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Frequent loss of chromosome arm 1p DNA in parathyroid adenomas
1Laboratory of Endocrine Oncology, Massachusetts General Hospital, Boston 02114, USA.
Abstract:
Two molecular defects have been described in parathyroid adenomas: rearrangement and overexpression of the PRAD1/cyclin D1 oncogene and allelic loss of chromosome 11 DNA, often including the multiple endocrine neoplasia type 1 (MEN1) putative tumor suppressor gene region. In an effort to identify additional parathyroid tumor suppressor genes, we examined 25 parathyroid adenomas for tumor-specific allelic loss of polymorphic DNA loci located near known or candidate tumor suppressor genes. Control leukocyte DNA from all 25 patients was heterozygous for 1 or more of the 9 chromosome 1 markers examined. Allelic loss at 1 or more of these informative loci on chromosome 1 was observed in 10 of 25 (40%) adenomas. Although many tumors lost extensive regions on chromosome 1, all but one of these tumors had allelic loss of distal 1p (1p32-pter); four tumors also lost loci on 1q. Allelic loss at 11q13, the site of the MEN1 gene, was detected in 5 of 21 (24%) informative cases, including 3 with 1p loss. In contrast, allelic loss was rarely observed at loci on 9q and 10p and was not observed at loci on 3p, 3q, 4p, 5q, 12q, 14q, 18q, 22q, or Xp. In summary, clonal allelic loss of loci on chromosome arm 1p is a frequent feature of parathyroid adenomas, implying that inactivation of a tumor suppressor gene(s) on 1p commonly contributes to their pathogenesis.
Insights
Tumor suppressor genes on chromosome 1p are frequently lost in parathyroid adenomas, suggesting their inactivation contributes to tumor development. This study identified new genetic alterations in parathyroid tumor pathogenesis.
Area of Science:
- Oncology
- Genetics
- Endocrinology
Background:
- Parathyroid adenomas are associated with PRAD1/cyclin D1 oncogene alterations and chromosome 11 loss, including the MEN1 gene region.
- The existence of additional tumor suppressor genes in parathyroid adenoma development is suspected.
- Identifying these genes is crucial for understanding parathyroid tumor pathogenesis.
Purpose of the Study:
- To investigate allelic loss of DNA loci near known or candidate tumor suppressor genes in parathyroid adenomas.
- To identify novel tumor suppressor genes involved in parathyroid tumorigenesis.
- To determine the frequency and location of chromosomal abnormalities in parathyroid tumors.
Main Methods:
- Analysis of 25 parathyroid adenomas for tumor-specific allelic loss.
- Examination of polymorphic DNA loci on various chromosomes, with a focus on chromosome 1 and 11.
- Comparison of tumor DNA with control leukocyte DNA from the same patients.
Main Results:
- Allelic loss on chromosome 1 was observed in 40% (10 of 25) of parathyroid adenomas.
- Distal 1p (1p32-pter) allelic loss was the most common finding on chromosome 1.
- Allelic loss at the MEN1 gene locus (11q13) was detected in 24% (5 of 21) of informative cases.
Conclusions:
- Clonal allelic loss on chromosome arm 1p is a frequent event in parathyroid adenomas.
- Inactivation of tumor suppressor gene(s) on 1p likely plays a significant role in parathyroid tumor development.
- These findings suggest novel genetic targets for understanding and potentially treating parathyroid adenomas.