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Transforming Growth Factor ß Receptor 1 Polyalanine Polymorphism and Exon 5 Mutation Analysis in Breast and Ovarian Cancer

Cancer Genetics Laboratory, Victorian Breast Cancer Research Consortium, Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne, Victoria 3002, Australia [S. W. B., D. Y. H. C., I. G. C.]. Wessex Clinical Genetics Service, Princess Anne Hospital, Southhampton, SO16 5YA, United Kingdom [D. M. E.]

The inactivation or altered expression of TGF-ß receptors or other components of the TGF-ß signaling pathway are common in many cancer types. A germ-line sequence variant of transforming growth factor-ß receptor-1 (TßR-I), which involves the deletion of three alanines (6A) from a nine-alanine stretch (9A), has impaired mediation of TGF-ß antiproliferative signaling. The TßR-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 TßR-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 TßR-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 CTCTGGCTGCGTGG insertion mutation in exon 5 of TßR-I was reported in >30% of ovarian cancers. If verified, this would indicate that inactivation of TßR-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 TßR-I were detected in any case. Our study provides additional evidence for an association of the TßR-I (6A) allele with cancer predisposition, but we find no evidence of a mutational hot-spot in exon 5 of TßR-I in either ovarian or breast cancers.

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