TGF-ß signaling alterations and susceptibility to colorectal cancer
Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
* To whom correspondence should be addressed. Tel: +1 3126950320; Fax: +1 3126950318; Email: b-pasche{at}northwestern.edu
Received December 26, 2006; Accepted January 3, 2007
In 2006, more than 55 000 patients died of colorectal cancer in the US, accounting for 
10% of all cancer deaths. Despite significant progress in screening combined with the development of novel effective therapies, colorectal cancer ranks second to lung cancer as a cause of cancer death. Twin studies indicate that 35% of all colorectal cancers are inherited, but high-penetrance tumor susceptibility genes only account for 3–6% of all cases. The remainder of the unexplained familial risk is presumably due to other high-penetrance genes, but polygenic mechanisms and low-penetrance tumor susceptibility genes are likely to account for a greater proportion of familial colorectal cancers. In this regard, there is growing evidence that a common hypomorphic variant of the type I TGF-ß receptor, TGFBR1*6A, may account for 3% of all colorectal cancer cases, a fraction higher than that attributable to mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Furthermore, TGFBR1*6A is emerging as a potent modifier of colorectal cancer risk among individuals with a strong family of colorectal cancer. The TGF-ß signaling pathway plays a central but paradoxical role in the predisposition and progression of colorectal cancer. TGF-ß is a potent inhibitor of normal colonic epithelial cells acting as a tumor suppressor. However, TGF-ß promotes the survival, invasion and metastasis of colorectal cancer cells, thereby acting as an oncogene. Understanding how selective alterations of the TGF-ß signaling pathway contribute to colorectal cancer development and progression will likely permit the identification of an additional fraction of inherited colorectal cancer cases and provide novel opportunities for therapeutic intervention.
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  Y. Bian, T. J. Knobloch, M. Sadim, V. Kaklamani, A. Raji, G.-Y. Yang, C. M. Weghorst, and B. Pasche Somatic acquisition of TGFBR1*6A by epithelial and stromal cells during head and neck and colon cancer development Hum. Mol. Genet., December 15, 2007; 16(24): 3128 - 3135. [Abstract] [Full Text] [PDF]
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