David Otohinoyi, Katherine Pavleszek, Danielle Dooley, Brian Carr, Triston Mabry, Chindo Hicks, Valentine Nfonsam
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引用次数: 0
Abstract
Background: Among the facets of colon cancer pathogenesis is the survival paradox between T4N0 (stage II) colon cancer and anyTN1 (stage III) colon cancer. There are limited genomic studies investigating why a T4N0 disease is deemed worse than stage III colon cancer.
Objective: We demonstrate a multifaceted approach in unraveling the genomic intricacies of T4N0 colon cancer and how it differs from T123N0 and anyTN1 colon cancer using somatic mutation information.
Design: Retrospective study of somatic mutations and their prognostic impact on survival.
Settings: Conducted using The Cancer Genome Atlas and National cBioPortal for Cancer Genomics.
Patients: We stratified our samples based on TNM staging: T4N0, T123N0 and anyTN1.
Main outcome measures: We compared mutation frequency between groups using fishers exact test at P ≤ 0.05. We performed pathway analysis to map biological networks enriched with somatic mutations. We investigated somatic mutation interaction and validated our results with Kaplan-Meier survival analysis on independent datasets.
Results: We observed 30 significantly differentially mutated genes that are unique to T4N0 colon cancer after T123N0 and anyTN1 comparisons. Among these genes, DIDO1, CACNA1B and ALMS1 showed somatic mutation interaction in a co-occurring pattern with other mutated genes. Pathway analysis revealed Ephrin B signaling, Nitric oxide signaling, and calcium signaling to be enriched with mutations and contributory to T4N0 pathogenesis. Survival analysis further substantiated our findings.
Limitations: Retrospective study and patient numbers.
Conclusions: There are patterns of somatic mutation in T4N0 colon cancer tumors that are significantly absent in T123N0 and anyTN1 colon tumors. Somatic mutation interaction highlighted the role of DIDO1, CACNA1B and ALMS1 in T4N0 pathogenesis which contained appreciable mutations that were predicted to be severe. Among these genes, DIDO1 was associated with a decrease in survival. See Video Abstract.
背景：结肠癌发病机制的一个方面是T4N0（II期）结肠癌与任何TN1（III期）结肠癌之间的生存悖论。关于 T4N0 疾病为何被认为比 III 期结肠癌更严重的基因组研究十分有限：我们展示了一种多方面的方法，利用体细胞突变信息揭示 T4N0 结肠癌基因组的复杂性及其与 T123N0 和 anyTN1 结肠癌的不同之处：设计：体细胞突变及其对生存预后影响的回顾性研究：利用癌症基因组图谱（The Cancer Genome Atlas）和国家癌症基因组学门户网站（National cBioPortal for Cancer Genomics）进行研究：我们根据TNM分期对样本进行了分层：主要结果指标：采用鱼类精确检验比较组间突变频率，P≤0.05。我们进行了通路分析，以绘制体细胞突变富集的生物网络。我们研究了体细胞突变的相互作用，并在独立数据集上用Kaplan-Meier生存分析验证了我们的结果：结果：在T123N0和anyTN1比较后，我们观察到30个明显不同的突变基因，这些基因是T4N0结肠癌所特有的。在这些基因中，DIDO1、CACNA1B 和 ALMS1 与其他突变基因以共存模式发生体细胞突变相互作用。通路分析表明，Ephrin B 信号转导、一氧化氮信号转导和钙信号转导富含突变，并与 T4N0 的发病机制有关。生存分析进一步证实了我们的发现：局限性：回顾性研究和患者人数：T4N0结肠癌肿瘤中存在体细胞突变模式，而T123N0和anyTN1结肠癌肿瘤中则明显缺乏。体细胞突变相互作用突显了DIDO1、CACNA1B和ALMS1在T4N0发病机制中的作用，这些基因含有明显的突变，被预测为严重突变。在这些基因中，DIDO1与存活率下降有关。参见视频摘要。
期刊介绍：
Diseases of the Colon & Rectum (DCR) is the official journal of the American Society of Colon and Rectal Surgeons (ASCRS) dedicated to advancing the knowledge of intestinal disorders by providing a forum for communication amongst their members. The journal features timely editorials, original contributions and technical notes.
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