Comprehensive genetic characterization of human thyroid cancer cell lines

A validated panel for preclinical studies

Iñigo Landa, Nikita Pozdeyev, Christopher Korch, Laura A. Marlow, Robert Christian Smallridge, John A III Copland, Ying C. Henderson, Stephen Y. Lai, Gary L. Clayman, Naoyoshi Onoda, Aik Choon Tan, Maria E.R. Garcia-Rendueles, Jeffrey A. Knauf, Bryan R. Haugen, James A. Fagin, Rebecca E. Schweppe

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Purpose: Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers. Experimental Design: We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers. Results: Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS, or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAF V600E versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization. Conclusions: This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.

Original languageEnglish (US)
Pages (from-to)3141-3151
Number of pages11
JournalClinical Cancer Research
Volume25
Issue number10
DOIs
StatePublished - Jan 1 2019

Fingerprint

Medical Genetics
Thyroid Neoplasms
Cell Line
Neoplasms
Mutation
Thyroid Gland
Histone Acetyltransferases
DNA Mismatch Repair
Chromatin Assembly and Disassembly
Gene Fusion
Mitogen-Activated Protein Kinase Kinases
Cell Cycle Checkpoints
Tumor Cell Line
Transcriptome
Research Design
Research Personnel

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Comprehensive genetic characterization of human thyroid cancer cell lines : A validated panel for preclinical studies. / Landa, Iñigo; Pozdeyev, Nikita; Korch, Christopher; Marlow, Laura A.; Smallridge, Robert Christian; Copland, John A III; Henderson, Ying C.; Lai, Stephen Y.; Clayman, Gary L.; Onoda, Naoyoshi; Tan, Aik Choon; Garcia-Rendueles, Maria E.R.; Knauf, Jeffrey A.; Haugen, Bryan R.; Fagin, James A.; Schweppe, Rebecca E.

In: Clinical Cancer Research, Vol. 25, No. 10, 01.01.2019, p. 3141-3151.

Research output: Contribution to journalArticle

Landa, I, Pozdeyev, N, Korch, C, Marlow, LA, Smallridge, RC, Copland, JAIII, Henderson, YC, Lai, SY, Clayman, GL, Onoda, N, Tan, AC, Garcia-Rendueles, MER, Knauf, JA, Haugen, BR, Fagin, JA & Schweppe, RE 2019, 'Comprehensive genetic characterization of human thyroid cancer cell lines: A validated panel for preclinical studies', Clinical Cancer Research, vol. 25, no. 10, pp. 3141-3151. https://doi.org/10.1158/1078-0432.CCR-18-2953
Landa, Iñigo ; Pozdeyev, Nikita ; Korch, Christopher ; Marlow, Laura A. ; Smallridge, Robert Christian ; Copland, John A III ; Henderson, Ying C. ; Lai, Stephen Y. ; Clayman, Gary L. ; Onoda, Naoyoshi ; Tan, Aik Choon ; Garcia-Rendueles, Maria E.R. ; Knauf, Jeffrey A. ; Haugen, Bryan R. ; Fagin, James A. ; Schweppe, Rebecca E. / Comprehensive genetic characterization of human thyroid cancer cell lines : A validated panel for preclinical studies. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 10. pp. 3141-3151.
@article{f4c3dc304a35403fbe3ec2da61002c5b,
title = "Comprehensive genetic characterization of human thyroid cancer cell lines: A validated panel for preclinical studies",
abstract = "Purpose: Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers. Experimental Design: We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers. Results: Unsupervised transcriptomic analysis showed that 94{\%} of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS, or gene fusions). Mutations in the TERT promoter (83{\%}) and TP53 (71{\%}) were highly prevalent. There were frequent alterations in PTEN, PIK3CA, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAF V600E versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization. Conclusions: This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.",
author = "I{\~n}igo Landa and Nikita Pozdeyev and Christopher Korch and Marlow, {Laura A.} and Smallridge, {Robert Christian} and Copland, {John A III} and Henderson, {Ying C.} and Lai, {Stephen Y.} and Clayman, {Gary L.} and Naoyoshi Onoda and Tan, {Aik Choon} and Garcia-Rendueles, {Maria E.R.} and Knauf, {Jeffrey A.} and Haugen, {Bryan R.} and Fagin, {James A.} and Schweppe, {Rebecca E.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1158/1078-0432.CCR-18-2953",
language = "English (US)",
volume = "25",
pages = "3141--3151",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

TY - JOUR

T1 - Comprehensive genetic characterization of human thyroid cancer cell lines

T2 - A validated panel for preclinical studies

AU - Landa, Iñigo

AU - Pozdeyev, Nikita

AU - Korch, Christopher

AU - Marlow, Laura A.

AU - Smallridge, Robert Christian

AU - Copland, John A III

AU - Henderson, Ying C.

AU - Lai, Stephen Y.

AU - Clayman, Gary L.

AU - Onoda, Naoyoshi

AU - Tan, Aik Choon

AU - Garcia-Rendueles, Maria E.R.

AU - Knauf, Jeffrey A.

AU - Haugen, Bryan R.

AU - Fagin, James A.

AU - Schweppe, Rebecca E.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers. Experimental Design: We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers. Results: Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS, or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAF V600E versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization. Conclusions: This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.

AB - Purpose: Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers. Experimental Design: We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers. Results: Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS, or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAF V600E versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization. Conclusions: This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.

UR - http://www.scopus.com/inward/record.url?scp=85065769458&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065769458&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-2953

DO - 10.1158/1078-0432.CCR-18-2953

M3 - Article

VL - 25

SP - 3141

EP - 3151

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 10

ER -