Most random gene expression signatures are significantly associated with breast cancer outcome.
Bridging the gap between animal or in vitro models and human disease is essential in medical research. Researchers often suggest that a biological mechanism is relevant to human cancer from the statistical association of a gene expression marker (a signature) of this mechanism, that was discovered i...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-10-01
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| Series: | PLoS Computational Biology |
| Online Access: | http://europepmc.org/articles/PMC3197658?pdf=render |
| _version_ | 1811268299235786752 |
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| author | David Venet Jacques E Dumont Vincent Detours |
| author_facet | David Venet Jacques E Dumont Vincent Detours |
| author_sort | David Venet |
| collection | DOAJ |
| description | Bridging the gap between animal or in vitro models and human disease is essential in medical research. Researchers often suggest that a biological mechanism is relevant to human cancer from the statistical association of a gene expression marker (a signature) of this mechanism, that was discovered in an experimental system, with disease outcome in humans. We examined this argument for breast cancer. Surprisingly, we found that gene expression signatures-unrelated to cancer-of the effect of postprandial laughter, of mice social defeat and of skin fibroblast localization were all significantly associated with breast cancer outcome. We next compared 47 published breast cancer outcome signatures to signatures made of random genes. Twenty-eight of them (60%) were not significantly better outcome predictors than random signatures of identical size and 11 (23%) were worst predictors than the median random signature. More than 90% of random signatures >100 genes were significant outcome predictors. We next derived a metagene, called meta-PCNA, by selecting the 1% genes most positively correlated with proliferation marker PCNA in a compendium of normal tissues expression. Adjusting breast cancer expression data for meta-PCNA abrogated almost entirely the outcome association of published and random signatures. We also found that, in the absence of adjustment, the hazard ratio of outcome association of a signature strongly correlated with meta-PCNA (R(2) = 0.9). This relation also applied to single-gene expression markers. Moreover, >50% of the breast cancer transcriptome was correlated with meta-PCNA. A corollary was that purging cell cycle genes out of a signature failed to rule out the confounding effect of proliferation. Hence, it is questionable to suggest that a mechanism is relevant to human breast cancer from the finding that a gene expression marker for this mechanism predicts human breast cancer outcome, because most markers do. The methods we present help to overcome this problem. |
| first_indexed | 2024-04-12T21:20:25Z |
| format | Article |
| id | doaj.art-6bb0bd5caaba43e6b6888c2c7280cbf8 |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-12T21:20:25Z |
| publishDate | 2011-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-6bb0bd5caaba43e6b6888c2c7280cbf82022-12-22T03:16:20ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582011-10-01710e100224010.1371/journal.pcbi.1002240Most random gene expression signatures are significantly associated with breast cancer outcome.David VenetJacques E DumontVincent DetoursBridging the gap between animal or in vitro models and human disease is essential in medical research. Researchers often suggest that a biological mechanism is relevant to human cancer from the statistical association of a gene expression marker (a signature) of this mechanism, that was discovered in an experimental system, with disease outcome in humans. We examined this argument for breast cancer. Surprisingly, we found that gene expression signatures-unrelated to cancer-of the effect of postprandial laughter, of mice social defeat and of skin fibroblast localization were all significantly associated with breast cancer outcome. We next compared 47 published breast cancer outcome signatures to signatures made of random genes. Twenty-eight of them (60%) were not significantly better outcome predictors than random signatures of identical size and 11 (23%) were worst predictors than the median random signature. More than 90% of random signatures >100 genes were significant outcome predictors. We next derived a metagene, called meta-PCNA, by selecting the 1% genes most positively correlated with proliferation marker PCNA in a compendium of normal tissues expression. Adjusting breast cancer expression data for meta-PCNA abrogated almost entirely the outcome association of published and random signatures. We also found that, in the absence of adjustment, the hazard ratio of outcome association of a signature strongly correlated with meta-PCNA (R(2) = 0.9). This relation also applied to single-gene expression markers. Moreover, >50% of the breast cancer transcriptome was correlated with meta-PCNA. A corollary was that purging cell cycle genes out of a signature failed to rule out the confounding effect of proliferation. Hence, it is questionable to suggest that a mechanism is relevant to human breast cancer from the finding that a gene expression marker for this mechanism predicts human breast cancer outcome, because most markers do. The methods we present help to overcome this problem.http://europepmc.org/articles/PMC3197658?pdf=render |
| spellingShingle | David Venet Jacques E Dumont Vincent Detours Most random gene expression signatures are significantly associated with breast cancer outcome. PLoS Computational Biology |
| title | Most random gene expression signatures are significantly associated with breast cancer outcome. |
| title_full | Most random gene expression signatures are significantly associated with breast cancer outcome. |
| title_fullStr | Most random gene expression signatures are significantly associated with breast cancer outcome. |
| title_full_unstemmed | Most random gene expression signatures are significantly associated with breast cancer outcome. |
| title_short | Most random gene expression signatures are significantly associated with breast cancer outcome. |
| title_sort | most random gene expression signatures are significantly associated with breast cancer outcome |
| url | http://europepmc.org/articles/PMC3197658?pdf=render |
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