Identification and Clinical Validation of a Novel 4 Gene-Signature with Prognostic Utility in Colorectal Cancer.

Published on Aug 5, 2019in International Journal of Molecular Sciences4.556
· DOI :10.3390/IJMS20153818
Pankaj Ahluwalia6
Estimated H-index: 6
(Georgia Regents University),
Ashis K. Mondal14
Estimated H-index: 14
(Georgia Regents University)
+ 8 AuthorsRavindra Kolhe19
Estimated H-index: 19
Sources
Abstract
Colorectal cancer (CRC) is a high burden disease with several genes involved in tumor progression. The aim of the present study was to identify, generate and clinically validate a novel gene signature to improve prediction of overall survival (OS) to effectively manage colorectal cancer. We explored The Cancer Genome Atlas (TCGA), COAD and READ datasets (597 samples) from The Protein Atlas (TPA) database to extract a total of 595 candidate genes. In parallel, we identified 29 genes with perturbations in > 6 cancers which are also affected in CRC. These genes were entered in cBioportal to generate a 17 gene panel with highest perturbations. For clinical validation, this gene panel was tested on the FFPE tissues of colorectal cancer patients (88 patients) using Nanostring analysis. Using multivariate analysis, a high prognostic score (composite 4 gene signature—DPP7/2, YWHAB, MCM4 and FBXO46) was found to be a significant predictor of poor prognosis in CRC patients (HR: 3.42, 95% CI: 1.71–7.94, p < 0.001 *) along with stage (HR: 4.56, 95% CI: 1.35–19.15, p = 0.01 *). The Kaplan-Meier analysis also segregated patients on the basis of prognostic score (log-rank test, p = 0.001 *). The external validation using GEO dataset (GSE38832, 122 patients) corroborated the prognostic score (HR: 2.7, 95% CI: 1.99–3.73, p < 0.001 *). Additionally, higher score was able to differentiate stage II and III patients (130 patients) on the basis of OS (HR: 2.5, 95% CI: 1.78–3.63, p < 0.001 *). Overall, our results identify a novel 4 gene prognostic signature that has clinical utility in colorectal cancer.
Download
📖 Papers frequently viewed together
28 Citations
2 Citations
References48
Newest
#1Qian Liu (Peking Union Medical College)H-Index: 65
#2Junjie Deng (Peking Union Medical College)H-Index: 2
Last. Jie Ma (Peking Union Medical College)H-Index: 9
view all 5 authors...
: Colorectal cancer (CRC) is a common malignant tumor with high morbidity and mortality around the world. The aim of this study was to determine the genes significantly associated with the overall survival (OS) of CRC patients and predict their function in the competing endogenous RNA (ceRNA) regulation networks. We constructed the lncRNA-miRNA-mRNA networks according to the differentially expressed RNAs from the The Cancer Genome Atlas data sets of 561 CRC patients. Twelve differentially expres...
7 CitationsSource
#1Raju Kandimalla (Baylor University Medical Center)H-Index: 16
#2Tsuyoshi Ozawa (UTokyo: University of Tokyo)H-Index: 9
Last. Miriam CuatrecasasH-Index: 33
view all 17 authors...
11 CitationsSource
#1Yan Li (Southern Medical University)H-Index: 5
#2Meizhi He (Southern Medical University)H-Index: 4
Last. Lang Xie (Southern Medical University)H-Index: 2
view all 8 authors...
Background: Studies evaluating the prognostic significance of programmed death-ligand 1 (PD-L1) expression in colorectal cancer (CRC) are limited and remain controversial. This meta-analysis was conducted in order to evaluate the clinicopathological and prognostic significance of PD-L1 expression in CRC patients. Methods: A comprehensive search was performed against the Medline/PubMed, Embase, Cochrane Library, Web of Science (WoS) and Scopus databases. Data were extracted with name of the first...
41 CitationsSource
#1Yanping Yu (University of Pittsburgh)H-Index: 8
#2Peng Liu (University of Pittsburgh)H-Index: 6
Last. Jianhua Luo (University of Pittsburgh)H-Index: 41
view all 14 authors...
Chromosome changes are one of the hallmarks of human malignancies. Chromosomal rearrangement is frequent in human cancers. One of the consequences of chromosomal rearrangement is gene fusions in the cancer genome. We have previously identified a panel of fusion genes in aggressive prostate cancers. In this study, we showed that 6 of these fusion genes are present in 7 different types of human malignancies with variable frequencies. Among them, the CCNH-C5orf30 and TRMT11-GRIK2 gene fusions were ...
18 CitationsSource
#1Jing-Hua Pan (JNU: Jinan University)H-Index: 8
#2Hong Zhou (JNU: Jinan University)H-Index: 6
Last. Lijun Rong (UIC: University of Illinois at Chicago)H-Index: 24
view all 9 authors...
Background: Layilin (LAYN) is a critical gene that regulates T cell function. However, the correlations of LAYN to prognosis and tumor-infiltrating lymphocytes in different cancers remain unclear. Methods: LAYN expression was analyzed via the Oncomine database and Tumor Immune Estimation Resource (TIMER) site. We evaluated the influence of LAYN on clinical prognosis using Kaplan-Meier plotter, the PrognoScan database and Gene Expression Profiling Interactive Analysis (GEPIA). The correlations be...
