THE RELATIVELY HIGH-FREQUENCY OF P53 GENE-MUTATIONS IN MULTIPLE AND MALIGNANT PHEOCHROMOCYTOMAS

To explore the clinical significance of p53 in the pathogenesis of adr enal neoplasms, we investigated the incidence of p53 gene mutations in functioning human adrenal tumours using the polymerase chain reaction -single strand conformation polymorphism (PCR-SSCP) technique to scree n p53 exons 4 to 9. We examined 29 adrenocortical adenomas (primary al dosteronism, n=17; Gushing's syndrome, n=12, all benign), and 33 phaeo chromocytomas (benign solitary, n=18; benign multiple, n=5; malignant, n=10) in Japanese and Chinese patients. PCR-SSCP did not show any abn ormal band-shifts in any of the adrenocortical adenoma and benign soli tary phaeochromocytoma tissues. In contrast, six phaeochromocytoma tis sues (two cases benign multiple, four cases malignant) showed PCR-SSCP band-shifts. Subsequent DNA sequencing analysis of the shifted bands revealed six cases with nine mutations or intronic sequence alteration s: three cases contained sequence alterations within intronic regions, three cases with silent mutation (sequence alteration in codon withou t amino acid alteration), and three cases contained missense mutations (one case each in exons 5, 6 and 9). Immunohistochemical staining dem onstrated that two of three cases with missense mutations and one case with an intronic sequence alteration over-expressed p53 protein in tu mour cell. nuclei. We observed no association between p53 gene mutatio n and p21/WAF1/Cip-1 expression. The relatively high incidence of p53 gene mutations or intronic sequence alteration in multiple and maligna nt phaeochromocytomas, but not in benign solitary cases, suggests that p53 mutation could play some role in the pathogenesis of multiple and /or malignant phaeochromocytomas.