Progression of uremic hyperparathyroidism involves allelic loss on chromosome 11.

Falchetti, Alberto; Bale, Allen E.; Amorosi, Andrea; Bordi, Cesare; Cicchi, P; Bandini, S.; Marx, StephenJ.; Brandi, Maria Luisa

doi:10.1210/jcem.76.1.8421078

Cited by 47 publications

(14 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These findings indicated that nodules in the hyperplastic parathyroids ofpatients with uremia consisted predominantly of cells with low levels of VDR, which are hyperactive in regard to proliferation. Moreover, recent reports have shown cellular monoclonalities in the secondary parathyroid hyperplasia of uremia (32,33). Of particular note, Falchetti et al suggest that, even in the same patient, the parathyroid glands show different clonalities, the glands with clonal abnormalities being larger than all the other glands.…”

Section: Discussionmentioning

confidence: 99%

Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients.

Fukuda¹,

Tanaka²,

Tominaga³

et al. 1993

J. Clin. Invest.

563

264

View full text Add to dashboard Cite

The resistance of parathyroid cells to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in uremic hyperparathyroidism is thought to be caused, in part, by a 1,25(OH)2D3 receptor (VDR) deficiency in the parathyroids. However, results of biochemical studies addressing VDR numbers in the parathyroids are controversial. Several studies have found VDR content to be decreased in the parathyroids of uremic patients and animals, while others have found no such decrease in the parathyroids of uremic animals.To clarify the role of VDR, we investigated VDR distribution in surgically-excised parathyroids obtained from chronic dialysis patients by immunohistochemistry. We classified the parathyroids as exhibiting nodular or diffuse hyperplasia. Our studies demonstrated a lower density of VDR in the parathyroids showing nodular hyperplasia than in those showing diffuse hyperplasia. Even in the parathyroids showing diffuse hyperplasia, nodule-forming areas were present; these areas were virtually negative for VDR staining. A significant negative correlation was found between VDR density and the weight of the parathyroids. These findings indicate that the conflicting results of biochemical studies may be caused by the heterogeneous distribution of VDR; the decreased VDR density in parathyroids may contribute to the progression of secondary hyperparathyroidism and to the proliferation of parathyroid cells that is seen in uremia. (J. Clin.

show abstract

Section: Discussionmentioning

confidence: 99%

Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients.

Fukuda¹,

Tanaka²,

Tominaga³

et al. 1993

J. Clin. Invest.

563

264

View full text Add to dashboard Cite

show abstract

“…Subgroups of parathyroid adenomas contain rearrangement of the PRADI /cyclin DI oncogene (34)(35)(36) or exhibit loss of a presumed tumor suppressor gene on llq13 (2) or Ip (37). While PRADI or Ip loci have not been assessed in parathyroid hyperplasia, Falchetti et al (5) found allelic loss of 1lq13 DNA markers, thereby demonstrating monoclonality, in only 2 of 12 uremic parathyroid glands. We found no examples of 1 1q13 allelic loss in 18 informative uremic glands, confirming that loss of a chromosome 11 tumor suppressor gene does not appear to be a common mechanism underlying what we show here to be the frequent development of monoclonal tumors in the setting of uremia.…”

Section: Dna Sample Preparationmentioning

confidence: 99%

Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia.

Arnold¹,

Brown²,

Ureña³

et al. 1995

J. Clin. Invest.

373

144

View full text Add to dashboard Cite

The pathogeneses of parathyroid disease in patients with uremia and nonfamilial primary parathyroid hyperplasia are poorly understood. Because of multigland involvement, it has been assumed that these common diseases predominantly involve polyclonal (non-neoplastic) cellular proliferations, but an overall assessment of their clonality has not been done. We examined the clonality of these hyperplastic parathyroid tumors using X-chromosome inactivation analysis with the M27,B (DXS255) DNA polymorphism and by searching for monoclonal allelic losses at M27f3 and at loci on chromosome band 11q13. Fully 7 of 11 informative hemodialysis patients (64%) with uremic refractory hyperparathyroidism harbored at least one monoclonal parathyroid tumor (with a minimum of 12 of their 19 available glands being monoclonal). Tumor monoclonality was demonstrable in 6 of 16 informative patients (38%) with primary parathyroid hyperplasia. Histopathologic categories of nodular versus generalized hyperplasia were not useful predictors of clonal status. These observations indicate that monoclonal parathyroid neoplasms are common in patients with uremic refractory hyperparathyroidism and also develop in a substantial group of patients with sporadic primary parathyroid hyperplasia, thereby changing our concept of the pathogenesis of these diseases. Neoplastic transformation of preexisting polyclonal hyperplasia, apparently due in large part to genes not yet implicated in parathyroid tumorigenesis and possibly including a novel X-chromosome tumor suppressor gene, is likely to play a central role in these disorders. (J. Clin. Invest. 1995. 95

