Distinct target regions for chromosome 1p deletions in parathyroid adenomas and carcinomas.
Primary hyperparathyroidism is a common endocrine disease with a multifaceted genetic background, the elucidation of which has only begun. Among others, loss of the short arm of chromosome 1 and somatic inactivation of the multiple endocrine neoplasia type 1 gene (MEN1) in 11q13 represent significant alterations in the tumorigenesis. In the present study deletions of 1p were characterized and the findings were evaluated in relation to the loci of MEN1 and histone deacetylase 1 gene (HDAC1), a menin interacting partner in 1p, as well as to the clinical characteristics. Overall 1p LOH was detected in 18 of the 42 tumors analyzed (43%), and from the deletion patterns a main target interval of 40 cM was identified within 1p band 32.3-36.2. The mapping of HDAC1 centromeric of the main interval, and the lack of altered mRNA expression in tumors with LOH, suggest that HDAC1 is not the main target for 1p deletions in parathyroid tumors. Twenty-five of the 42 tumors (60%) showed alteration of either 1p, of the MEN1 locus, or both. Tumors with LOH at 11q13 had a significantly higher weight than tumors with 1p LOH. In conclusion, LOH in primary sporadic parathyroid adenomas occur frequently on the distal part of chromosome 1p and are thus clearly different from parathyroid carcinomas where the deletions are more proximally located. The findings support that the short arm of chromosome 1 harbors at least two different tumor suppressor genes involved in parathyroid tumorigenesis, the exact identification of which may provide a molecular basis for differential diagnosis of benign and malignant disease in the future.
Välimäki
S
S
Department of Molecular Medicine, Endocrine Tumor Unit, CMM L8:01, Karolinska Hospital, SE-171 76 Stockholm, Sweden. stiina.valimaki@cmm.ki.se
Forsberg
L
L
Farnebo
L-O
LO
Larsson
C
C
D000236:Adenoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics*; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1; D005260:Female; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009693:Nucleic Acid Hybridization; D010282:Parathyroid Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D021101:Radiation Hybrid Mapping
D012333:RNA, Messenger; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases