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Open Access Highly Accessed Research article

Gene expression anti-profiles as a basis for accurate universal cancer signatures

Héctor Corrada Bravo1*, Vasyl Pihur2, Matthew McCall3, Rafael A Irizarry2 and Jeffrey T Leek2

Author affiliations

1 Department of Computer Science, Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, USA

2 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

3 Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA

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Citation and License

BMC Bioinformatics 2012, 13:272  doi:10.1186/1471-2105-13-272

Published: 22 October 2012

Abstract

Background

Early screening for cancer is arguably one of the greatest public health advances over the last fifty years. However, many cancer screening tests are invasive (digital rectal exams), expensive (mammograms, imaging) or both (colonoscopies). This has spurred growing interest in developing genomic signatures that can be used for cancer diagnosis and prognosis. However, progress has been slowed by heterogeneity in cancer profiles and the lack of effective computational prediction tools for this type of data.

Results

We developed anti-profiles as a first step towards translating experimental findings suggesting that stochastic across-sample hyper-variability in the expression of specific genes is a stable and general property of cancer into predictive and diagnostic signatures. Using single-chip microarray normalization and quality assessment methods, we developed an anti-profile for colon cancer in tissue biopsy samples. To demonstrate the translational potential of our findings, we applied the signature developed in the tissue samples, without any further retraining or normalization, to screen patients for colon cancer based on genomic measurements from peripheral blood in an independent study (AUC of 0.89). This method achieved higher accuracy than the signature underlying commercially available peripheral blood screening tests for colon cancer (AUC of 0.81). We also confirmed the existence of hyper-variable genes across a range of cancer types and found that a significant proportion of tissue-specific genes are hyper-variable in cancer. Based on these observations, we developed a universal cancer anti-profile that accurately distinguishes cancer from normal regardless of tissue type (ten-fold cross-validation AUC > 0.92).

Conclusions

We have introduced anti-profiles as a new approach for developing cancer genomic signatures that specifically takes advantage of gene expression heterogeneity. We have demonstrated that anti-profiles can be successfully applied to develop peripheral-blood based diagnostics for cancer and used anti-profiles to develop a highly accurate universal cancer signature. By using single-chip normalization and quality assessment methods, no further retraining of signatures developed by the anti-profile approach would be required before their application in clinical settings. Our results suggest that anti-profiles may be used to develop inexpensive and non-invasive universal cancer screening tests.

Keywords:
Gene expression; Cancer; Genomic signatures; Microarray normalization and quality assessment; Anti-profiles