TbetaR-I(6A) is a candidate tumor susceptibility allele.
We have previously described a type I transforming growth factor (TGF)-beta receptor (TbetaR-I) polymorphic allele, TbetaR-I(6A), that has a deletion of three alanines from a nine-alanine stretch. We observed a higher than expected number of TbetaR-I(6A) homozygotes among tumor and nontumor DNA from patients with a diagnosis of cancer. To test the hypothesis that TbetaR-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 TbetaR-I(6A) homozygotes among 851 patients with cancer. In comparison, there were no TbetaR-I(6A) homozygotes among 735 healthy volunteers (P < 0.01). We also observed an excess of TbetaR-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 TbetaR-I(6A) homozygotes (P < 0.01). Using mink lung epithelial cell lines devoid of TbetaR-I, we established stably transfected TbetaR-I and TbetaR-I(6A) cell lines. We found that, compared to TbetaR-I, TbetaR-I(6A) was impaired as a mediator of TGF-beta antiproliferative signals. We conclude that TbetaR-I(6A) acts as a tumor susceptibility allele that may contribute to the development of cancer, especially colon cancer, by means of reduced TGF-beta-mediated growth inhibition.
Pasche
B
B
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Kolachana
P
P
Nafa
K
K
Satagopan
J
J
Chen
Y G
YG
Lo
R S
RS
Brener
D
D
Yang
D
D
Kirstein
L
L
Oddoux
C
C
Ostrer
H
H
Vineis
P
P
Varesco
L
L
Jhanwar
S
S
Luzzatto
L
L
Massagué
J
J
Offit
K
K
D030201:Activin Receptors, Type I; D000483:Alleles; D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000208:ethnology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D018237:Germinoma / Q000208:ethnology / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000208:ethnology / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000208:ethnology / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I