Transforming Growth Factor (cid:1) Receptor 1 Polyalanine Polymorphism and Exon 5 Mutation Analysis in Breast and Ovarian Cancer

The inactivation or altered expression of TGF- (cid:1) receptors or other components of the TGF- (cid:1) signaling pathway are common in many cancer types. A germ-line sequence variant of transforming growth factor- (cid:1) receptor-1 ( T (cid:1) R-I ), which involves the deletion of three alanines (6A) from a nine-alanine stretch (9A), has impaired mediation of TGF- (cid:1) antiproliferative signaling. The T (cid:1) R-I (6A) variant has been reported to occur at an increased frequency in a variety of cancer types and may represent an important hereditary predisposing factor. We have investigated the possible influence of the T (cid:1) R-I (6A) allele on cancer risk in a cases-control study of 248 controls; 304 women with ovarian cancer; 98 women with endometriosis; and 355 women with breast cancer occurring under the age of 40 years, bilateral breast cancer, or a family history of breast cancer. The T (cid:1) R-I (6A) allele was significantly associated with breast cancer (odds ratio, 1.6; 95% confidence interval, 1.1–2.5). There was no significant association of this allele with ovarian cancers as a whole, although stratifying according to their histological subtype revealed a significant association with the endometrioid and clear-cell cancers (odds ratio, 2.1; 95% confidence interval, 1.2–3.6). Recently a recurrent somatic CTCTGG 3 CTGCGTGG insertion mutation in exon 5 of T (cid:1) R-I was reported in (cid:1) 30% of ovarian cancers. If verified, this would indicate that inactivation of T (cid:1) R-I is a key step in the development of ovarian cancer, perhaps second only to the inactivation of TP53 . We analyzed 55 ovarian and 33 breast cancers for mutations using both single-stranded conformational polymorphism/heteroduplex analysis and direct sequencing. No somatic mutations in exon 5 of T (cid:1) R-I were detected in any case. Our study provides additional evidence for an association of the T (cid:1) R-I (6A) allele with cancer predisposition, but we find no evidence of a mutational hot-spot in exon 5 of T (cid:1) R-I in either ovarian or breast cancers.