SPORADIC PRIMARY HYPERPARATHYROIDISM: GENETIC ALTERATIONS BEHIND THIS PATHOLOGY AND CDKN1B GENE SCREENING

Alvelos M.^1,3, Barbosa E.², Teixeira Gomes M.², Soares P.^3,4

¹ Faculty of Science, University of Porto, Portugal, ²Biomedical Institute Abel Salazar, University of Porto, Portugal, ³1nstitute of Molecular Pathology and Immunology of University of Porto, Portugal, ⁴Department of Pathology, Medical Faculty, University of Porto, Portugal.

Primary hyperparathyroidism is a common endocrine disorder usually due to parathyroid adenoma (80-85%), hyperplasia (15-20%) or carcinoma (1 %). The majority ofPHPT cases are sporadic, nevertheless about 10% of the PHPT cases correspond to hereditary forms that include germ line mutations in MEN 1, RET or HRPT2 genes. Recently a germline mutation in CDKNI B gene has been identified in one patient clinically suspected of MEN1 (parathyroid and pituitary tumours) but without MEN 1 gene mutation.

The molecular mechanisms underlying the pathogenesis of sporadic PHPT are incompletely understood although somatic alterations in MEN 1 ,HRPT2 and Cyclin Dl(PRAD7) genes have already been reported. Cyclin 01 overexpression is found in about 20% – 40% of parathyroid adenomas.

In the present work, we aim to perform the genetic characterization of a series of apparently sporadic PHPT cases and to evaluate the prevalence of germ line and/or somatic CDKNI B mutations in PHPT patients.

Constitutional DNA samples were obtained from the apparently sporadic PHPT patients. Mutations in RET, CDKN1B and MENI genes were searched by PCR/SSCP and direct DNA sequencing. Analysis of Cyclin 01 expression was performed by immunohistochemistry in the tumour samples.

No case had an identified germline mutation in RET or CDKNI B genes, although polymorphic variants were observed. These results confirm that none of the cases in our series corresponds to hereditary forms of MEN2 or MEN1-like syndrome. In one case a MENI germline mutation was detected, showing that this patient harbors, in fact, a familial form of MEN1.

The Cyclin 01 immunohistochemistry study revealed that four of the 29 (14%) cases analyzed had nuclear staining in the tumor cells.

The absence of RET, CDKN1B and MENI genes mutations in all but one cases of our series, points to true sporadic forms of PHPT. CDKNI B gene alterations display a limited role, if any, in the etiopathogenesis of the disease. Moreover, an overexpression ofCyciin 01 was observed in 14% of the studied cases, raising the possibility of Cyclin Dl gene alterations in sporadic PHPT. Further studies are needed in order to fully characterize the molecular alterations underlying apparently sporadic PHPT.

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