{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T18:20:41Z","timestamp":1791051641131,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2003,3,5]],"date-time":"2003-03-05T00:00:00Z","timestamp":1046822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"De Drie Lichten Foundation"},{"name":"Jan Dekker and Dr. Ludgardine Bouwman Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2003,6,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The Von Hippel\u2010Lindau <jats:italic>(VHL)<\/jats:italic> gene product has a wide spectrum of tissue\u2010specific functions, and specific germline mutations are associated with clinical phenotypes in VHL disease. In particular, missense mutations are correlated with the susceptibility to pheochromocytomas. An association between <jats:italic>VHL<\/jats:italic> aberrations and prognosis has been suggested in renal clear cell carcinoma but has not been studied in pheochromocytomas. We studied the frequency and spectrum of <jats:italic>VHL<\/jats:italic> alterations in apparently sporadic pheochromocytomas in relation to the clinical behavior in 72 patients, including 48 patients with clinically benign and 24 patients with malignant pheochromocytomas. Single\u2010strand conformation polymorphism (SSCP) analysis followed by DNA sequencing, loss of heterozygosity analysis of the <jats:italic>VHL<\/jats:italic> locus and immunohistochemistry for VHL protein expression were used to investigate somatic <jats:italic>VHL<\/jats:italic> gene alterations. In 2 patients, 1 with a malignant tumor, germline mutations were identified in the stop codon. Tumor\u2010specific intragenic <jats:italic>VHL<\/jats:italic> mutations and accompanying loss of heterozygosity were identified in 2 (4.3%) of 47 sporadic benign pheochromocytomas compared to 4 (17.4%) of 23 malignant tumors (<jats:italic>p<\/jats:italic> = 0.064). Only one of these mutations has been previously described, in a renal clear cell carcinoma. Expression of the VHL protein was observed in all pheochromocytomas. No distinction in the nature of <jats:italic>VHL<\/jats:italic> alterations between benign and malignant pheochromocytomas and no correlation with histopathologic or clinical features was observed. We report novel <jats:italic>VHL<\/jats:italic> mutations in sporadic pheochromocytomas, which are slightly correlated with malignancy. <jats:italic>VHL<\/jats:italic> mutations may have some impact on the malignant transformation of pheochromocytomas. \u00a9 2003 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.11060","type":"journal-article","created":{"date-parts":[[2003,4,2]],"date-time":"2003-04-02T17:37:48Z","timestamp":1049305068000},"page":"190-195","source":"Crossref","is-referenced-by-count":32,"title":["Von Hippel\u2010Lindau gene alterations in sporadic benign and malignant pheochromocytomas"],"prefix":"10.1002","volume":"105","author":[{"given":"Hilde","family":"Dannenberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald R.","family":"De Krijger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwin","family":"van der 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