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Recurrent chromosomal copy number alterations in sporadic chordomas.

Le LP, Nielsen GP, Rosenberg AE, Thomas D, Batten JM, Deshpande V, Schwab J, Duan Z, Xavier RJ, Hornicek FJ, Iafrate AJ - PLoS ONE (2011)

Bottom Line: One copy loss of the 10q23.31 region which encodes PTEN was found in 16/20 (80%) cases.Our sporadic chordoma cases did not show hotspot point mutations in some common cancer gene targets.Moreover, most of these sporadic tumors are not associated with T (brachyury) duplication or amplification.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. lple@partners.org

ABSTRACT
The molecular events in chordoma pathogenesis have not been fully delineated, particularly with respect to copy number changes. Understanding copy number alterations in chordoma may reveal critical disease mechanisms that could be exploited for tumor classification and therapy. We report the copy number analysis of 21 sporadic chordomas using array comparative genomic hybridization (CGH). Recurrent copy changes were further evaluated with immunohistochemistry, methylation specific PCR, and quantitative real-time PCR. Similar to previous findings, large copy number losses, involving chromosomes 1p, 3, 4, 9, 10, 13, 14, and 18, were more common than copy number gains. Loss of CDKN2A with or without loss of CDKN2B on 9p21.3 was observed in 16/20 (80%) unique cases of which six (30%) showed homozygous deletions ranging from 76 kilobases to 4.7 megabases. One copy loss of the 10q23.31 region which encodes PTEN was found in 16/20 (80%) cases. Loss of CDKN2A and PTEN expression in the majority of cases was not attributed to promoter methylation. Our sporadic chordoma cases did not show hotspot point mutations in some common cancer gene targets. Moreover, most of these sporadic tumors are not associated with T (brachyury) duplication or amplification. Deficiency of CDKN2A and PTEN expression, although shared across many other different types of tumors, likely represents a key aspect of chordoma pathogenesis. Sporadic chordomas may rely on mechanisms other than copy number gain if they indeed exploit T/brachyury for proliferation.

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Chromosome 9 array CGH results.Array CGH results for chromosome 9 are shown for select chordoma cases                            showing homozygous CDKN2A deletion. Plots were                            generated with the Agilent Genomic Workbench Standard Edition 5.0                            software. The sizes of the homozygous deletions for the five respective                            cases are as follows: 512 kb, 4.7 Mb, 76 kb, 76 kb, and 158 kb. Note                            that cases CH34 and CH37 are recurrent tumors from the same patient.                            Cases CH7 (158 kb) and CH36 (1.9 Mb) also harbor homozygous                                CDKN2A deletions and are not depicted above.                            kb = kilobases,                            Mb = megabases.
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pone-0018846-g003: Chromosome 9 array CGH results.Array CGH results for chromosome 9 are shown for select chordoma cases showing homozygous CDKN2A deletion. Plots were generated with the Agilent Genomic Workbench Standard Edition 5.0 software. The sizes of the homozygous deletions for the five respective cases are as follows: 512 kb, 4.7 Mb, 76 kb, 76 kb, and 158 kb. Note that cases CH34 and CH37 are recurrent tumors from the same patient. Cases CH7 (158 kb) and CH36 (1.9 Mb) also harbor homozygous CDKN2A deletions and are not depicted above. kb = kilobases, Mb = megabases.

Mentions: Loss of 9p, either through entire chromosome 9 loss or partial 9p loss alone, was observed in 15/20 cases (75%). Including one case with a submicroscopic deletion of approximately 158 kilobases involving CDKN2A only (CH7), 16 of 20 cases (80%) demonstrated loss of the CDKN2A/CDKN2B gene, six (30%) of which had a homozygous deletion of the gene (CH2, CH7, CH14, CH34, CH36, and CH39). Various patterns of homozygous CDKN2A/CDKN2B deletions were noted (Figure 3). Other homozygous submicroscopic deletions were detected by array CGH in regions of known benign copy number variation (CNV). Homozygous deletions of other pertinent tumor suppressor genes were not observed.