show abstract

“…[18][19][20] 11q13, the MEN1 gene locus, is another spot where LOH has been demonstrated in uremic parathyroid hyperplasia. 10,11) Whether or not MEN1 gene abnormality plays a role in the tumorigenesis of uremic parathyroid hyperplasia has not been studied previously, so unraveling this issue was another purpose of our study. Neither LOH nor somatic mutation in the MEN1 gene was detected.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, a MEN1 gene abnormality may play a role in clonal emergence in uremic parathyroid hyperplasia. 10,11) In an attempt to elucidate whether uremic parathyroid hyperplasia is of monoclonal origin and how often monoclonal proliferation is associated with MEN1 gene abnormality, we examined this issue in uremic parathyroid hyperplasia.…”

mentioning

confidence: 99%

Clonal Emergence in Uremic Parathyroid Hyperplasia Is Not Related to MEN1 Gene Abnormality

Shan¹,

Nakamura²,

Murakami³

et al. 1999

Japanese Journal of Cancer Research

View full text Add to dashboard Cite

It is difficult to differentiate between parathyroid neoplasia and hyperplasia. In an attempt to elucidate the clonality of uremic parathyroid hyperplasia and the molecular genetic abnormalities accounting for clonal emergence, we analyzed 20 cases of uremic parathyroid hyperplasia. Clonalities were determined using the X-chromosome-linked human androgen receptor (HUMARA) gene and the phosphoglycerate kinase (PGK) gene, and multiple endocrine neoplasia type 1 (MEN1) gene abnormality was analyzed by studying loss of heterozygosity (LOH) in 11q13 and somatic mutations in the MEN1 gene. As a positive control, a case of MEN1 with Zollinger-Ellison syndrome was analyzed simultaneously. Our analysis revealed that a majority (75%) of the uremic parathyroid hyperplasia tissues, including an autograft with recurrent hyperparathyroidism, was of monoclonal origin. Clonality did not correlate with serum carboxyl-terminal parathyroid hormone (C-PTH) level, calcium level, hemodialytic duration, gland weight or pathological features. Neither LOH in 11q13 nor somatic mutation in the MEN1 gene was detected. For the MEN1 case, a germline mutation (W198X) was detected in exon 3. We concluded that a majority of the uremic parathyroid hyperplasia cases was in fact monoclonal neoplasia. MEN1 gene abnormality played a minor role, if any, in the clonal emergence in uremic parathyroid hyperplasia.Key words: Parathyroid -Uremic parathyroid hyperplasia -Clonality -MEN1 gene Uremic parathyroid hyperplasia is characterized by hypersecretion of parathyroid hormone (PTH) and enlargement of more than one gland. Because of these features, uremic parathyroid hyperplasia is traditionally interpreted as reactive hyperplasia of the parenchymal cells.1, 2) Parathyroid tumors may occur in uremic parathyroid hyperplasia but are considered rare. Recently this concept has been challenged by molecular analysis and clinical longterm follow-up. Molecular analysis has demonstrated that some uremic parathyroid hyperplasia specimens are of monoclonal origin and should therefore be interpreted as neoplastic. 3,4) Clinical studies showed that about 3% and 7% of patients receiving a subtotal parathyroidectomy developed recurrent hyperparathyroidism 5 and 7 years later, respectively. A much higher recurrence rate was observed in autografts, with a frequency of 10, 20 and 30% occurring 3, 5 and 7 years, respectively, after total parathyroidectomy and autotransplantation. 5)In these cases, pathological observation of the autografts often revealed a distinct nodular proliferation of the parenchymal cells with larger and more irregular nuclei. Occasionally, apparent mitotic activity and nuclear pleomorphism were noted. A striking finding by Klempa et al. was the presence of small nests of parathyroid tissue next to or at some distance from the autografts. 6) These observations and evidence are suggestive of a neoplastic nature of uremic parathyroid hyperplasia. However, little is known about the molecular abnormalities accounting for this neoplastic proliferation. In...

show abstract

Progression of uremic hyperparathyroidism involves allelic loss on chromosome 11.

Cited by 47 publications

References 0 publications

Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients.

Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients.

Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia.

Clonal Emergence in Uremic Parathyroid Hyperplasia Is Not Related to MEN1 Gene Abnormality

Contact Info

Product

Resources

About