116 CitationsSource
#1Shuguang Zuo (Henan University)H-Index: 6
#2Gongpeng Dai (Henan University)H-Index: 4
Last. Xuequn Ren (Henan University)H-Index: 3
view all 3 authors...
An accurate and robust gene signature is of the utmost importance in assisting oncologists to make a more accurate evaluation in clinical practice. In our study, we extracted key mRNAs significantly related to colorectal cancer (CRC) prognosis and we constructed an expression-based gene signature to predict CRC patients’ survival. mRNA expression profiles and clinicopathological data of colon adenocarcinoma (COAD) cases and rectum adenocarcinoma (READ) were collected from The Cancer Genome Atlas...
32 CitationsSource
#1Rebecca L. Siegel (ACS: American Cancer Society)H-Index: 67
#2Kimberly D. Miller (ACS: American Cancer Society)H-Index: 28
Last. Ahmedin Jemal (ACS: American Cancer Society)H-Index: 139
view all 3 authors...
: Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the Nati...
10.5k CitationsSource
#1Zhixun Zhao (HMU: Harbin Medical University)H-Index: 8
#2Shuangmei Zou (Peking Union Medical College)H-Index: 3
Last. Xishan Wang (HMU: Harbin Medical University)H-Index: 12
view all 12 authors...
Apolipoprotein E (ApoE) plays a key role in tumorigenesis and progression, such as cell proliferation, angiogenesis and metastasis. ApoE overexpression was associated with aggressive biological behaviors and poor prognosis in a variety of tumor according to previous studies. This study aimed to assess the prognostic value and explore the potential relationship with tumor progression in colorectal cancer (CRC). We collected the expression profiling microarray data from the Gene Expression Omnibus...
17 CitationsSource
#1Rosa M. Xicola (Yale Cancer Center)H-Index: 27
#2Zarko Manojlovic (SC: University of Southern California)H-Index: 10
Last. Nathan A. Ellis (UA: University of Arizona)H-Index: 25
view all 11 authors...
: African Americans (AAs) have higher incidence and mortality rates of colorectal cancer (CRC) compared with other US populations. They present with more right-sided, microsatellite stable disease and are diagnosed at earlier ages compared with non-Hispanic Whites (NHWs). To gain insight into these trends, we conducted exome sequencing (n = 45), copy number (n = 33) and methylation analysis (n = 11) of microsatellite stable AA CRCs. Results were compared with data from The Cancer Genome Atlas (T...
16 CitationsSource
#1Chuanpeng Dong (Fudan University)H-Index: 10
#2Danni Cui (Fudan University)H-Index: 2
Last. Lei Liu (Fudan University)H-Index: 53
view all 7 authors...
Previous studies have suggested that cancer stem cells serve crucial functions in tumorigenesis, metastasis and therapy failure. Stem cell signaling transduction pathways are frequently dysregulated in cancer and associated with tumorigenesis, metastasis and the cell cycle, which are necessary for cancer proliferation. However, cancer stem cell-associated gene signatures have not been established for predicting patient outcomes in colorectal cancer. Using a gene-mining approach, the present stud...
3 CitationsSource
Cited By14
Newest
#1Gangga Anuraga (TMU: Taipei Medical University)H-Index: 2
#2Wan-Chun Tang (TMU: Taipei Medical University)
Last. Chih-Yang Wang (TMU: Taipei Medical University)H-Index: 7
view all 8 authors...
Colorectal cancer (CRC) has the fourth-highest incidence of all cancer types, and its incidence has steadily increased in the last decade. The general transcription factor III (GTF3) family, comprising GTF3A, GTF3B, GTF3C1, and GTFC2, were stated to be linked with the expansion of different types of cancers; however, their messenger (m)RNA expressions and prognostic values in colorectal cancer need to be further investigated. To study the transcriptomic expression levels of GTF3 gene members in ...
3 CitationsSource
#1Pankaj Ahluwalia (Georgia Regents University)H-Index: 6
#2Meenakshi Ahluwalia (Georgia Regents University)H-Index: 6
Last. Ravindra Kolhe (Georgia Regents University)H-Index: 19
view all 8 authors...
Complex interactions in tumor microenvironment between ECM (extra-cellular matrix) and cancer cell plays a central role in the generation of tumor supportive microenvironment. In this study, the expression of ECM-related genes was explored for prognostic and immunological implication in clear cell renal clear cell carcinoma (ccRCC). Out of 964 ECM genes, higher expression (z-score > 2) of 35 genes showed significant association with overall survival (OS), progression-free survival (PFS) and dise...
1 CitationsSource
#1He Huang (SYSU: Sun Yat-sen University)H-Index: 5
#2Shilei Xu (SYSU: Sun Yat-sen University)H-Index: 6
Last. Kunpeng Hu (SYSU: Sun Yat-sen University)H-Index: 10
view all 7 authors...
