Clinical Significance of a Gene Signature Generated from Tumor Budding Grade in Colon Cancer
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ORIGINAL ARTICLE – TRANSLATIONAL RESEARCH AND BIOMARKERS
Clinical Significance of a Gene Signature Generated from Tumor Budding Grade in Colon Cancer Eiji Shinto, MD1, Yuichiro Yoshida, PhD2, Yoshiki Kajiwara, MD1, Koichi Okamoto, MD1, Satsuki Mochizuki, PhD1, Masato Yamadera, MD1, Takehiro Shiraishi, MD1, Ken Nagata, MD1, Hitoshi Tsuda, MD3, Kazuo Hase, MD1, Yoji Kishi, MD1, and Hideki Ueno, MD1 Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan; 2Central Research Laboratories, Sysmex Corporation, Kobe, Japan; 3Department of Pathology, National Defense Medical College, Tokorozawa, Saitama, Japan 1
ABSTRACT Background. Tumor budding, a microscopic finding of dedifferentiation at the invasive margin, has been reported as a definite prognostic marker in colon cancer (CC). Herein, we aimed to generate a molecular budding signature (MBS) based on DNA microarray data and to examine its prognostic significance. Methods. Frozen tissue samples from 85 patients with stage II/III CC were used for DNA microarray analyses. First, we selected candidate genes that were differentially expressed (twofold change) between the invasive frontal regions and corresponding tumor centers of three extremely high-grade budding tumors. Subsequently, using microarray data from whole-tissue sections of the 85 patients, we selected MBS-constituent genes from the candidates based on correlation to the pathological budding grade. The MBS score was calculated using the sum of the logarithm of the expression of each gene. Results. We selected seven MBS-constituent genes: MSLN, SLC4A11, WNT11, SCEL, RUNX2, MGAT3,
Eiji Shinto and Yuichiro Yoshida have contributed equally to this work.
Electronic supplementary material The online version of this article (https://doi.org/10.1245/s10434-020-08498-3) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2020 First Received: 25 September 2019 E. Shinto, MD e-mail: [email protected]
FOXC1. A comparison of relapse-free survival (RFS) rates revealed a significant impact of the MBS score [5-year RFS, 77.4% (score-high) vs. 95.1% (score-low); P = 0.044]. Analyses of public databases revealed that low MBS score patients exhibited better prognosis than those with high-score cancers (GSE14333: 5-year RFS, 83.1% vs. 66.6%, P = 0.028; GSE39582: 5-year disease-free survival, 72.2% vs. 58.1%, P = 0.0005). Multivariate analysis revealed that the MBS score is an independent prognostic indicator in GSE39582 (hazard ratio, 1.611; P = 0.013). Conclusions. We developed a new gene classification method, i.e., MBS, and demonstrated its clinical relevance as an indicator of high recurrence risk of CC.
Gene expression profiling is increasingly being used for colorectal cancer (CRC) diagnosis, prognosis, and treatment decisions. The leading classifier, OncotypeDX Colon Cancer Assay, improves the prediction of the recurrence risk for patients with stage II colon cancer (CC) and significantly improves prognostic accuracy in predicting t
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