Increased upstream methylation has no influence on the overexpression of the parathyroid hormone-related protein gene in squamous cell carcinoma of the lung

Humoral hypercalcaemia of malignancy (HHM) commonly results from the excess ive production of a parathyroid hormone-related protein (PTHrP) by tumours. We have previously shown malignancy is associated with increased DNA methy lation in the 5' region of the: PTHrP gene. In a series of patients with lu ng carcinoma and relatively high serum calcium levels: 3 patients showed su bstantially increased PTHrP gene methylation while 5 patients showed no cha nge in methylation status in this region. Patients showed marked tumour-spe cific expression of PTHrP through the P1 and P3 promoters with more general tumour and non-tumour expression through the P2 promoter. The lack of pote ntial key regulatory CpG sites in the PI promoter and the complete demethyl ation in the P2 and P3 promoters suggests methylation does not influence tu mour-specific expression of PTHrP. Although demethylation may be a prerequi site for P2 and P3 expression, the overexpression of the PTHrP gene in canc er cells must be mediated through mechanisms other than DNA methylation. (C ) 2000 Elsevier Science Ltd, All rights reserved.