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Ploidy status and copy number aberrations in primary glioblastomas defined by integrated analysis of allelic ratios, signal ratios and loss of heterozygosity using 500K SNP Mapping Arrays.

Gardina PJ, Lo KC, Lee W, Cowell JK, Turpaz Y - BMC Genomics (2008)

Bottom Line: These results suggest a re-interpretation of previous findings based only on total signal ratios.One interesting observation is that many single or multiple-copy deletions occur at common putative tumor suppressor sites subsequent to chromosomal duplication; these losses do not necessarily result in LOH, but nonetheless occur in conspicuous patterns.The 500 K Mapping array was also capable of detecting many sub-mega base losses and gains that were overlooked by CGH-BAC arrays, and was superior to CGH-BAC arrays in resolving regions of complex CN variation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Affymetrix, Inc., 3420 Central Expressway, Santa Clara, California 95051, USA. paul_gardina@affymetrix.com

ABSTRACT

Background: Genomic hybridization platforms, including BAC-CGH and genotyping arrays, have been used to estimate chromosome copy number (CN) in tumor samples by detecting the relative strength of genomic signal. The methods rely on the assumption that the predominant chromosomal background of the samples is diploid, an assumption that is frequently incorrect for tumor samples. In addition to generally greater resolution, an advantage of genotyping arrays over CGH arrays is the ability to detect signals from individual alleles, allowing estimation of loss-of-heterozygosity (LOH) and allelic ratios to enhance the interpretation of copy number alterations. Copy number events associated with LOH potentially have the same genetic consequences as deletions.

Results: We have utilized allelic ratios to detect patterns that are indicative of higher ploidy levels. An integrated analysis using allelic ratios, total signal and LOH indicates that many or most of the chromosomes from 24 glioblastoma tumors are in fact aneuploid. Some putative whole-chromosome losses actually represent trisomy, and many apparent sub-chromosomal losses are in fact relative losses against a triploid or tetraploid background.

Conclusion: These results suggest a re-interpretation of previous findings based only on total signal ratios. One interesting observation is that many single or multiple-copy deletions occur at common putative tumor suppressor sites subsequent to chromosomal duplication; these losses do not necessarily result in LOH, but nonetheless occur in conspicuous patterns. The 500 K Mapping array was also capable of detecting many sub-mega base losses and gains that were overlooked by CGH-BAC arrays, and was superior to CGH-BAC arrays in resolving regions of complex CN variation.

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Discrepancies between 500 K and 19 K BAC arrays for Chr:9 of sample C111. A 5 Mb loss at 33.65 – 38.70 Mb, and two small homozygous deletions at 21.86 – 22.21 Mb and 103.42 – 103.85 Mb are apparent in the 500 K mapping, but not definitively detected by CGH.
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Figure 10: Discrepancies between 500 K and 19 K BAC arrays for Chr:9 of sample C111. A 5 Mb loss at 33.65 – 38.70 Mb, and two small homozygous deletions at 21.86 – 22.21 Mb and 103.42 – 103.85 Mb are apparent in the 500 K mapping, but not definitively detected by CGH.

Mentions: In a detailed survey of the same 24 samples analyzed on the 500 K arrays, 422 chromosomal subregions were defined that deviate from a CN of two. There were 129 discrepancies found in CNAs that involve either gains/losses not found in the CGH analysis, or large differences (> 2 Mb) in the borders of altered regions. Of these discrepancies, 38 represented gains or losses smaller than 1 Mb that were identified only with 500 K arrays, including many in the 50 Kb range. The smaller CNAs are either not detected by any individual BAC clones (i.e., they are smaller than the resolution of the CGH) or were too inconsistent over the small region of the CNA to make a call, as shown in Fig. 9 and 10.


Ploidy status and copy number aberrations in primary glioblastomas defined by integrated analysis of allelic ratios, signal ratios and loss of heterozygosity using 500K SNP Mapping Arrays.

Gardina PJ, Lo KC, Lee W, Cowell JK, Turpaz Y - BMC Genomics (2008)

Discrepancies between 500 K and 19 K BAC arrays for Chr:9 of sample C111. A 5 Mb loss at 33.65 – 38.70 Mb, and two small homozygous deletions at 21.86 – 22.21 Mb and 103.42 – 103.85 Mb are apparent in the 500 K mapping, but not definitively detected by CGH.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2576260&req=5

Figure 10: Discrepancies between 500 K and 19 K BAC arrays for Chr:9 of sample C111. A 5 Mb loss at 33.65 – 38.70 Mb, and two small homozygous deletions at 21.86 – 22.21 Mb and 103.42 – 103.85 Mb are apparent in the 500 K mapping, but not definitively detected by CGH.
Mentions: In a detailed survey of the same 24 samples analyzed on the 500 K arrays, 422 chromosomal subregions were defined that deviate from a CN of two. There were 129 discrepancies found in CNAs that involve either gains/losses not found in the CGH analysis, or large differences (> 2 Mb) in the borders of altered regions. Of these discrepancies, 38 represented gains or losses smaller than 1 Mb that were identified only with 500 K arrays, including many in the 50 Kb range. The smaller CNAs are either not detected by any individual BAC clones (i.e., they are smaller than the resolution of the CGH) or were too inconsistent over the small region of the CNA to make a call, as shown in Fig. 9 and 10.

Bottom Line: These results suggest a re-interpretation of previous findings based only on total signal ratios.One interesting observation is that many single or multiple-copy deletions occur at common putative tumor suppressor sites subsequent to chromosomal duplication; these losses do not necessarily result in LOH, but nonetheless occur in conspicuous patterns.The 500 K Mapping array was also capable of detecting many sub-mega base losses and gains that were overlooked by CGH-BAC arrays, and was superior to CGH-BAC arrays in resolving regions of complex CN variation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Affymetrix, Inc., 3420 Central Expressway, Santa Clara, California 95051, USA. paul_gardina@affymetrix.com

ABSTRACT

Background: Genomic hybridization platforms, including BAC-CGH and genotyping arrays, have been used to estimate chromosome copy number (CN) in tumor samples by detecting the relative strength of genomic signal. The methods rely on the assumption that the predominant chromosomal background of the samples is diploid, an assumption that is frequently incorrect for tumor samples. In addition to generally greater resolution, an advantage of genotyping arrays over CGH arrays is the ability to detect signals from individual alleles, allowing estimation of loss-of-heterozygosity (LOH) and allelic ratios to enhance the interpretation of copy number alterations. Copy number events associated with LOH potentially have the same genetic consequences as deletions.

Results: We have utilized allelic ratios to detect patterns that are indicative of higher ploidy levels. An integrated analysis using allelic ratios, total signal and LOH indicates that many or most of the chromosomes from 24 glioblastoma tumors are in fact aneuploid. Some putative whole-chromosome losses actually represent trisomy, and many apparent sub-chromosomal losses are in fact relative losses against a triploid or tetraploid background.

Conclusion: These results suggest a re-interpretation of previous findings based only on total signal ratios. One interesting observation is that many single or multiple-copy deletions occur at common putative tumor suppressor sites subsequent to chromosomal duplication; these losses do not necessarily result in LOH, but nonetheless occur in conspicuous patterns. The 500 K Mapping array was also capable of detecting many sub-mega base losses and gains that were overlooked by CGH-BAC arrays, and was superior to CGH-BAC arrays in resolving regions of complex CN variation.

Show MeSH
Related in: MedlinePlus