most random gene expression signatures are significantly associated with breast cancer outcome大部分随机基因表达特征明显与乳腺癌相关的结果.pdfVIP

Most Random Gene Expression Signatures Are Significantly Associated with Breast Cancer Outcome 1 2 2,3 David Venet , Jacques E. Dumont , Vincent Detours * ´ ´ 1 IRIDIA-CoDE, Universite Libre de Bruxelles (U.L.B.), Brussels, Belgium, 2 IRIBHM, Universite Libre de Bruxelles (U.L.B.), Campus Erasme, Brussels, Belgium, 3 WELBIO, ´ Universite Libre de Bruxelles (U.L.B.), Campus Erasme, Brussels, Belgium Abstract 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 a