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Type I Transforming Growth Factor ß Receptor Maps to 9q22 and Exhibits a Polymorphism and a Rare Variant within a Polyalanine Tract¹

Cell Biology Program [B. P., Y. L., P. H. R., J. M.], Department of Medicine [B. P., S. D. N., E. D., P. C.], Department of Human Genetics [L. L., K. O.], Department of Pathology [C. C.-C.], Department of Epidemiology and Biostatistics [J. M. S.], and Howard Hughes Medical Institute [J. M.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021; Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461 [B. R.]; and Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York 10021 [V. V. V. S. M.]

In a search for mutations of the type I transforming growth factor ß receptor (TßR-I), we mapped the gene to 9q22 and found a common polymorphism [TßR-I(6A)] and a rare variant [TßR-I(10A)] of TßR-I, causing an in-frame deletion of three alanines and an in-frame insertion of one alanine, respectively, in the receptor's extracellular domain. The biological relevance of the polymorphism TßR-I(6A) was investigated. When TßR-I(6A) was transiently transfected into TßR-I-deficient cells, the growth-inhibitory effects of transforming growth factor ß were restored. TßR-I(6A) and TßR-I(10A) frequency were assessed in 108 tumor samples and 80 nontumor samples from patients with a diagnosis of cancer, as well as in 118 normal blood donors of comparable ethnic composition. The frequency of TßR-I(6A) heterozygotes was fairly similar in normal blood donors (8%), in nontumor DNA of patients with a diagnosis of cancer (10%), and in tumor samples (14%). However, the frequency of TßR-I(6A) homozygotes among nontumor (4%) and tumor (8%) samples obtained from patients with a diagnosis of cancer was higher than that predicted by the Hardy-Weinberg law. The clinical and biological significance of TßR-I(6A) homozygosity needs to be further investigated.

¹ This work was supported by NIH Grants K12 CA01712-04 (to B. P.), CA34610 (to J. M.), DK43025 (to S. D. N.), and CA 54494 and CA 62275 (to E. D.); by the DeWitt Wallace Foundations (to S. D. N.); and by a Cancer Center Grant to Memorial Sloan-Kettering Cancer Center. J. M. is a Howard Hughes Medical Institute Investigator.

² To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, Box 116, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-8975; Fax: (212) 717-3298; E-mail: j-massague@ski.mskcc.org.

Received 4/ 9/98. Accepted 5/13/98.

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