Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma

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Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma

Journal Article (2017)

Author(s)

Sjors M. Kas (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Julian J. de Ruiter (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Koen Schipper (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Stefano Annunziato (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Eva Schut (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Sjoerd Klarenbeek (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Anne Paulien Drenth (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Eline van der Burg (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Christiaan Klijn (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Jelle J. ten Hoeve (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

David J. Adams (Wellcome Trust Sanger Institute)

Marco J. Koudijs (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Jelle Wesseling (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Micha Nethe (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Lodewyk F.A. Wessels (TU Delft - Pattern Recognition and Bioinformatics)

Jos Jonkers (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Research Group

Pattern Recognition and Bioinformatics

DOI related publication

https://doi.org/10.1038/ng.3905

Transcriptomics Mutagenesis Breast cancerq

To reference this document use:

https://resolver.tudelft.nl/uuid:1a6f15f2-1921-4280-80cd-ba79c364264a

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Publication Year

2017

Language

English

Research Group

Pattern Recognition and Bioinformatics

Volume number

49

Pages (from-to)

1219-1230

Downloads counter

289

Abstract

Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype and accounts for 8–14% of all cases. Although the majority of human ILCs are characterized by the functional loss of E-cadherin (encoded by CDH1), inactivation of Cdh1 does not predispose mice to develop mammary tumors, implying that mutations in additional genes are required for ILC formation in mice. To identify these genes, we performed an insertional mutagenesis screen using the Sleeping Beauty transposon system in mice with mammary-specific inactivation of Cdh1. These mice developed multiple independent mammary tumors of which the majority resembled human ILC in terms of morphology and gene expression. Recurrent and mutually exclusive transposon insertions were identified in Myh9, Ppp1r12a, Ppp1r12b and Trp53bp2, whose products have been implicated in the regulation of the actin cytoskeleton. Notably, MYH9, PPP1R12B and TP53BP2 were also frequently aberrated in human ILC, highlighting these genes as drivers of a novel oncogenic pathway underlying ILC development.

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