Frequency and distribution of Notch mutations in tumor cell lines.

Anders Peter Mutvei,Erik Fredlund,Urban Lendahl

doi:10.1186/s12885-015-1278-x

Anders Peter Mutvei, Erik Fredlund + Show 1 more

Open Access

https://doi.org/10.1186/s12885-015-1278-x

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Journal: BMC cancer	Publication Date: Apr 25, 2015
Citations: 47	License type: CC BY 4.0

Affiliation: Science for Life Laboratory, Karolinska Institutet

Abstract

BackgroundDeregulated Notch signaling is linked to a variety of tumors and it is therefore important to learn more about the frequency and distribution of Notch mutations in a tumor context.MethodsIn this report, we use data from the recently developed Cancer Cell Line Encyclopedia to assess the frequency and distribution of Notch mutations in a large panel of cancer cell lines in silico.ResultsOur results show that the mutation frequency of Notch receptor and ligand genes is at par with that for established oncogenes and higher than for a set of house-keeping genes. Mutations were found across all four Notch receptor genes, but with notable differences between protein domains, mutations were for example more prevalent in the regions encoding the LNR and PEST domains in the Notch intracellular domain. Furthermore, an in silico estimation of functional impact showed that deleterious mutations cluster to the ligand-binding and the intracellular domains of NOTCH1. For most cell line groups, the mutation frequency of Notch genes is higher than in associated primary tumors.ConclusionsOur results shed new light on the spectrum of Notch mutations after in vitro culturing of tumor cells. The higher mutation frequency in tumor cell lines indicates that Notch mutations are associated with a growth advantage in vitro, and thus may be considered to be driver mutations in a tumor cell line context.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1278-x) contains supplementary material, which is available to authorized users.

Highlights

Deregulated Notch signaling is linked to a variety of tumors and it is important to learn more about the frequency and distribution of Notch mutations in a tumor context
We ask a number of questions regarding the frequency of Notch mutations in tumor cell lines and primary tumors: How frequent are Notch mutations in tumor cell lines as compared to other well-established oncogenes and house-keeping genes? How are mutations distributed across the various Notch receptors? Is there a preference for particular mutations in specific tumor cell line types? Our data indicate that Notch mutations occur at a frequency that suggests that they may confer growth advantage during in vitro culture, i.e. that they would be driver mutations, and we identify receptorspecific patterns of mutations
The mutation frequency of Notch receptors and ligands compared to other oncogenes and tumor suppressor genes In Cell Line Encyclopedia (CCLE), more than 1,600 genes, including most known oncogenes and tumor suppressor genes, have been sequenced across more than 900 human tumor cell lines [3]

Summary

Introduction

Deregulated Notch signaling is linked to a variety of tumors and it is important to learn more about the frequency and distribution of Notch mutations in a tumor context. Our understanding of the molecular basis for cancer is rapidly improving, to a large extent owing to the recent progress in DNA sequencing technologies, which allows the mutational landscape to be explored in a genome-wide manner both in primary tumors and in tumor cell lines [1]. Thanks to these efforts, it is becoming increasingly apparent that there are a small number of very frequently mutated genes, along with a longer “tail” of genes with fewer mutations. Notch ICD relocates from the membrane to the nucleus and binds to the DNA-binding protein CSL ( referred to as RBP-Jκ or CBF1), leading to activation of Notch downstream genes [5,6]

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