Genomic integrity of human induced pluripotent stem cells across nine studies in the NHLBI NextGen program

•NextGen: A collection of publicly available hiPSCs from more than 1,500 individuals.•Determined genomic structural integrity of 506 lines, 71% show no detectable CNVs.•Enrichment of cancer related biological processes in regions of acquired CNVs.•Recurrent aberrant regions on five chromosomes encompass cancer associated loci.•Amplification on chr20 includes transcriptomic signatures for known cancer gene HCK. Human induced pluripotent stem cell (hiPSC) lines have previously been generated through the NHLBI sponsored NextGen program at nine individual study sites. Here, we examined the structural integrity of 506 hiPSC lines as determined by copy number variations (CNVs). We observed that 149 hiPSC lines acquired 258 CNVs relative to donor DNA. We identified six recurrent regions of CNVs on chromosomes 1, 2, 3, 16 and 20 that overlapped with cancer associated genes. Furthermore, the genes mapping to regions of acquired CNVs show an enrichment in cancer related biological processes (IL6 production) and signaling cascades (JNK cascade & NFκB cascade). The genomic region of instability on chr20 (chr20q11.2) includes transcriptomic signatures for cancer associated genes such as ID1, BCL2L1, TPX2, PDRG1 and HCK. Of these HCK shows statistically significant differential expression between carrier and non-carrier hiPSC lines. Overall, while a low level of genomic instability was observed in the NextGen generated hiPSC lines, the observation of structural instability in regions with known cancer associated genes substantiates the importance of systematic evaluation of genetic variations in hiPSCs before using them as disease/research models.