T beta R-I(6A) is a candidate tumor susceptibility allele

We have previously described a type I transforming growth factor (TGF)-beta receptor (T beta R-I) polymorphic allele, T beta R-I(6A), that has a delet ion of three alanines from a nine-alanine stretch. We observed a higher tha n expected number of T beta R-I(6A) homozygotes among tumor and nontumor DN A from patients with a diagnosis of cancer. To test the hypothesis that T b eta R-I(6A) homozygosity is associated with cancer, we performed a case-cen tral study in patients with a diagnosis of cancer and matched healthy indiv iduals with no history of cancer and who were identical in their gender and their geographical and ethnic background to determine the relative germ-li ne frequencies of this allele. We round nine T beta R-I(6A) homozygotes amo ng 851 patients with canter. In comparison, there were no T beta R-I(6A) ho mozygotes among 735 healthy volunteers (P < 0.01). We also observed an exce ss of T beta R-E(6A) heterozygotes in cancer cases compared to controls (14 .6% versus 10.6%; P = 0.02, Fisher's exact test). A subset analysis reveale d that 4 of 112 patients with colorectal cancer were T beta R-I(6A) homozyg otes (P < 0.01). Using mink lung epithelial cell lines devoid of T beta R-I , we established stably transfected T beta R-I and T beta R-I(6A) cell line s. We found that, compared to T beta R-I, T beta R-I(6A) was impaired as a mediator of TGF-beta antiproliferative signals, We conclude that T beta R-I (6A) acts as a tumor susceptibility allele that may contribute to the devel opment of cancer, especially colon cancer, by means of reduced TGF-beta-med iated growth inhibition.