Background. Although accumulating evidence suggested that a molecular signature panel may be more effective for the prognosis prediction than routine clinical characteristics, current studies mainly focused on colorectal or colon cancers. No reports specifically focused on the signature panel for rectal cancers (RC). Our present study was aimed at developing a novel prognostic signature panel for RC. Methods. Sequencing (or microarray) data and clinicopathological details of patients with RC wer...
Source
#1Yan Xu (TMUCIH: Tianjin Medical University Cancer Institute and Hospital)H-Index: 3
#2Xueling Yang (TMUCIH: Tianjin Medical University Cancer Institute and Hospital)H-Index: 6
Last. Zhi Guo (TMUCIH: Tianjin Medical University Cancer Institute and Hospital)H-Index: 12
view all 7 authors...
Hepatocellular carcinoma (HCC) remains a major public health problem. MCM4, a constitutive member of the minichromosomal maintenance protein family, has been reported to play a vital role in cancer malignancy behavior. However, the function of MCM4 in HCC remains largely unknown. The present study explored the specific role of MCM4 in HCC. The data from public datasets including TCGA and GTEx showed that MCM4 was overexpressed in HCC and significantly associated with poor prognosis. Immunohistoc...
Source
#1Eleana Parajon (Johns Hopkins University)H-Index: 1
#2Alexandra Surcel (Johns Hopkins University)H-Index: 9
Last. Douglas N. Robinson (Johns Hopkins University)H-Index: 31
view all 3 authors...
Cancer progression is dependent on heightened mechanical adaptation, both for the cells’ ability to change shape and to interact with varying mechanical environments. This type of adaptation is dep...
1 CitationsSource
#1Zhe Yu (PKU: Peking University)
#2Xuemei Ma (Chinese PLA General Hospital)H-Index: 1
Last. Yongping Yang (PKU: Peking University)H-Index: 1
view all 9 authors...
Several studies have demonstrated that chronic hepatitis delta virus (HDV) infection is associated with a worsening of hepatitis B virus (HBV) infection and increased risk of hepatocellular carcinoma (HCC). However, there is limited data on the role of HDV in the oncogenesis of HCC. This study is aimed at assessing the potential mechanisms of HDV-associated hepatocarcinogenesis, especially to screen and identify key genes and pathways possibly involved in the pathogenesis of HCC. We selected thr...
Source
#1Pankaj Ahluwalia (G.N.D.U.: Guru Nanak Dev University)
#2Ravindra Kolhe (Georgia Regents University)H-Index: 19
Last. Gagandeep K. Gahlay (G.N.D.U.: Guru Nanak Dev University)H-Index: 11
view all 3 authors...
Abstract Colorectal cancer (CRC) is one of the most prevalent cancers, with more than one million new cases every year. In the last few decades, several advancements in therapeutic and preventative levels have reduced the mortality rate, but new biomarkers are required for improved prognosis. The alterations at the genetic and epigenetic level have been recognized as major players in tumorigenesis. The products of gene expression in the form of mRNA, microRNA, and long-noncoding RNA, have starte...
10 CitationsSource
#1Zhen-Jiang Wang (JNU: Jinan University)
#2Mingyi Guo (JNU: Jinan University)
Last. Yu-Ping Chen (JNU: Jinan University)
view all 7 authors...
Colorectal cancer (CRC) is one of the most common neoplastic diseases worldwide. With high recurrence rate among all cancers, treatment of CRC only improved a little over the last two decades. The mortality and morbidity rates can be significantly lessened by earlier diagnosis and prompt treatment. Available biomarkers are not sensitive enough for the diagnosis of CRC, whereas the standard diagnostic method, endoscopy, is an invasive test and expensive. Hence, seeking the diagnostic and prognost...
Source
#1Yucheng Qian (ZJU: Zhejiang University)H-Index: 1
#2Jingsun Wei (ZJU: Zhejiang University)H-Index: 1
Last. Kefeng Ding (ZJU: Zhejiang University)H-Index: 14
view all 13 authors...
Colorectal cancer (CRC) is a leading cause of cancer-related death in human. Several studies have investigated whether immune-related genes (IRGs) or tumor immune microenvironment (TIME) could be indicators of CRC prognoses. This study aimed to develop an improved prognostic signature for CRC based on IRGs to predict overall survival (OS) and provide new therapeutic targets for colorectal cancer treatment. Based on the screened IRGs, the Cox regression model was used to build a prediction model ...
Source
#1Mengyu Sun (HUST: Huazhong University of Science and Technology)
#2Tongyue Zhang (HUST: Huazhong University of Science and Technology)H-Index: 3
Last. Limin Xia (HUST: Huazhong University of Science and Technology)H-Index: 11
view all 5 authors...
Colorectal cancer (CRC) has the characteristics of high morbidity and mortality. LncRNA not only participates in the progression of CRC through genes and transcription levels, but also regulates the tumor microenvironment and leads to the malignant phenotype of tumors. Therefore, we identified immune-related LncRNAs for the construction of clinical prognostic model. We searched The Cancer Genome Atlas (TCGA) database for original data. Then we identified differentially expressed irlncRNA (DEirln...
Source