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Exome-level comparison of primary well-differentiated neuroendocrine tumors and their cell lines
Ganesh K Boora1, Rahul Kanwar1, Amit A Kulkarni1
1Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
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.
Insights
Neuroendocrine tumor cell lines may not accurately represent primary tumors. Genomic analysis reveals differences, suggesting caution when interpreting experimental results from these cell lines in neuroendocrine cancer research.
Area of Science:
- Oncology
- Genomics
- Cancer Cell Line Research
Background:
- Neuroendocrine tumors (NETs) are studied using cell lines to identify therapeutic targets.
- Previous research has focused on pathways like PI3K/AKT/mTOR, VEGF, and somatostatin analogues.
- The genomic similarity of NET cell lines to primary NETs remains unverified.
Purpose of the Study:
- To perform comprehensive, unbiased genome sequencing on established neuroendocrine tumor cell lines.
- To compare the genomic profiles of bronchopulmonary NET (BP-NET) and pancreatic NET (panNET) cell lines with primary NETs.
- To assess the suitability of these cell lines for modeling NET in research.
Main Methods:
- Exome sequencing was performed on four BP-NET cell lines (NCI-H720, NCI-H727, NCI-H835, UMC11) and two panNET cell lines (BON-1, QGP1).
- Bioinformatic analyses were conducted using GATK and EXCAVATOR.
- Detected variants were analyzed for mutation rate, copy number variations, and mutational spectra.
Main Results:
- A total of 1,764 nonsynonymous single nucleotide variants were identified across the cell lines.
- BP-NET cell lines showed mutation rates and patterns more akin to small cell lung cancer than primary BP-NETs.
- panNET cell lines (BON-1, QGP1) lacked key mutations (ATRX, DAXX, MEN1, YY1) found in primary panNETs, indicating a lack of genetic signatures.
Conclusions:
- The genomic profiles of BP-NET and panNET cell lines do not fully recapitulate the genetic landscape of their primary tumor counterparts.
- These findings suggest that experimental results derived from these specific cell lines should be interpreted with caution.
- Further research is needed to develop or validate NET cell line models that accurately reflect primary tumor genomics.
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