Karyotypic divergence confounds cellular phenotypes in large pharmacogenomic studies

Abstract

BackgroundSomatic copy-number alterations that affect large genomic regions are a major source of genomic diversity in cancer and can impact cellular phenotypes. Clonal heterogeneity within cancer cell lines can affect phenotypic presentation, including drug response.\n\nMethodsWe aggregated and analyzed SNP and copy number profiles from six pharmacogenomic datasets encompassing 1,691 cell lines screened for 13 molecules. To look for sources of genotype and karyotype discordances, we compared SNP genotypes and segmental copy-ratios across 5 kb genomic bins. To assess the impact of genomic discordances on pharmacogenomic studies, we assessed gene expression and drug sensitivity data for compared discordant and concordant lines.\n\nResultsWe found 6/1,378 (0.4%) cell lines profiled in two studies to be discordant in both genotypic and karyotypic identity, 51 (3.7%) discordant in genotype, 97 (7.0%) discordant in karyotype, and 125 (9.1%) potential misidentifications. We highlight cell lines REH, NCI-H23 and PSN1 as having drug response discordances that may hinge on divergent copy-number q\n\nConclusionsOur study highlights the low level of misidentification as evidence of effective cell line authentication standards in recent pharmacogenomic studies. However, the proclivity of cell lines to acquire somatic copy-number variants can alter the cellular phenotype, resulting in a biological and predictable effects on drug sensitivity. These findings highlight the need for verification of cell line copy number profiles to inform interpretation of drug sensitivity data in biomedical studies.