Molecular mechanisms of tumor development in hyperparathyroidism

Abstract

Loss of heterozygosity (LOH) analysis and comparative genomic hybridization (CGH) were used in an attempt to identify recurrent chromosomal alterations in different types of parathyroid tumors. These included familial and sporadic, benign and malignant, as well as primary, irradiation associated and secondary tumors. Hitherto unidentified tumor suppressor genes were implicated on chromosomes 1p, 6q, 9p, 11p, 11q, 13q, 15q, 18q and X, as well as a putative oncogene locus represented by a gain of DNA copy number on chromosome 19 (Papers I and V).

Since many genes responsible for familial cancer syndromes also are mutated in their sporadic counterparts, another approach was to search for deletions of chromosomal regions to which familial syndromes are mapped. The 11q13 region, which harbors the multiple endocrine neoplasia type 1 (MEN 1) tumor suppressor gene, is deleted in the majority of parathyroid tumors from MEN 1 patients. Similarly, a third of tumors from patients with sporadic primary HPT showed LOH at 11q13 (Papers 1 and II) and in half of these cases a somatic MEN1 mutation could be demonstrated (Paper II). The sporadic adenomas with MEN1 involvement also displayed a significantly higher number of CGH aberrations as compared with the non-MEN1 associated group (p< 0.05) (Paper V). The genetic profile obtained for the radiation associated adenomas closely resembled that of the ordinary adenomas with involvement of the MEN1 gene, i.e. multiple CGH alterations and frequent losses of 11q. Indeed, inactivating mutations of the MEN1 gene were identified in four of the eight irradiation associated tumors analyzed (Paper V).

Changes in the calcium receptor (CaR) have been proposed to be responsible for the increase in set-point of parathyroid hormone secretion seen in primary HPT. The level of CaR mRNA in the adenomas was in the range of 41-98 % (median of 64 %) of the expression level in the normal parathyroid tissue (Paper VI). The mRNA level was not found to correlate with serum calcium, parathyroid hormone or adenoma weight. It seems likely that the reduced levels of receptor mRNAs and protein is a secondary phenomenon, rather than a primary event.

Two families with HPT-JT syndrome were investigated and in both families renal hamartomas or cystic kidney disease were prominent associated features, possibly representing a new phenotypic variant of the HPT-JT syndrome. A sex dependent penetrance of HPT was seen, resulting in mainly male affected cases (Paper III). Three large previously unreported FIHP families in whom the disease was linked to the chromosome 1q21-q32 region were analyzed and two of these families were considered to be true FIHP families, i.e. there was no evidence of jaw or renal lesions despite careful radiological investigations. In the third family, a parathyroid cancer and two cases of polycystic kidney disease were found and that family was therefore considered as being affected by the classical HPT-JT syndrome. The same sex-dependent penetrance of HPT was seen in the FIHP families as in the HPT-JT families reported in paper III. LOH analysis showed loss in the l q region of the wild type allele in the renal hamartomas and in some of the parathyroid tumors, including the parathyroid cancer, suggesting that this gene is a tumor suppressor gene.

Parathyroid cancer is a rare cause of primary HPT. Nevertheless this group creates diagnostic and therapeutic problems, since in the absence of invasion of adjacent organs or structures and/or metastases, the diagnosis of parathyroid cancer cannot be definitely established based on histopathology. The expression of Ki-67, RB and Gelatinase A were investigated as possible tumor markers in parathyroid cancers. However, none of these markers was suitable for reliable differentiation between benign and malignant parathyroid tumors (Papers VII and VIII).