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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. L. Thompson, S. J. Plummer, L. S. Acheson, T. C. Tucker, G. Casey, and L. Li Association of common genetic variants in SMAD7 and risk of colon cancer Carcinogenesis, June 1, 2009; 30(6): 982 - 986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Valle, T. Serena-Acedo, S. Liyanarachchi, H. Hampel, I. Comeras, Z. Li, Q. Zeng, H.-T. Zhang, M. J. Pennison, M. Sadim, et al. Germline Allele-Specific Expression of TGFBR1 Confers an Increased Risk of Colorectal Cancer Science, September 5, 2008; 321(5894): 1361 - 1365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|