Copy-number analysis of topoisomerase and thymidylate synthase genes in frozen and FFPE DNAs of colorectal cancers

Archived formalin-fixed, paraffin-embedded specimens represent an important resource for pharmacogenomic analysis in retrospective clinical studies but the quality of results from formalin-fixed, paraffin-embedded samples is of concern due to the fact of the degradation of DNAs and RNAs from formali...

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Bibliographic Details
Published in:	Pharmacogenomics Vol. 9; no. 10; p. 1459
Main Authors:	Yu, Jinsheng, Miller, Ryan, Zhang, Wanghai, Sharma, Mala, Holtschlag, Vicky, Watson, Mark A, McLeod, Howard L
Format:	Journal Article
Language:	English
Published:	England 01-10-2008
Subjects:	Adult Aged Aged, 80 and over Case-Control Studies Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology DNA Topoisomerases, Type I - analysis DNA Topoisomerases, Type I - genetics DNA, Neoplasm - analysis DNA, Neoplasm - genetics Female Formaldehyde - analysis Freezing Gene Dosage - genetics Humans Immunohistochemistry Male Middle Aged Neoplasm Staging Paraffin Embedding Thymidylate Synthase - analysis Thymidylate Synthase - genetics Tissue Fixation - methods
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Summary:	Archived formalin-fixed, paraffin-embedded specimens represent an important resource for pharmacogenomic analysis in retrospective clinical studies but the quality of results from formalin-fixed, paraffin-embedded samples is of concern due to the fact of the degradation of DNAs and RNAs from formalin-fixed, paraffin-embedded tissues. In the present study, we used DNA from fresh frozen as well as formalin-fixed, paraffin-embedded tumor to detect copy-number changes in colorectal cancer, and our data shows that formalin-fixed, paraffin-embedded DNAs were able to deliver reliable copy-number data, and that quantitative PCR had the ability to detect copy-number changes from deletion to amplification, with high concordance of copy-number calls among formalin-fixed, paraffin-embedded and frozen DNAs. The amplification of topoisomerase I and deletion of thymidylate synthase were found in 23% (12/52) and 27% (14/52) of colorectal cancers, but EGF receptor amplification was not common (5/52, <10%). Among 52 colorectal cancers, 31 tumors were both topoisomerase I and thymidylate synthase diploid, which may have a worse outcome for tumor chemotherapy; and there were five tumors with favorable genomics (topoisomerase I amplification and thymidylate synthase deletion). Furthermore, topoisomerase I-amplified tumors had a two-times higher RNA level and a nearly twofold higher protein expression level than did the diploid tumors (p < 0.001 and 0.01, respectively), but there were no correlations between copy-number status and RNA or protein level for thymidylate synthase. Our study suggests a potential pharmacogenomic influence of topoisomerase I copy-number alteration on its RNA/protein expressions, which could be reflected on tumor response to chemotherapy in human colorectal cancer.
ISSN:	1744-8042
DOI:	10.2217/14622416.9.10.1459