Alves Inês Teles, Cano David, Böttcher René, van der Korput Hetty, Dinjens Winand, Jenster Guido, Trapman Jan
Department of Urology, Erasmus MC, Rotterdam, The Netherlands.
Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
Oncotarget. 2017 Jan 24;8(4):6043-6056. doi: 10.18632/oncotarget.13464.
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.
DNA错配修复（MMR）系统可校正DNA复制错配，从而有助于维持基因组稳定性。在前列腺癌中已观察到MMR缺陷，但其对这些肿瘤基因组格局的影响尚不清楚。为了鉴定前列腺癌中与MMR相关的突变，我们对MMR缺陷的PC346C前列腺癌细胞系进行了全基因组测序。我们在PC346C中共检测到1196个突变，这比MMR功能正常的前列腺癌样本（G089）高1.5倍。在所有不同的突变类型中，单核苷酸重复（MNR）序列中的移码突变在PC346C样本中显著富集。因此，我们进一步评估了一组在前列腺癌、卵巢癌、子宫内膜癌和结肠癌细胞系中具有MNR移码突变的基因的突变状态。我们发现PRRT2和DAB2IP在MMR缺陷的细胞系、结直肠癌和子宫内膜癌患者样本中经常发生突变。对PRRT2的进一步表征揭示了该基因在癌症生物学中的重要作用。正常前列腺细胞系和结肠癌细胞系在表达PRRT2的突变形式（ΔPRRT2）时，增殖、迁移和侵袭均增加。野生型PRRT2（PRRT2wt）对增殖有抑制作用，这与PRRT2在癌组织与正常前列腺样本中的低表达水平一致。
