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Genetic Alterations of the Transforming Growth Factor ß Receptor Genes in Pancreatic and Biliary Adenocarcinomas¹

Departments of Oncology [M. G., C. J. Y., R. H. H., S. E. K.], Pathology [M. S., K. T., R. H. H., S. E. K.], and Surgery [C. J. Y.], Johns Hopkins Medical Institutions, Baltimore, Maryland 21205

Transforming growth factor ß (TGF-ß) is an extracellular ligand that binds to a heterodimeric receptor, initiating signals that regulate growth, differentiation, and apoptosis. Many cancers, including pancreatic cancer, harbor defects in TGF-ß signaling and are resistant to TGF-ß-mediated growth suppression. Genetic alterations of DPC4, which encodes a DNA binding protein that is a downstream component of the pathway, most frequently occur in pancreatic and biliary carcinomas. We searched for other targets of mutation of the TGF-ß pathway in these cancers. We report somatic alterations of the TGF-ß type I receptor gene ALK-5. Homozygous deletions of ALK-5 were identified in 1 of 97 pancreatic and 1 of 12 biliary adenocarcinomas. A germ-line variant of ALK-5, presumably a polymorphism, was identified, but no somatic intragenic mutations were identified upon sequencing of all coding regions of ALK-5. Somatic alterations of the TGF-ß type II receptor gene (TGFBR2) were identified in 4 of 97 (4.1%) pancreas cancers, including a homozygous deletion in a replication error-negative cancer and three homozygous frameshift mutations of the poly(A) tract of the TGF-ß type II receptor in replication error-positive cancers. We also studied other related type I receptors of the TGF-ß superfamily. In a panel of pancreas cancers preselected for loss of heterozygosity at the ALK-1 locus, sequencing of all coding exons of the ALK-1 gene revealed no alterations. No homozygous deletions were detected in the ALK-1, ALK-2, ALK-3, or ALK-6 genes in a panel of 86 pancreatic cancer xenografts and 11 pancreatic cancer and 22 breast cancer cell lines. The rate of genetic inactivation of TGF-ß pathway members was determined in 45 pancreatic cancers. Eighty-two % of these pancreatic cancers had genetic inactivation of the DPC4, p15, ALK-5, or TGFBR2 genes. Our results indicate that the TGF-ß type I and type II receptor genes are selective targets of genetic inactivation in pancreatic and biliary cancers.

¹ This work was supported by NIH Grant CA68228.

² To whom requests for reprints should be addressed, at Department of Oncology, 628 Ross Building, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205-2196. Phone: (410) 614-3316; Fax: (410) 614-0671; E-mail: sk@welchlink.welch.jhu.edu.

Received 9/ 4/98. Accepted 10/20/98.

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