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R-I(6A) Is a Candidate Tumor Susceptibility Allele1
Cell Biology Program [B. P., Y-G. C., R. S .L., L. K., J. M.], Department of Human Genetics [P. K., K. N., D. B., D. Y., S. J., L. L., K. O.], and Department of Epidemiology and Biostatistics [J. S.], Memorial Sloan-Kettering Cancer Center, New York, New York; Human Genetics Program, Department of Pediatrics, New York University Medical Center, New York, New York [C. O., H. O.]; Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021 [J. M.]; Unit of Cancer Epidemiology, Dipartimento di Scienze Biomediche e Oncologia Umana, Università di Torino e CPO-Piemonte, 10126 Torino, Italy [P. V.]; and Experimental Oncology Laboratory, National Cancer Institute, 16132 Genova, Italy [L. V.]
We have previously described a type I transforming growth factor (TGF)-
receptor (TR-I) polymorphic allele, TR-I(6A), that has a deletion of three alanines from a nine-alanine stretch. We observed a higher than expected number of TR-I(6A) homozygotes among tumor and nontumor DNA from patients with a diagnosis of cancer. To test the hypothesis that TR-I(6A) homozygosity is associated with cancer, we performed a case-control study in patients with a diagnosis of cancer and matched healthy individuals with no history of cancer and who were identical in their gender and their geographical and ethnic background to determine the relative germ-line frequencies of this allele. We found nine T R-I(6A) homozygotes among 851 patients with cancer. In comparison, there were no TR-I(6A) homozygotes among 735 healthy volunteers (P < 0.01). We also observed an excess of TR-I(6A) heterozygotes in cancer cases compared to controls (14.6% versus 10.6%; P = 0.02, Fisher’s exact test). A subset analysis revealed that 4 of 112 patients with colorectal cancer were TR-I(6A) homozygotes (P < 0.01). Using mink lung epithelial cell lines devoid of TR-I, we established stably transfected TR-I and TR-I(6A) cell lines. We found that, compared to TR-I, TR-I(6A) was impaired as a mediator of TGF- antiproliferative signals. We conclude that T R-I(6A) acts as a tumor susceptibility allele that may contribute to the development of cancer, especially colon cancer, by means of reduced TGF--mediated growth inhibition.
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