Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer

Chuncheng Hao, Li Wang, Shaohua Peng, Mengru Cao, Hongyu Li, Jing Hu, Xiao Huang, Wei Liu, Hui Zhang, Shuhong Wu, Apar Pataer, John V. Heymach, Agda Karina Eterovic, Qingxiu Zhang, Kenna R. Shaw, Ken Chen, Andrew Futreal, Michael Wang, Wayne Hofstetter, Reza Mehran & 8 others David Rice, Jack A. Roth, Boris Sepesi, Stephen G. Swisher, Ara Vaporciyan, Garrett L. Walsh, Faye M. Johnson, Bingliang Fang

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in ≥3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies.

Original languageEnglish (US)
Pages (from-to)179-185
Number of pages7
JournalCancer Letters
Volume357
Issue number1
DOIs
StatePublished - Feb 1 2015
Externally publishedYes

Fingerprint

Heterografts
Non-Small Cell Lung Carcinoma
Mutation
Genes
Neoplasms
Exome
Neoplasm Genes
Gene Frequency
Lung Neoplasms
Pharmaceutical Preparations

Keywords

  • Biomarkers
  • Gene mutations
  • Lung cancer
  • Patient-derived xenografts
  • Tumor models

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer. / Hao, Chuncheng; Wang, Li; Peng, Shaohua; Cao, Mengru; Li, Hongyu; Hu, Jing; Huang, Xiao; Liu, Wei; Zhang, Hui; Wu, Shuhong; Pataer, Apar; Heymach, John V.; Eterovic, Agda Karina; Zhang, Qingxiu; Shaw, Kenna R.; Chen, Ken; Futreal, Andrew; Wang, Michael; Hofstetter, Wayne; Mehran, Reza; Rice, David; Roth, Jack A.; Sepesi, Boris; Swisher, Stephen G.; Vaporciyan, Ara; Walsh, Garrett L.; Johnson, Faye M.; Fang, Bingliang.

In: Cancer Letters, Vol. 357, No. 1, 01.02.2015, p. 179-185.

Research output: Contribution to journalArticle

Hao, C, Wang, L, Peng, S, Cao, M, Li, H, Hu, J, Huang, X, Liu, W, Zhang, H, Wu, S, Pataer, A, Heymach, JV, Eterovic, AK, Zhang, Q, Shaw, KR, Chen, K, Futreal, A, Wang, M, Hofstetter, W, Mehran, R, Rice, D, Roth, JA, Sepesi, B, Swisher, SG, Vaporciyan, A, Walsh, GL, Johnson, FM & Fang, B 2015, 'Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer', Cancer Letters, vol. 357, no. 1, pp. 179-185. https://doi.org/10.1016/j.canlet.2014.11.024
Hao, Chuncheng ; Wang, Li ; Peng, Shaohua ; Cao, Mengru ; Li, Hongyu ; Hu, Jing ; Huang, Xiao ; Liu, Wei ; Zhang, Hui ; Wu, Shuhong ; Pataer, Apar ; Heymach, John V. ; Eterovic, Agda Karina ; Zhang, Qingxiu ; Shaw, Kenna R. ; Chen, Ken ; Futreal, Andrew ; Wang, Michael ; Hofstetter, Wayne ; Mehran, Reza ; Rice, David ; Roth, Jack A. ; Sepesi, Boris ; Swisher, Stephen G. ; Vaporciyan, Ara ; Walsh, Garrett L. ; Johnson, Faye M. ; Fang, Bingliang. / Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer. In: Cancer Letters. 2015 ; Vol. 357, No. 1. pp. 179-185.
@article{fc44d1eef71b42e3ab69e8d3de11dc1f,
title = "Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer",
abstract = "Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5{\%}, 21.7{\%}, 17.4{\%}, 17.4{\%}, 13.0{\%}, and 8.7{\%}, respectively. Other genes with deleterious mutations in ≥3 (13.0{\%}) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93{\%}) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies.",
keywords = "Biomarkers, Gene mutations, Lung cancer, Patient-derived xenografts, Tumor models",
author = "Chuncheng Hao and Li Wang and Shaohua Peng and Mengru Cao and Hongyu Li and Jing Hu and Xiao Huang and Wei Liu and Hui Zhang and Shuhong Wu and Apar Pataer and Heymach, {John V.} and Eterovic, {Agda Karina} and Qingxiu Zhang and Shaw, {Kenna R.} and Ken Chen and Andrew Futreal and Michael Wang and Wayne Hofstetter and Reza Mehran and David Rice and Roth, {Jack A.} and Boris Sepesi and Swisher, {Stephen G.} and Ara Vaporciyan and Walsh, {Garrett L.} and Johnson, {Faye M.} and Bingliang Fang",
year = "2015",
month = "2",
day = "1",
doi = "10.1016/j.canlet.2014.11.024",
language = "English (US)",
volume = "357",
pages = "179--185",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
number = "1",

}

TY - JOUR

T1 - Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer

AU - Hao, Chuncheng

AU - Wang, Li

AU - Peng, Shaohua

AU - Cao, Mengru

AU - Li, Hongyu

AU - Hu, Jing

AU - Huang, Xiao

AU - Liu, Wei

AU - Zhang, Hui

AU - Wu, Shuhong

AU - Pataer, Apar

AU - Heymach, John V.

AU - Eterovic, Agda Karina

AU - Zhang, Qingxiu

AU - Shaw, Kenna R.

AU - Chen, Ken

AU - Futreal, Andrew

AU - Wang, Michael

AU - Hofstetter, Wayne

AU - Mehran, Reza

AU - Rice, David

AU - Roth, Jack A.

AU - Sepesi, Boris

AU - Swisher, Stephen G.

AU - Vaporciyan, Ara

AU - Walsh, Garrett L.

AU - Johnson, Faye M.

AU - Fang, Bingliang

PY - 2015/2/1

Y1 - 2015/2/1

N2 - Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in ≥3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies.

AB - Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in ≥3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies.

KW - Biomarkers

KW - Gene mutations

KW - Lung cancer

KW - Patient-derived xenografts

KW - Tumor models

UR - http://www.scopus.com/inward/record.url?scp=84920374898&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920374898&partnerID=8YFLogxK

U2 - 10.1016/j.canlet.2014.11.024

DO - 10.1016/j.canlet.2014.11.024

M3 - Article

VL - 357

SP - 179

EP - 185

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

IS - 1

ER -