title: Exome-level comparison of primary well-differentiated neuroendocrine tumors and their cell lines.
abstract: Neuroendocrine cancer cell lines are used to investigate therapeutic targets in neuroendocrine tumors (NET) and have been instrumental in the design of clinical trials targeting the PI3K/AKT/mTOR pathways, VEGF inhibitors, and somatostatin analogues. It remains unknown, however, whether the genomic makeup of NET cell lines reflect that of primary NET since comprehensive unbiased genome sequencing has not been performed on the cell lines. Four bronchopulmonary NET (BP-NET)-NCI-H720, NCI-H727, NCI-H835, and UMC11-and two pancreatic neuroendocrine tumors (panNET)-BON-1 and QGP1-were cultured. DNA was isolated, and exome sequencing was done. GATK and EXCAVATOR were used for bioinformatic analysis. We detected a total of 1,764 nonsynonymous single nucleotide variants at a rate of 8 per Mb in BP-NET and 4.3 per Mb in panNET cell lines, including 52 mutated COSMIC cancer genes in these cell lines, such as TP53, BRCA1, RB1, TSC2, NOTCH1, EP300, GNAS, KDR, STK11, and APC but not ATRX, DAXX, nor MEN1. Our data suggest that mutation rate, the pattern of copy number variations, and the mutational spectra in the BP-NET cell lines are more similar to the changes observed in small cell lung cancer than those found in primary BP-NET. Likewise, mutation rate and pattern including the absence of mutations in ATRX/DAXX, MEN1, and YY1 in the panNET cell lines BON1 and QGP1 suggest that these cell lines do not have the genetic signatures of a primary panNET. These results suggest that results from experiments with BP-NET and panNET cell lines need to be interpreted with caution.
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ganesh K
authors.initials: GK
authors.lastname: Boora
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kanwar
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Amit A
authors.initials: AA
authors.lastname: Kulkarni
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Josef
authors.initials: J
authors.lastname: Pleticha
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ames
authors.affiliation: Illumina, San Diego, CA, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Schroth
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA; Mayo Clinic Cancer Center, Rochester, MN, USA. Electronic address: beutler.andreas@mayo.edu.
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Beutler
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA; Mayo Clinic Cancer Center, Rochester, MN, USA. Electronic address: banck.michaela@mayo.edu.
authors.forename: Michaela S
authors.initials: MS
authors.lastname: Banck
mesh_terms: D001984:Bronchial Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D056915:DNA Copy Number Variations; D059472:Exome / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D009154:Mutation; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology
keywords: Pancreatic neuroendocrine tumor; bronchopulmonary carcinoid; cell lines; exome; next-generation sequencing