TGFBR1*6A may represent a potential therapeutic target in 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.
Transforming growth factor beta ( TGF-beta ) is a potent naturally occurring inhibitor of cell growth.
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. TGFBR1*6A is a common polymorphism of TGFBR1.
Previous studies have shown that TGFBR1*6A is one of the first candidate tumor susceptibility alleles that is found in a large proportion of the general population 13.7 percen) and significantly increases cancer risk by approximately 24 percent.
How TGFBR1*6A contributes to cancer development is largely unknown.
Boris Pasche, 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 TGFBR1*6A, 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 TGFBR1*6A gene is 55 percent greater than cancer cells that do not carry this gene, indicating that TGFBR1*6A give cancer cells a selective advantage.
This, together with the findings that TGFBR1*6A is acquired by tumors, may explain why half of all liver metastases from colorectal cancer carried the TGFBR1*6A 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 TGFBR1*6A 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.
Source: American Medical Association, 2005