AMPLIFICATION OF THE PARATHYROID HORMONE-RELATED PEPTIDE GENE IN A COLONIC-CARCINOMA

PTH-related peptide (PTHrP) is the major factor responsible for humora l hypercalcemia of malignancy. This paraneoplastic syndrome has been d escribed in association with a number of malignancies, but rarely with carcinoma of the colon. Moreover, little is known about the molecular mechanisms that underlie PTHrP overexpression in tumors. Here we repo rt a patient who presented with hypercalcemia 6 months after resection of a neuroendocrine colonic carcinoma (tumor I). At the time of admis sion, intact PTH was decreased, circulating PTHrP levels were elevated , and there was tumor recurrence (tumor II). Immunohistochemical stain ing of paraffin-embedded sections from tumor I did not stain for PTHrP , whereas cells from tumor II stained intensely positive. Southern blo t analysis and differential PCR of genomic DNAs from tumor specimens a nd the patient's leukocytes demonstrated amplification of the PTHrP ge ne in tumor II. Moreover, staining for p53 protein was evident in tumo r II, but not in tumor I, consistent with the presence of a mutant for m of p53 and associated loss of tumor suppressor function in the recur rent tumor. PTHrP gene amplification was also detected in one of five other tumors associated with humoral hypercalcemia of malignancy. Thes e findings suggest that a potential mechanism contributing to PTHrP ov erexpression in malignancies is gene amplification, which could arise from increased genomic instability associated with the progressive sta ges of neoplasia.