title: A mononucleotide repeat in PRRT2 is an important, frequent target of mismatch repair deficiency in cancer.
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.
authors.affiliation: Department of Urology, Erasmus MC, Rotterdam, The Netherlands.|Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Inês Teles
authors.initials: IT
authors.lastname: Alves
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Cano
authors.affiliation: Department of Urology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Böttcher
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Hetty
authors.initials: H
authors.lastname: van der Korput
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Winand
authors.initials: W
authors.lastname: Dinjens
authors.affiliation: Department of Urology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Guido
authors.initials: G
authors.lastname: Jenster
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Trapman
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics; D053843:DNA Mismatch Repair; D016889:Endometrial Neoplasms / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D009369:Neoplasms / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics; D000073336:Whole Genome Sequencing / Q000379:methods*; D020703:ras GTPase-Activating Proteins / Q000235:genetics*
chemical_list: C462952:DAB2IP protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C569370:PRRT2 protein, human; D020703:ras GTPase-Activating Proteins
keywords: PRRT2; colorectal cancer; mismatch repair; mononucleotide repeat; prostate cancer