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Pheochromocytomas and abdominal paragangliomas are rare catecholamine-producing tumours arising from neural crest derived chromaffin cells. Histopathological distinction of malignant tumors from their benign counterparts is notoriously difficult; therefore search for novel biomarkers capable of indicating malignant b ehaviour is warranted. The p16 tumor suppressor gene is often inactivated in a wide variety of primary human neoplasias including tumors of ectodermal origin. P16 is one of the most commonly hypermethylated tumor suppressor genes. Several lines of indirect evidence suggest the involvment of p16 in pheochromocytoma genesis. We have assessed the occurrence of p16 promoter methylation in a series of human pheochromocytomas/abdominal paragangliomas. Materials and Methods: Genomic DNA from a panel of 45 pheochromocytomas and 15 abdominal paragangliomas (47 benign, 13 malignant, 58 primary, 2 metastases) was assessed for CpG methylation in the p16 promoter utilizing Methylation Specific PCR (MSP) after bisulphite treatment. Malignant status was established by the presence of distant metastases or extensive local invasion at the time of diagnosis or during follow up. Results: 6 out of 60 tumors were found to be methylated. Interestingly all methylated tumors were malignant. In two cases both primary tumor and its distant metastasis were methylated. No methylation was detected in normal adrenal medullary controls. Conclusions: promoter methylation in the p16 gene occurs in about 10 % of human pheochromocytomas/ abdominal paragangliomas and is strongly associated with malignant behaviour (P≤0.05).

[Proc Amer Assoc Cancer Res, Volume 46, 2005]