Journal Article

TGF-β signaling alterations and susceptibility to colorectal cancer

Yanfei Xu and Boris Pasche

in Human Molecular Genetics

Volume 16, issue R1, pages R14-R20
Published in print April 2007 | ISSN: 0964-6906
Published online April 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddl486
TGF-β signaling alterations and susceptibility to colorectal cancer

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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-β 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-β signaling pathway plays a central but paradoxical role in the predisposition and progression of colorectal cancer. TGF-β is a potent inhibitor of normal colonic epithelial cells acting as a tumor suppressor. However, TGF-β promotes the survival, invasion and metastasis of colorectal cancer cells, thereby acting as an oncogene. Understanding how selective alterations of the TGF-β 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.

Journal Article.  4497 words.  Illustrated.

Subjects: Genetics and Genomics

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