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

Kanika Kanchan; Kruthika Iyer; Lisa R. Yanek; Ivan Carcamo-Orive; Margaret A. Taub; Claire Malley; Kristin Baldwin; Lewis C. Becker; Ulrich Broeckel; Linzhao Cheng; Chad Cowan; Matteo D'Antonio; Kelly A. Frazer; Thomas Quertermous; Gustavo Mostoslavsky; George Murphy; Marlene Rabinovitch; Daniel J. Rader; Martin H. Steinberg; Eric Topol; Wenli Yang; Joshua W. Knowles; Cashell E. Jaquish; Ingo Ruczinski; Rasika A. Mathias

doi:10.1016/j.scr.2020.101803

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

Kanika Kanchan, Kruthika Iyer, Lisa R. Yanek, Ivan Carcamo-Orive, Margaret A. Taub, Claire Malley, Kristin Baldwin, Lewis C. Becker, Ulrich Broeckel, Linzhao Cheng, Chad Cowan, Matteo D'Antonio, Kelly A. Frazer, Thomas Quertermous, Gustavo Mostoslavsky, George Murphy, Marlene Rabinovitch, Daniel J. Rader, Martin H. Steinberg, Eric TopolWenli Yang, Joshua W. Knowles, Cashell E. Jaquish, Ingo Ruczinski, Rasika A. Mathias

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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.

Original language	English (US)
Article number	101803
Journal	Stem Cell Research
Volume	46
DOIs	https://doi.org/10.1016/j.scr.2020.101803
State	Published - Jul 2020

Keywords

GWAS, VanillaICE
Oncogenes
Structural integrity
Tumor suppressor genes
hiPSCs

ASJC Scopus subject areas

Developmental Biology
Cell Biology

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Kanchan, K., Iyer, K., Yanek, L. R., Carcamo-Orive, I., Taub, M. A., Malley, C., Baldwin, K., Becker, L. C., Broeckel, U., Cheng, L., Cowan, C., D'Antonio, M., Frazer, K. A., Quertermous, T., Mostoslavsky, G., Murphy, G., Rabinovitch, M., Rader, D. J., Steinberg, M. H., ... Mathias, R. A. (2020). Genomic integrity of human induced pluripotent stem cells across nine studies in the NHLBI NextGen program. Stem Cell Research, 46, Article 101803. https://doi.org/10.1016/j.scr.2020.101803

Kanchan, K, Iyer, K, Yanek, LR, Carcamo-Orive, I, Taub, MA, Malley, C, Baldwin, K, Becker, LC, Broeckel, U, Cheng, L, Cowan, C, D'Antonio, M, Frazer, KA, Quertermous, T, Mostoslavsky, G, Murphy, G, Rabinovitch, M, Rader, DJ, Steinberg, MH, Topol, E, Yang, W, Knowles, JW, Jaquish, CE, Ruczinski, I & Mathias, RA 2020, 'Genomic integrity of human induced pluripotent stem cells across nine studies in the NHLBI NextGen program', Stem Cell Research, vol. 46, 101803. https://doi.org/10.1016/j.scr.2020.101803

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

abstract = "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.",

keywords = "GWAS, VanillaICE, Oncogenes, Structural integrity, Tumor suppressor genes, hiPSCs",

author = "Kanika Kanchan and Kruthika Iyer and Yanek, {Lisa R.} and Ivan Carcamo-Orive and Taub, {Margaret A.} and Claire Malley and Kristin Baldwin and Becker, {Lewis C.} and Ulrich Broeckel and Linzhao Cheng and Chad Cowan and Matteo D'Antonio and Frazer, {Kelly A.} and Thomas Quertermous and Gustavo Mostoslavsky and George Murphy and Marlene Rabinovitch and Rader, {Daniel J.} and Steinberg, {Martin H.} and Eric Topol and Wenli Yang and Knowles, {Joshua W.} and Jaquish, {Cashell E.} and Ingo Ruczinski and Mathias, {Rasika A.}",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = jul,

doi = "10.1016/j.scr.2020.101803",

language = "English (US)",

volume = "46",

journal = "Stem Cell Research",

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T1 - Genomic integrity of human induced pluripotent stem cells across nine studies in the NHLBI NextGen program

AU - Kanchan, Kanika

AU - Iyer, Kruthika

AU - Yanek, Lisa R.

AU - Carcamo-Orive, Ivan

AU - Taub, Margaret A.

AU - Malley, Claire

AU - Baldwin, Kristin

AU - Becker, Lewis C.

AU - Broeckel, Ulrich

AU - Cheng, Linzhao

AU - Cowan, Chad

AU - D'Antonio, Matteo

AU - Frazer, Kelly A.

AU - Quertermous, Thomas

AU - Mostoslavsky, Gustavo

AU - Murphy, George

AU - Rabinovitch, Marlene

AU - Rader, Daniel J.

AU - Steinberg, Martin H.

AU - Topol, Eric

AU - Yang, Wenli

AU - Knowles, Joshua W.

AU - Jaquish, Cashell E.

AU - Ruczinski, Ingo

AU - Mathias, Rasika A.

PY - 2020/7

Y1 - 2020/7

N2 - 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.

AB - 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.

KW - GWAS, VanillaICE

KW - Oncogenes

KW - Structural integrity

KW - Tumor suppressor genes

KW - hiPSCs

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VL - 46

JO - Stem Cell Research

JF - Stem Cell Research

M1 - 101803

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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