Protein Serine-Threonine Kinases (genetics)
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (genetics)
• Stromal Cells (metabolism, pathology)