KRT17 as a prognostic biomarker for stage II colorectal cancer
KRT17 as a prognostic biomarker for stage II colorectal cancer
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DOI：
10.1093/carcin/bgz192
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发表时间：
2020-05-01
期刊：
影响因子：
4.7
通讯作者：
Kono, Koji
中科院分区：
文献类型：
--
作者：
Ujiie, Daisuke;Okayama, Hirokazu;Kono, Koji
辅助化疗被考虑用于临床病理特征预后较差的II期结直肠癌(CRC)患者；然而，目前的分层算法仍然不足以识别高危患者。为了发展预后分析，我们基于多个平台对9个II期患者队列进行了逐步筛选和验证策略，包括微阵列、RNA测序(RNA-SEQ)和福尔马林固定石蜡包埋(FFPE)组织的免疫组织化学(IHC)。使用四个微阵列数据集(总共n=458个)作为发现集，以筛选与术后复发相关的单基因。候选基因的预后价值在三个独立的微阵列/序列验证队列中进行评估(n=，n=93和n=183)，然后在两个独立的FFPE序列中进行KRT17的IHC(分别为n=110和n=44)。我们发现，高水平的KRT17转录表达不仅在发现组中，而且在三个验证队列中都与较差的无复发生存率(RFS)显著相关，通过多因素分析，其预后影响独立于传统因素。在两个独立的FFPE队列中，KRT17蛋白阳性表达与较差的RFS显著相关。在对包括高危临床病理特征在内的常规变量进行调整的多变量模型中，KRT17蛋白的表达对RFS有独立的预后影响。总之，利用由997名II期患者组成的9个独立队列，我们确定并验证了KRT17转录本和KRT17蛋白的表达是一个强有力的预后生物标志物，可以区分术后复发的II期患者，在目前可用的高危因素之外提供额外的预后分层。
Adjuvant chemotherapy is considered for patients with stage II colorectal cancer (CRC) characterized by poor prognostic clinicopathological features; however, current stratification algorithms remain inadequate for identifying high-risk patients. To develop prognostic assays, we conducted a step-wise screening and validation strategy using nine cohorts of stage II patients based on multiple platforms, including microarray, RNA-sequencing (RNA-seq) and immunohistochemistry (IHC) on formalin-fixed paraffin-embedded (FFPE) tissues. Four microarray datasets (total n = 458) were used as the discovery set to screen for single genes associated with postoperative recurrence. Prognostic values of candidate genes were evaluated in three independent microarray/RNA-seq validation cohorts (n = 89, n = 93 and n = 183, respectively), and then IHC for KRT17 was conducted in two independent FFPE series (n = 110 and n = 44, respectively). We found that high levels of KRT17 transcript expression were significantly associated with poor relapse-free survival (RFS) not only in the discovery set, but also in three validation cohorts, and its prognostic impact was independent of conventional factors by multivariate analyses. Positive staining of KRT17 protein was significantly associated with poor RFS in two independent FFPE cohorts. KRT17 protein expression had independent prognostic impact on RFS in a multivariate model adjusted for conventional variables, including high-risk clinicopathological features. In conclusion, using nine independent cohorts consisting of 997 stage II patients, we identified and validated the expression of KRT17 transcript and KRT17 protein as a robust prognostic biomarker that can discriminate postoperative stage II patients who are at high probability of disease recurrence, providing additional prognostic stratification beyond the currently available high-risk factors.