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Infrequent CDKN2 mutation in human differentiated thyroid cancers
W S Tung1, D W Shevlin, D Bartsch
1Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
Abstract:
We examined the frequency of cyclin-dependent kinase (CDK) N2 alterations in differentiated and anaplastic thyroid cancers to assess the involvement of CDKN2 in the development of these cancers. The CDKN2 gene, which encodes the cell-cycle regulator p16, was recently shown to be mutated or deleted in many tumor cell lines. Its role in the genesis of primary tumors is uncertain, however. Tumor and corresponding normal DNAs were prepared by microdissection of paraffin-embedded tissue blocks or from frozen surgical specimens of 15 papillary, 15 follicular, and five anaplastic thyroid carcinomas. The entire CDKN2 coding region was screened by single-strand conformational variant analysis and direct sequencing of variants. The presence of homozygous deletions was evaluated by multiplex polymerase chain reaction (PCR) analysis. Loss of heterozygosity (LOH) in the CDKN2 region was assessed by using flanking polymorphic markers. Two somatic missense mutations were found among the 35 thyroid cancers, one in a follicular tumor and one in an anaplastic tumor. Multiplex PCR suggested the presence of homozygous deletion in one anaplastic tumor and hemizygous deletions in four tumors. LOH studies revealed loss of 9p sequences in four follicular (27%) and two anaplastic (50%) cancers. Our data suggest that alterations in CDKN2 played a role in a minority of thyroid cancers (three of 35). LOH in the region of CDKN2 is seen in a significant proportion of follicular and anaplastic but not papillary cancers. Loss of 9p sequences suggests a role for a tumor suppressor gene in the development of follicular and anaplastic thyroid cancers.
Insights
Alterations in the CDKN2 gene, a cell-cycle regulator, were investigated in thyroid cancers. CDKN2 gene alterations were found in a small subset of thyroid tumors, suggesting a role in specific cancer types.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The cyclin-dependent kinase inhibitor 2 (CDKN2) gene encodes the p16 cell-cycle regulator.
- CDKN2 alterations (mutations, deletions) are observed in various tumor cell lines.
- Its role in primary thyroid tumor development remains unclear.
Purpose of the Study:
- To investigate the frequency of CDKN2 alterations in differentiated and anaplastic thyroid cancers.
- To assess the involvement of CDKN2 in thyroid cancer genesis.
Main Methods:
- Analysis of tumor and normal DNA from 35 thyroid carcinomas (papillary, follicular, anaplastic).
- Screening of the CDKN2 coding region using single-strand conformational variant analysis and direct sequencing.
- Evaluation of homozygous deletions via multiplex polymerase chain reaction (PCR).
- Assessment of loss of heterozygosity (LOH) using polymorphic markers.
Main Results:
- Two somatic missense mutations in CDKN2 were identified (one follicular, one anaplastic).
- Homozygous or hemizygous deletions were suggested in five anaplastic tumors.
- Loss of heterozygosity (LOH) in the 9p region (near CDKN2) was observed in 27% of follicular and 50% of anaplastic thyroid cancers.
- No CDKN2 alterations were noted in papillary thyroid cancers.
Conclusions:
- CDKN2 alterations play a role in a minority of thyroid cancers.
- LOH in the CDKN2 region is frequent in follicular and anaplastic thyroid cancers, but not papillary.
- Loss of 9p sequences suggests a tumor suppressor gene's involvement in follicular and anaplastic thyroid cancer development.