Department for Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Department for Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
Clin Cancer Res. 2015 Aug 15;21(16):3759-70. doi: 10.1158/1078-0432.CCR-14-3294. Epub 2015 Apr 24.
Colorectal cancer has high incidence and mortality worldwide. Patients with microsatellite instable (MSI) tumors have significantly better prognosis than patients with microsatellite stable (MSS) tumors. Considerable variation in disease outcome remains a challenge within each subgroup, and our purpose was to identify biomarkers that improve prediction of colorectal cancer prognosis.
Mutation analyses of 42 MSI target genes were performed in two independent MSI tumor series (n = 209). Markers that were significantly associated with prognosis in the test series were assessed in the validation series, followed by functional and genetic explorations. The clinical potential was further investigated by immunohistochemistry in a population-based colorectal cancer series (n = 903).
We identified the cell-cycle gene regulator of chromosome condensation 2 (RCC2) as a cancer biomarker. We found a mutation in the 5' UTR region of RCC2 that in univariate and multivariate analyses was significantly associated with improved outcome in the MSI group. This mutation caused reduction of protein expression in dual luciferase gene reporter assays. siRNA knockdown in MSI colon cancer cells (HCT15) caused reduced cell proliferation, cell-cycle arrest, and increased apoptosis. Massive parallel sequencing revealed few RCC2 mutations in MSS tumors. However, weak RCC2 protein expression was significantly associated with poor prognosis, independent of clinical high-risk parameters, and stratifies clinically important patient subgroups with MSS tumors, including elderly patients (>75 years), stage II patients, and those with rectal cancer.
Impaired RCC2 affects functional and clinical endpoints of colorectal cancer. High-risk patients with either MSI or MSS tumors can be identified with cost-effective routine RCC2 assays.
结直肠癌在全球范围内具有较高的发病率和死亡率。微卫星不稳定（MSI）肿瘤患者的预后明显优于微卫星稳定（MSS）肿瘤患者。在每个亚组内，疾病结局仍存在相当大的差异，我们的目的是确定可改善结直肠癌预后预测的生物标志物。
在两个独立的 MSI 肿瘤系列（n=209）中进行了 42 个 MSI 靶基因的突变分析。在测试系列中与预后显著相关的标志物在验证系列中进行了评估，随后进行了功能和遗传探索。通过免疫组织化学方法在基于人群的结直肠癌系列（n=903）中进一步研究了其临床潜力。
我们确定了染色体凝聚 2（RCC2）的细胞周期基因调节剂为癌症生物标志物。我们在 RCC2 的 5'UTR 区域发现了一个突变，该突变在单变量和多变量分析中与 MSI 组的改善预后显著相关。该突变导致双荧光素酶基因报告基因检测中蛋白表达减少。在 MSI 结肠癌细胞（HCT15）中进行 siRNA 敲低导致细胞增殖减少、细胞周期停滞和凋亡增加。大规模平行测序显示 MSS 肿瘤中 RCC2 突变很少。然而，RCC2 蛋白表达较弱与预后不良显著相关，独立于临床高危参数，并对 MSS 肿瘤的重要临床亚组进行分层，包括老年患者（>75 岁）、II 期患者和直肠癌患者。
RCC2 功能障碍影响结直肠癌的功能和临床终点。具有 MSI 或 MSS 肿瘤的高危患者可以通过具有成本效益的常规 RCC2 检测来识别。
