Clonal chromosomal defects in the molecular pathogenesis of refractory hyperparathyroidism of uremia.
Indirect X chromosome-inactivation analyses have demonstrated that most parathyroid glands from patients with uremic refractory secondary/tertiary hyperparathyroidism are monoclonal neoplasms. However, little is known regarding the specific acquired genetic abnormalities that must underlie such clonal expansion or the molecular pathogenetic features of this disorder, compared with primary parathyroid adenomas. To address these issues in a uniquely powerful manner, both comparative genomic hybridization (CGH) and genome-wide molecular allelotyping were performed with a large group of uremia-associated parathyroid tumors. As indicated by CGH, one or more chromosomal changes were present in 24% of the tumors, which is markedly different from the value for common sporadic adenomas (72%). Two recurrent abnormalities that had not been previously described for sporadic parathyroid adenomas were noted with CGH, i.e., gains on chromosomes 7 (9%) and 12 (11%). Losses on chromosome 11 occurred in only one of the 46 uremia-associated tumors (2%); the tumor also contained a somatic mutation of the remaining MEN1 allele (221del18). A total of 13% of tumors demonstrated recurrent allelic loss on 18q, with 18q21.1-q21.2 being defined as the putative tumor suppressor-containing region. In conclusion, the powerful combination of genome-wide molecular allelotyping and CGH has identified recurrent clonal DNA abnormalities that suggest the existence and locations of genes important in uremic hyperparathyroidism. In addition, genome-wide patterns of somatic DNA alterations, including disparate roles for MEN1 gene inactivation, indicate that markedly different molecular pathogenetic processes exist for clonal outgrowth in severe uremic hyperparathyroidism versus common parathyroid adenomas.
Imanishi
Yasuo
Y
Center for Molecular Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030-3101, USA.
Tahara
Hideki
H
Palanisamy
Nallasivam
N
Spitalny
Sarah
S
Salusky
Isidro B
IB
Goodman
William
W
Brandi
Maria Luisa
ML
Drüeke
Tilman B
TB
Sarfati
Emile
E
Ureña
Pablo
P
Chaganti
R S K
RS
Arnold
Andrew
A
D000328:Adult; D000368:Aged; D000483:Alleles; D002869:Chromosome Aberrations; D006801:Humans; D006961:Hyperparathyroidism / Q000209:etiology / Q000235:genetics*; D019656:Loss of Heterozygosity; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins; D014511:Uremia / Q000235:genetics*
C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins