Oncotarget

Research Papers:

A mononucleotide repeat in PRRT2 is an important, frequent target of mismatch repair deficiency in cancer

Inês Teles Alves, David Cano, René Böttcher, Hetty van der Korput, Winand Dinjens, Guido Jenster _ and Jan Trapman

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Oncotarget. 2017; 8:6043-6056. https://doi.org/10.18632/oncotarget.13464

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Abstract

Inês Teles Alves1,2, David Cano2, René Böttcher1, Hetty van der Korput2, Winand Dinjens2, Guido Jenster1, Jan Trapman2

1Department of Urology, Erasmus MC, Rotterdam, The Netherlands

2Department of Pathology, Erasmus MC, Rotterdam, The Netherlands

Correspondence to:

Guido Jenster, email: g.jenster@erasmusmc.nl

Keywords: PRRT2, mismatch repair, mononucleotide repeat, prostate cancer, colorectal cancer

Received: November 22, 2015     Accepted: October 21, 2016     Published: November 19, 2016

ABSTRACT

The DNA mismatch repair (MMR) system corrects DNA replication mismatches thereby contributing to the maintenance of genomic stability. MMR deficiency has been observed in prostate cancer but its impact on the genomic landscape of these tumours is not known. In order to identify MMR associated mutations in prostate cancer we have performed whole genome sequencing of the MMR deficient PC346C prostate cancer cell line. We detected a total of 1196 mutations in PC346C which was 1.5-fold higher compared to a MMR proficient prostate cancer sample (G089). Of all different mutation classes, frameshifts in mononucleotide repeat (MNR) sequences were significantly enriched in the PC346C sample. As a result, a selection of genes with frameshift mutations in MNR was further assessed regarding its mutational status in a comprehensive panel of prostate, ovarian, endometrial and colorectal cancer cell lines. We identified PRRT2 and DAB2IP to be frequently mutated in MMR deficient cell lines, colorectal and endometrial cancer patient samples. Further characterization of PRRT2 revealed an important role of this gene in cancer biology. Both normal prostate cell lines and a colorectal cancer cell line showed increased proliferation, migration and invasion when expressing the mutated form of PRRT2 (ΔPRRT2). The wild-type PRRT2 (PRRT2wt) had an inhibitory effect in proliferation, consistent with the low expression level of PRRT2 in cancer versus normal prostate samples.


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