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Editorial |
Endocrine Signaling and Oncogenesis Section, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1752
Address all correspondence and requests for reprints to: William F. Simonds, M.D., Metabolic Diseases Branch/National Institute of Diabetes and Digestive and Kidney Diseases, Building 10, Room 8C-101, MSC 1752, Bethesda, Maryland 20892-1752. E-mail: wfs{at}helix.nih.gov.
Endocrinologists, oncologists, and other clinicians benefit from molecular diagnostic testing of tumors if such analysis leads to improved prognostication and/or therapy. In the most favorable circumstances, the identification of key signaling intermediaries essential to the process of neoplastic transformation promotes the development of molecular therapeutics with superior efficacy and specificity. This promise is bearing fruit with the success of new drugs like imatinib (Gleevec) and erlotinib (Tarceva) that inhibit specific tyrosine kinases important in the pathophysiology of chronic myelogenous leukemia and in non-small cell lung cancer, respectively. The molecular diagnosis and identification of key signaling abnormalities in endocrine tumors is similarly important, although such tumors are typically less life threatening than nonendocrine neoplasms.
In molecular detective work, the tortuous process leading to the definitive identification of molecules and pathways critical for tumor formation necessarily involves the exclusion of candidate genes along the way. During the investigation of endocrine neoplasms, it is essential to rule out such molecular "suspects," especially molecules with known associations to neoplasia other contexts. One target of the Wnt pathway, ß-catenin, encoded by the CTNNB1 gene, was an excellent "suspect" for parathyroid tumor formation that had already been firmly implicated in endometrioid ovarian carcinoma, hepatoblastoma, and Wilms tumor. Indeed, universal dysregulation of ß-catenin in a series of 37 parathyroid adenomas, including stabilizing missense mutation in a minority of tumors, was recently reported by a group in Sweden (1). This dramatic finding was contrary, however, to two previous reports from Japan that had failed to identify CTNNB1 mutation in a series of benign parathyroid tumors (2, 3). Against this background and employing more than twice the number of tumors studied by the Swedish group, the paper by Costa-Guda and Arnold (4) in this issue makes a major contribution to our understanding of the process of parathyroid neoplasia with the strong exclusion of CTNNB1 mutation in the pathogenesis of most parathyroid adenomas, the most common cause of primary hyperparathyroidism.
Wnt signaling involving ß-catenin as a critical central component represents a highly evolutionarily conserved set of pathways that regulates cellular growth and differentiation in most tissues (5). Binding of a Wnt ligand to a plasma membrane receptor initiates the Wnt signaling pathway. In the canonical pathway, Wnt signal inhibits the degradation of ß-catenin that, when so stabilized, translocates to the nucleus where it coactivates Wnt target genes in conjunction with the lymphoid enhancer factor/T cell factor family of transcription factors (6). One Wnt target gene is cyclin D1, a key regulatory protein in control of the cell cycle that was first identified in parathyroid tumors as the PRAD1 oncogene (7) and was subsequently implicated in the pathogenesis of nonendocrine malignancies, including breast cancer (8) and mantle cell lymphoma (9). Another potential connection between the Wnt pathway and parathyroid neoplasia is the recent discovery that parafibromin, the product of the HRPT2 tumor suppressor gene implicated in the hyperparathyroidism-jaw tumor familial cancer syndrome as well as sporadic parathyroid cancer, binds directly to ß-catenin and is necessary for the nuclear transduction of the Wnt signal (10).
Mutation or dysregulation of many individual components of the Wnt signaling pathway often promotes neoplastic transformation (11). The product of the adenomatous polyposis coli (APC) gene, for example, plays a key role in the degradation of ß-catenin as a key component of a ß-catenin destruction complex. APC was first identified as a tumor suppressor gene, whose germline loss of function mutation predisposes to colorectal cancer in the familial adenomatous polyposis hereditary cancer syndrome, and has been subsequently implicated in the majority of sporadic colorectal cancers. Mutational inactivation of APC impairs the function of the ß-catenin destruction complex, resulting in the stabilization, accumulation, and nuclear translocation of ß-catenin and constitutive activation of Wnt target genes (11, 12). Another component of the ß-catenin destruction complex is glycogen synthase kinase-3ß (GSK3), a serine/threonine kinase that marks ß-catenin for degradation by phosphorylation in a region of the protein encoded by exon 3 of CTNNB1. In a subset of ovarian, gastric, hepatoblastoma, and other cancers, exon 3 of CTNNB1 has been identified as a mutational hot spot. This is presumably because missense mutation and interstitial deletion of residues in this portion of ß-catenin abrogate GSK binding and phosphorylation, resulting in the aberrant stabilization of ß-catenin. Indeed, it was identical homozygous missense mutations of residue serine 37 in this CTNNB1 exon 3 region, a target of GSK3 phosphorylation, that were recently reported in 15% (3 of 20) of parathyroid adenomas by the Swedish group (1).
Besides the stabilizing missense mutations reported by Björklund et al. (1), the authors found immunohistochemical evidence of ß-catenin overexpression and accumulation in the cytosol and nucleus in the entire series of 37 parathyroid adenomas as well as in 10 hyperplastic parathyroid glands excised from patients with renal failure, compared with control parathyroid tissue. Using a monoclonal antibody to the nonphosphorylated form of ß-catenin, these authors were able to document that the parathyroid tumors, but not normal parathyroid glands, were accumulating the transcriptionally active form of ß-catenin (1). It is worth noting that the stabilization and accumulation of ß-catenin in the absence of CTNNB1 mutation in tumors may well reflect secondary or late events in tumorigenesis that cause the indirect activation of the Wnt signaling pathway. Two earlier studies by groups in Japan, examining the mutation status of CTNNB1 exon 3 and immunohistochemistry of ß-catenin in parathyroid adenomas, found no CTNNB1 mutations or evidence of ß-catenin accumulation but employed smaller series of 12 (2) and 24 (3) tumors.
The power of the study by Costa-Guda and Arnold (4) in this issue derives from the large number of well-characterized parathyroid adenomas employed; they sequenced the CTNNB1 exon 3 region in DNA extracted from 97 sporadic benign parathyroid tumors and found no mutations. These results, taken together with the two earlier negative studies from Japan, document no DNA mutations in the ß-catenin gene hot spot in 133 parathyroid adenomas. A fair-minded observer, weighing these negative data in 133 tumors against the positive mutational results of Björklund et al. (1) in three of 20 tumors, must conclude that CTNNB1 mutation is an extremely rare event in benign parathyroid neoplasia. The differences between the findings of the American and Japanese investigations vs. the Swedish study are unclear. A larger unanswered question is the reason for the striking tumor specificity resulting from mutation of widely expressed proteins such as ß-catenin. The findings of Costa-Guda and Arnold (4) in no way exculpate other components in the Wnt signaling pathway from a possible role in parathyroid tumorigenesis, but despite its strong implication in ovarian, gastric, hepatoblastoma, and other cancers, ß-catenin must be ruled out as a "suspect" in the initiation or neoplastic progression of the typical parathyroid adenoma.
Footnotes
This work was supported by the intramural division of the National Institute of Diabetes and Digestive and Kidney Diseases.
Abbreviations: APC, Adenomatous polyposis coli; GSK3, glycogen synthase kinase-3ß.
Received February 9, 2007.
Accepted February 14, 2007.
References
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