Human Molecular Genetics Advance Access originally published online on September 21, 2007
Human Molecular Genetics 2007 16(24):3128-3135; doi:10.1093/hmg/ddm274
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Somatic acquisition of TGFBR1*6A by epithelial and stromal cells during head and neck and colon cancer development
1 Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine, Northwestern University, Chicago, IL 60611, USA, 2 Robert H. Lurie Comprehensive Cancer Center, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA, 3 Division of Environmental Health Sciences, School of Public Health, The Ohio State University, Columbus, OH 43210, USA, 4 Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA and 5 Department of Pathology, Northwestern University, Chicago, IL 60611, USA
* To whom correspondence should be addressed at: Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University 676 N. St Clair Street, Suite 880 Chicago, IL 60611, USA. Tel: +1 3129085284; Fax: +1 3126950319; Email: b-pasche{at}northwestern.edu
Received July 30, 2007; Revised August 27, 2007; Accepted September 14, 2007
TGFBR1*6A is a common hypomorphic variant of the type I transforming growth factor (TGF)-ß receptor (TGFBR1), which transduces TGF-ß 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-ß. 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-ß signaling during oncogenesis and the first report of a concordant mutation in the stromal and epithelial compartments in colon cancer.
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