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Kinome sequencing reveals RET G691S polymorphism in human neuroendocrine lung cancer cell lines

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Abstract

Neuroendocrine (NE) lung tumors comprise 20–25 % of all invasive lung malignancies. Currently, no effective treatments are available to cure these tumors, and it is necessary to identify a molecular alteration(s) that characterizes NE lung tumor cells. We aimed to identify a kinase mutation(s) associated with NE lung tumor by screening 517 kinase-encoding genes in human lung cancer cell lines. Our next-generation sequencing analysis of six NE lung tumor cell lines (four small cell lung cancer lines and two non-small cell lung cancer lines) and three non-NE lung tumor lines revealed various kinase mutations, including a nonsynonymous mutation in the proto-oncogene RET (c.2071G > A; p.G691S). Further evaluation of the RET polymorphism in total 15 lung cancer cell lines by capillary sequencing suggested that the frequency of the minor allele (A-allele) in NE lung tumor lines was significantly higher than its frequency in a reference population (p = 0.0001). However, no significant difference between non-NE lung tumor lines and a reference group was detected (p = 1.0). Nevertheless, neither RET expression levels were correlated with the levels of neuron-specific enolase (NSE), a key NE marker, nor vandetanib and cabozantinib, small molecule compounds that inhibit RET, affected NSE levels in lung cancer cells. Our data suggest a potential association of G691S RET polymorphism with NE lung tumor, proposing the necessity of more thorough evaluation of this possibility. The dataset of kinase mutation profiles in this report may help choosing cell line models for study of lung cancer.

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Abbreviations

CI:

Confidence interval

MEN2:

Multiple endocrine neoplasia type 2

NCBI:

National Center For Biotechnology Information

NE:

Neuroendocrine

NSE:

Neuron-specific enolase

NSCLC:

Non-small cell lung carcinoma

OR:

Odds ratio

RET:

Rearranged during transfection

SCLC:

Small cell lung carcinoma

SNP:

Single nucleotide polymorphism

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Acknowledgments

We thank Dr. Barry Nelkin at Johns Hopkins Medical Institute for cell lines, Dr. Ruta Brazauskas (Division of Biostatistics, Medical College of Wisconsin) for statistical analysis, and Dr. Jin-Hwan Kim and Cassandra Neitzel for technical assistance. This work was supported by Research Acceleration Grant (In Kind) for the American Cancer Society, FAMRI Young Investigator Award (062438), American Cancer Society (RSGM-10-189-01-TBE), and National Cancer Institute (R01CA138441) to J.P.

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All authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA

    Nadiya Sosonkina, Seung-Keun Hong, Dmytro Starenki & Jong-In Park

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  1. Nadiya Sosonkina
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  2. Seung-Keun Hong
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  3. Dmytro Starenki
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  4. Jong-In Park
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Correspondence to Jong-In Park.

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Sosonkina, N., Hong, SK., Starenki, D. et al. Kinome sequencing reveals RET G691S polymorphism in human neuroendocrine lung cancer cell lines. Genes Genom 36, 829–841 (2014). https://doi.org/10.1007/s13258-014-0217-6

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