 Impact of between-tissue differences on pan-cancer predictions of drug sensitivityJohn P Lloyd, Matthew B Soellner, Sofia D Merajver and Jun Z Li PLOS Computational Biology, 2021, vol. 17, issue 2, 1-25 Abstract: Increased availability of drug response and genomics data for many tumor cell lines has accelerated the development of pan-cancer prediction models of drug response. However, it is unclear how much between-tissue differences in drug response and molecular characteristics may contribute to pan-cancer predictions. Also unknown is whether the performance of pan-cancer models could vary by cancer type. Here, we built a series of pan-cancer models using two datasets containing 346 and 504 cell lines, each with MEK inhibitor (MEKi) response and mRNA expression, point mutation, and copy number variation data, and found that, while the tissue-level drug responses are accurately predicted (between-tissue ρ = 0.88–0.98), only 5 of 10 cancer types showed successful within-tissue prediction performance (within-tissue ρ = 0.11–0.64). Between-tissue differences make substantial contributions to the performance of pan-cancer MEKi response predictions, as exclusion of between-tissue signals leads to a decrease in Spearman’s ρ from a range of 0.43–0.62 to 0.30–0.51. In practice, joint analysis of multiple cancer types usually has a larger sample size, hence greater power, than for one cancer type; and we observe that higher accuracy of pan-cancer prediction of MEKi response is almost entirely due to the sample size advantage. Success of pan-cancer prediction reveals how drug response in different cancers may invoke shared regulatory mechanisms despite tissue-specific routes of oncogenesis, yet predictions in different cancer types require flexible incorporation of between-cancer and within-cancer signals. As most datasets in genome sciences contain multiple levels of heterogeneity, careful parsing of group characteristics and within-group, individual variation is essential when making robust inference.Author summary: One of the central goals for precision oncology is to tailor treatment of individual tumors by their molecular characteristics. While drug response predictions have traditionally been sought within each cancer type, it has long been hoped to develop more robust predictions by jointly considering diverse cancer types. While such pan-cancer approaches have improved in recent years, it remains unclear whether between-tissue differences are contributing to the reported pan-cancer prediction performance. This concern stems from the observation that, when cancer types differ in both molecular features and drug response, strong predictive information can come mainly from differences among tissue types. Our study finds that both between- and within-cancer type signals provide substantial contributions to pan-cancer drug response prediction models, and about half of the cancer types examined are poorly predicted despite strong overall performance across all cancer types. We also find that pan-cancer prediction models perform similarly or better than cancer type-specific models, and in many cases the advantage of pan-cancer models is due to the larger number of samples available for pan-cancer analysis. Our results highlight tissue-of-origin as a key consideration for pan-cancer drug response prediction models, and recommend cancer type-specific considerations when translating pan-cancer prediction models for clinical use. Date: 2021 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1008720 DOI: 10.1371/journal.pcbi.1008720 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
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