Study Demonstrates How Gene Variant May Contribute To Cancer Development

Transforming growth factor beta (TGF-beta) is a potent naturallyoccurring inhibitor of cell growth, according to background informationin the article. It exerts its action by binding to type I (TGFBR1) andtype II (TGFBR2) receptors located on the cell membrane. Increased cellgrowth due to decreased TGF-beta growth inhibition may contribute tocancer development. TGFBR1*6A is a common polymorphism (variation) ofTGFBR1. Previous studies have shown that TGFBR1*6A is one of the firstcandidate tumor susceptibility alleles (DNA codings of the same gene)that is found in a large proportion of the general population (13.7percent) and significantly increases cancer risk by approximately 24percent. How TGFBR1*6A contributes to cancer development is largelyunknown.

Boris Pasche, M.D., Ph.D., of Northwestern University Feinberg Schoolof Medicine, Chicago, and colleagues conducted a study that included531 patients with a diagnosis of head and neck cancer, colorectalcancer, or breast cancer recruited from 3 centers in the United Statesand 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. wassomatically acquired, in 13 of 44 (29.5 percent) colorectal cancermetastases, 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 104patients with breast cancer.

While TGF-beta inhibits the growth of normal cells, cancer cellssecrete larger amounts of TGF-beta than their normal counterparts. Theresearchers showed that, in the presence of TGF-beta, the growth ofcancer cells that carry the TGFBR1*6A gene is 55 percent greater thancancer cells that do not carry this gene, indicating that TGFBR1*6Agive cancer cells a selective advantage. This, together with thefindings that TGFBR1*6A is acquired by tumors, may explain why half ofall liver metastases from colorectal cancer carried the TGFBR1*6A genewhile it is only found in 14 percent of the general population.

"... individuals who carry the *6A allele, either in thegermline or somatically acquired by the tumor, may have a greaterlikelihood of developing metastases than individuals who do not carrythis allele. *6A may therefore serve as a useful biomarker in cancer."The authors add that TGFBR1*6A may bestow cancer cells with a growthadvantage in the presence of TGF-beta.

"Since 13.7 percent of the general population and 17.1 percent ofpatients with a diagnosis of cancer carry at least 1 copy of the *6Aallele, our findings may have substantial public health importance. Thehigh frequency of *6A carriers in the general population and themoderately increased risk of breast, colon, and ovarian cancer that itconfers implies that the dominant effects of *6A have an incompletepenetrance. Additional studies are needed to determine whichenvironmental and genetic factors may modify the penetrance of *6A inthese tumor types," the researchers write.

"The results highlight a new facet of TGF-beta signaling in cancer andsuggest that TGFBR1*6A may represent a potential therapeutic target incancer."