Recurrent chromosomal copy number alterations in sporadic chordomas.

Le LP, Nielsen GP, Rosenberg AE, Thomas D, Batten JM, Deshpande V, Schwab J, Duan Z, Xavier RJ, Hornicek FJ, Iafrate AJ - PLoS ONE (2011)

Chromosome 9 array CGH results.Array CGH results for chromosome 9 are shown for select chordoma cases                            showing homozygous CDKN2A deletion. Plots were                            generated with the Agilent Genomic Workbench Standard Edition 5.0                            software. The sizes of the homozygous deletions for the five respective                            cases are as follows: 512 kb, 4.7 Mb, 76 kb, 76 kb, and 158 kb. Note                            that cases CH34 and CH37 are recurrent tumors from the same patient.                            Cases CH7 (158 kb) and CH36 (1.9 Mb) also harbor homozygous                                CDKN2A deletions and are not depicted above.                            kb = kilobases,                            Mb = megabases.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3094331&req=5

pone-0018846-g003: Chromosome 9 array CGH results.Array CGH results for chromosome 9 are shown for select chordoma cases showing homozygous CDKN2A deletion. Plots were generated with the Agilent Genomic Workbench Standard Edition 5.0 software. The sizes of the homozygous deletions for the five respective cases are as follows: 512 kb, 4.7 Mb, 76 kb, 76 kb, and 158 kb. Note that cases CH34 and CH37 are recurrent tumors from the same patient. Cases CH7 (158 kb) and CH36 (1.9 Mb) also harbor homozygous CDKN2A deletions and are not depicted above. kb = kilobases, Mb = megabases.
Mentions: Loss of 9p, either through entire chromosome 9 loss or partial 9p loss alone, was observed in 15/20 cases (75%). Including one case with a submicroscopic deletion of approximately 158 kilobases involving CDKN2A only (CH7), 16 of 20 cases (80%) demonstrated loss of the CDKN2A/CDKN2B gene, six (30%) of which had a homozygous deletion of the gene (CH2, CH7, CH14, CH34, CH36, and CH39). Various patterns of homozygous CDKN2A/CDKN2B deletions were noted (Figure 3). Other homozygous submicroscopic deletions were detected by array CGH in regions of known benign copy number variation (CNV). Homozygous deletions of other pertinent tumor suppressor genes were not observed.

Bottom Line: One copy loss of the 10q23.31 region which encodes PTEN was found in 16/20 (80%) cases.Our sporadic chordoma cases did not show hotspot point mutations in some common cancer gene targets.Moreover, most of these sporadic tumors are not associated with T (brachyury) duplication or amplification.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. lple@partners.org

ABSTRACT
The molecular events in chordoma pathogenesis have not been fully delineated, particularly with respect to copy number changes. Understanding copy number alterations in chordoma may reveal critical disease mechanisms that could be exploited for tumor classification and therapy. We report the copy number analysis of 21 sporadic chordomas using array comparative genomic hybridization (CGH). Recurrent copy changes were further evaluated with immunohistochemistry, methylation specific PCR, and quantitative real-time PCR. Similar to previous findings, large copy number losses, involving chromosomes 1p, 3, 4, 9, 10, 13, 14, and 18, were more common than copy number gains. Loss of CDKN2A with or without loss of CDKN2B on 9p21.3 was observed in 16/20 (80%) unique cases of which six (30%) showed homozygous deletions ranging from 76 kilobases to 4.7 megabases. One copy loss of the 10q23.31 region which encodes PTEN was found in 16/20 (80%) cases. Loss of CDKN2A and PTEN expression in the majority of cases was not attributed to promoter methylation. Our sporadic chordoma cases did not show hotspot point mutations in some common cancer gene targets. Moreover, most of these sporadic tumors are not associated with T (brachyury) duplication or amplification. Deficiency of CDKN2A and PTEN expression, although shared across many other different types of tumors, likely represents a key aspect of chordoma pathogenesis. Sporadic chordomas may rely on mechanisms other than copy number gain if they indeed exploit T/brachyury for proliferation.

Show MeSH
Related in: MedlinePlus