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Evidence of Selection for Clones Having Genetic Inactivation of the Activin A Type II Receptor (ACVR2) Gene in Gastrointestinal Cancers¹

Departments of Oncology [P. M. H., L. Z., R. K. B., B. V., R. H. H., S. E. K.], Pathology [C. A. I-D., K. M. M., A. M., R. H. H., S. E. K.], and Surgery [C. J. Y.], The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232 [R. H. W.]; Ireland Cancer Center, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio 44106 [S. D. M., J. K. V. W.]; and Howard Hughes Medical Institutes, Chevy Chase, Maryland 20815 [B. V., S. D. M.]

The activin signaling pathway parallels the transforming growth factor (TGF)-ß pathway. Both use extracellular ligands and cell surface receptors that are structurally and functionally related, as well as the same intracellular mediators (SMADs 2–4) to transmit these signals. Members of both pathways have been characterized previously as tumor suppressor genes on the demonstration of inactivating mutations in human neoplasms, e.g., genetic inactivation of the activin type I receptor was reported recently in pancreatic cancer. Here, we present evidence of selection for mutations of the activin A type II receptor (ACVR2) gene during human gastrointestinal carcinogenesis. Two 8-bp polyadenine tracts of the ACVR2 gene are targets for inactivating frameshift mutations in gastrointestinal neoplasms having microsatellite instability (MSI). These mutations are similar to those of the 10-bp polyadenine tract within the TGF-ß type II receptor (TGFBR2), a well-characterized target of frameshift mutations in the same neoplasms. We identified biallelic mutations of ACVR2 in 25 of 28 MSI colorectal and pancreatic cancers. In addition, a mutation in the ACVR2 gene combined with loss of the wild-type allele was found in a non-MSI pancreatic cancer. This evidence is compatible with a high degree of selection for inactivation of the ACVR2 gene in tumorigenesis, supporting ACVR2 as a candidate tumor suppressor gene in gastrointestinal cancers.

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