Discovering novel pharmacogenomic biomarkers by imputing drug response in cancer patients from large genomics studies (original) (raw)

1. Zhenyu Zhang2,
2. Fan Wang1,
3. Robert F. Gruener1,
4. Aritro Nath1,
5. Gladys Morrison1,
6. Steven Bhutra1,
7. Robert L. Grossman2 and
8. R. Stephanie Huang1
9. 1Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois 60637, USA;
10. 2Center for Data Intensive Science, The University of Chicago, Chicago, Illinois 60637, USA

• Corresponding author: rhuang{at}medicine.bsd.uchicago.edu

Abstract

Obtaining accurate drug response data in large cohorts of cancer patients is very challenging; thus, most cancer pharmacogenomics discovery is conducted in preclinical studies, typically using cell lines and mouse models. However, these platforms suffer from serious limitations, including small sample sizes. Here, we have developed a novel computational method that allows us to impute drug response in very large clinical cancer genomics data sets, such as The Cancer Genome Atlas (TCGA). The approach works by creating statistical models relating gene expression to drug response in large panels of cancer cell lines and applying these models to tumor gene expression data in the clinical data sets (e.g., TCGA). This yields an imputed drug response for every drug in each patient. These imputed drug response data are then associated with somatic genetic variants measured in the clinical cohort, such as copy number changes or mutations in protein coding genes. These analyses recapitulated drug associations for known clinically actionable somatic genetic alterations and identified new predictive biomarkers for existing drugs.

Footnotes

• [Supplemental material is available for this article.]

• Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.221077.117.

• Received January 25, 2017.

• Accepted August 3, 2017.

• © 2017 Geeleher et al.; Published by Cold Spring Harbor Laboratory Press

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.