Outlier analysis of functional genomic profiles enriches for oncology targets and enables precision medicine.
Genome-scale functional genomic screens across large cell line panels provide a rich resource for discovering tumor vulnerabilities that can lead to the next generation of targeted therapies. Their data analysis typically has focused on identifying genes whose knockdown enhances response in various pre-defined genetic contexts, which are limited by biological complexities as well as the incompleteness of our knowledge. We thus introduce a complementary data mining strategy to identify genes with exceptional sensitivity in subsets, or outlier groups, of cell lines, allowing an unbiased analysis without any a priori assumption about the underlying biology of dependency.



Genes with outlier features are strongly and specifically enriched with those known to be associated with cancer and relevant biological processes, despite no a priori knowledge being used to drive the analysis. Identification of exceptional responders (outliers) may not lead only to new candidates for therapeutic intervention, but also tumor indications and response biomarkers for companion precision medicine strategies. Several tumor suppressors have an outlier sensitivity pattern, supporting and generalizing the notion that tumor suppressors can play context-dependent oncogenic roles.



The novel application of outlier analysis described here demonstrates a systematic and data-driven analytical strategy to decipher large-scale functional genomic data for oncology target and precision medicine discoveries.
Oncology Research Unit, Pfizer Worldwide Research & Development, La Jolla Laboratories, 10777 Science Center Drive, San Diego, CA, 92121, USA. Zhou.Zhu@pfizer.com.
Zhou
Z
Zhu
Oncology Research Unit, Pfizer Worldwide Research & Development, La Jolla Laboratories, 10777 Science Center Drive, San Diego, CA, 92121, USA.
Nathan T
NT
Ihle
Oncology Research Unit, Pfizer Worldwide Research & Development, La Jolla Laboratories, 10777 Science Center Drive, San Diego, CA, 92121, USA.
Paul A
PA
Rejto
Oncology Research Unit, Pfizer Worldwide Research & Development, La Jolla Laboratories, 10777 Science Center Drive, San Diego, CA, 92121, USA. pzarrinkar@yahoo.com.
Patrick P
PP
Zarrinkar
D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D055808:Drug Discovery; D020869:Gene Expression Profiling; D015894:Genome, Human; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D057285:Precision Medicine / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects
D014408:Biomarkers, Tumor
Cancer; Functional genomics; Oncogene addiction; Oncology; Outlier analysis; Precision medicine; Synthetic lethality; Target identification