Common cancer susceptibility gene appears to be frequently acquired in metastatic lesions from colorectal cancer

A relatively common cancer susceptibility gene appears to be frequently acquired in metastatic lesions from colorectal cancer, and give cancer cells a growth advantage, according to a study in the October 5 issue of JAMA: The Journal of the American Medical Association.

Transforming growth factor beta (TGF-beta) is a potent naturally occurring inhibitor of cell growth, according to background information in the article. It exerts its action by binding to type I (TGFBR1) and type II (TGFBR2) receptors located on the cell membrane. Increased cell growth due to decreased TGF-beta growth inhibition may contribute to cancer development. TGFBR16A is a common polymorphism (variation) of TGFBR1. Previous studies have shown that TGFBR16A is one of the first candidate tumor susceptibility alleles (DNA codings of the same gene) that is found in a large proportion of the general population (13.7 percent) and significantly increases cancer risk by approximately 24 percent. How TGFBR16A contributes to cancer development is largely unknown.

Boris Pasche, M.D., Ph.D., of Northwestern University Feinberg School of Medicine, Chicago, and colleagues conducted a study that included 531 patients with a diagnosis of head and neck cancer, colorectal cancer, or breast cancer recruited from 3 centers in the United States and from 1 center in Spain from June 1, 1994, through June 30, 2004. Multiple genetic testing of the cancer cells was conducted.

The researchers found that TGFBR1 mutated into TGFBR16A, i.e. was somatically acquired, in 13 of 44 (29.5 percent) colorectal cancer metastases, in 4 of 157 (2.5 percent) of colorectal tumors, in 4 of 226 (1.8 percent) head and neck primary tumors, and in none of the 104 patients with breast cancer.

While TGF-beta inhibits the growth of normal cells, cancer cells secrete larger amounts of TGF-beta than their normal counterparts. The researchers showed that, in the presence of TGF-beta, the growth of cancer cells that carry the TGFBR16A gene is 55 percent greater than cancer cells that do not carry this gene, indicating that TGFBR16A give cancer cells a selective advantage. This, together with the findings that TGFBR16A is acquired by tumors, may explain why half of all liver metastases from colorectal cancer carried the TGFBR16A gene while it is only found in 14 percent of the general population.

"… individuals who carry the 6A allele, either in the germline or somatically acquired by the tumor, may have a greater likelihood of developing metastases than individuals who do not carry this allele. 6A may therefore serve as a useful biomarker in cancer." The authors add that TGFBR16A may bestow cancer cells with a growth advantage in the presence of TGF-beta.

"Since 13.7 percent of the general population and 17.1 percent of patients with a diagnosis of cancer carry at least 1 copy of the 6A allele, our findings may have substantial public health importance. The high frequency of 6A carriers in the general population and the moderately increased risk of breast, colon, and ovarian cancer that it confers implies that the dominant effects of 6A have an incomplete penetrance. Additional studies are needed to determine which environmental and genetic factors may modify the penetrance of 6A in these tumor types," the researchers write.

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