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Distinct target regions for chromosome 1p deletions in parathyroid adenomas and carcinomas
S Välimäki1, L Forsberg, L-O Farnebo
1Department of Molecular Medicine, Endocrine Tumor Unit, CMM L8:01, Karolinska Hospital, SE-171 76 Stockholm, Sweden. stiina.valimaki@cmm.ki.se
Abstract:
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.
Insights
Loss of chromosome 1p occurs frequently in primary hyperparathyroidism tumors, distinct from parathyroid carcinomas. This suggests tumor suppressor genes on chromosome 1p are involved in parathyroid tumorigenesis.
Area of Science:
- Endocrinology
- Cancer Genetics
- Molecular Biology
Background:
- Primary hyperparathyroidism is a common endocrine disorder with complex genetic underpinnings.
- Loss of chromosome 1p and inactivation of the multiple endocrine neoplasia type 1 (MEN1) gene are implicated in tumorigenesis.
- The genetic landscape of parathyroid tumors is still being elucidated.
Purpose of the Study:
- To characterize deletions on chromosome 1p in primary hyperparathyroid tumors.
- To investigate the relationship between 1p deletions, MEN1 locus alterations, and histone deacetylase 1 (HDAC1) gene.
- To correlate genetic findings with clinical characteristics of parathyroid tumors.
Main Methods:
- Analysis of loss of heterozygosity (LOH) at 1p in 42 primary parathyroid tumors.
- Mapping of deletion intervals on chromosome 1p.
- Evaluation of MEN1 locus alterations and HDAC1 gene status.
- Assessment of mRNA expression of HDAC1.
- Correlation of genetic alterations with tumor weight and clinical data.
Main Results:
- 1p LOH was detected in 43% (18/42) of tumors, with a main target interval in 1p band 32.3-36.2.
- HDAC1 was mapped centromeric to the main deletion interval, and its mRNA expression was not altered in tumors with LOH, suggesting it's not the primary target.
- 60% (25/42) of tumors showed alterations in either 1p, the MEN1 locus, or both.
- Tumors with 11q13 LOH (MEN1 locus) were significantly heavier than those with 1p LOH.
- Distal 1p deletions in adenomas differ from proximal deletions observed in parathyroid carcinomas.
Conclusions:
- Loss of heterozygosity on the distal short arm of chromosome 1 is frequent in sporadic parathyroid adenomas.
- These findings suggest the involvement of at least two tumor suppressor genes on chromosome 1p in parathyroid tumorigenesis.
- The distinct deletion patterns between adenomas and carcinomas may offer a molecular basis for differential diagnosis.