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15. Association Mining Identifies MAL2 as a Novel Tumor Suppressor in Colorectal Cancer

Author

Wang,Kailai, Yang,Yanmei, Zheng,Shu, Hu,Wangxiong, Wang,Kailai, Yang,Yanmei, Zheng,Shu, and Hu,Wangxiong

Abstract

Kailai Wang,1,* Yanmei Yang,2,* Shu Zheng,1 Wangxiong Hu1 1Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China; 2Key Laboratory of Reproductive and Genetics, Ministry of Education, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wangxiong Hu; Shu Zheng, Tel +86-571-87784606 ; +86-571-87784501, Fax +86-571-87214404, Email wxhu@zju.edu.cn; zhengshu@zju.edu.cnIntroduction: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. However, the driver genes that promote CRC metastasis remain poorly understood. Association mining mines and extracts the repeated correlations and relevance in a dataset to predict the appearance of other data items according to the appearance of one item.Methods: Here, the Apriori algorithm was used to find the frequent mutational gene sets (FMGSs) and hidden association rules (ARs) within these FMGSs from 383 CRCs with whole exome sequencing datasets. The weighted correlation network analysis (WGCNA) was used to identify the hub genes in CRC. CCK8, colony formation, cell migration and invasion assays were adopted to detect the roles of hub genes in CRC.Results: Intriguingly, we found that MAL2 (myelin and lymphocyte protein 2) was associated with TP53 and APC in stage IV of CRC, and further subnetwork exploration based on WGCNA identified MAL2 as a potent hub gene. To validate the metastasis-related role of MAL2 in CRC, a lentivirus-based overexpression system was utilized to construct MAL2-overexpressing human CRC LOVO cells. Overexpression of MAL2 remarkably inhibited CRC cell proliferation and invasion.Conclusion: Our results highlighted that MAL2 acts as a tumor suppressor in CRC

Published
2022

17. Proteomics profiling of colorectal cancer progression identifies PLOD2 as a potential therapeutic target

Author

Shao, Yingkuan, primary, Xu, Kailun, additional, Zheng, Xi, additional, Zhou, Biting, additional, Zhang, Xiuli, additional, Wang, Lin, additional, Sun, Yaoting, additional, Li, Dan, additional, Chen, Ting, additional, Wang, Jian, additional, Yu, Shaojun, additional, Sun, Lifeng, additional, Xu, Xiaoming, additional, Dai, Shaozhi, additional, Gao, Huanhuan, additional, Ruan, Guan, additional, Liu, Wei, additional, Cai, Xue, additional, Zhu, Tiansheng, additional, Qi, Lina, additional, Chen, Jiani, additional, Hu, Wangxiong, additional, Weng, Xingyue, additional, Zhu, Yi, additional, Xiang, Xueping, additional, Hu, Zhiyuan, additional, Li, Jinfan, additional, Chen, Lirong, additional, Shao, Jimin, additional, Zheng, Shu, additional, and Guo, Tiannan, additional

Published
2021
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18. A novel 4-gene prognostic signature for hypermutated colorectal cancer

Author

Ge,Weiting, Cai,Wen, Bai,Rui, Hu,Wangxiong, Wu,Dehao, Zheng,Shu, and Hu,Hanguang

Subjects
Cancer Management and Research, hypermutation, colorectal cancer, prognosis, gene signature, digestive system diseases, Original Research
Abstract

Weiting Ge,1 Wen Cai,1,2 Rui Bai,1 Wangxiong Hu,1 Dehao Wu,1,2 Shu Zheng,1 Hanguang Hu1,2 1Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; 2Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China Background: Hypermutated colorectal cancer (CRC) reportedly accounts for 15%–17% of all cases of CRC. However, the proportion and number of patients with hypermutated CRC cannot be unappreciated. Additionally, therapy options for these patients differ from those for CRC patients, with a greater potential benefit from immunotherapy. Materials and methods: We sequenced the tumor mucosa of CRC patients with >24 months of follow-up data at our center and identified mutation profiles of hypermutated CRC as a training data set (Zhejiang University [ZJU]); we then collected patients from The Cancer Genome Atlas (TCGA) as a validation data set. Recurrently mutated genes were combined to calculate a compound score via Cox proportional hazards model. Patients with higher-than-median scores were segregated as the high-risk group. Outcomes were analyzed by Kaplan–Meier and Cox regression analyses using Python (3.6.0) and R (3.4.0). Results: We constructed a 4-gene signature (ACVR2A, APC, DOCK2, and POLE), with training in 45 hypermutated patients at ZJU and validation in 24 hypermutated patients from TCGA. Patients in the high-risk group showed poor survival (adjusted HR =9.85, 95% CI: 2.07–46.81, P=0.004). Further subgroup analysis was performed for stage II and III colon cancer (HR =10.91, 95% CI: 1.36–87.5, P=0.005) and high microsatellite instability (MSI-H) CRC (HR =12.57, 95% CI: 1.57–100.69, P=0.002) subgroups, which verified that our signature is universal. We then compared our prognostic signature with other risk factors (including MSI status, POLE driver mutation, BRAF-p.V600E, tumor mutational burden, and TNM staging). The results proved that our 4-gene signature is better than the other risk factor for prognosis in hypermutated CRC.Conclusion: Our 4-gene signature is a good predictor of survival for hypermutated CRC, and this signature is powerful in stage II and III colon cancer and MSI-H CRC. Future prospective studies are needed to confirm the power of the 4-gene signature in patients receiving immunotherapy. Keywords: colorectal cancer, hypermutation, gene signature, prognosis

Published
2019

26. High‐risk Stage III colon cancer patients identified by a novel five‐gene mutational signature are characterized by upregulation of IL‐23A and gut bacterial translocation of the tumor microenvironment

Author

Ge, Weiting, primary, Hu, Hanguang, additional, Cai, Wen, additional, Xu, Jinhong, additional, Hu, Wangxiong, additional, Weng, Xingyue, additional, Qin, Xin, additional, Huang, Yanqin, additional, Han, Weidong, additional, Hu, Yeting, additional, Yu, Jiekai, additional, Zhang, Wufeng, additional, Ye, Sisi, additional, Qi, Lina, additional, Huang, Pingjie, additional, Chen, Lirong, additional, Ding, Kefeng, additional, Wang, Li Dong, additional, and Zheng, Shu, additional

Published
2019
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31. Ultra‐mutated colorectal cancer patients with POLE driver mutations exhibit distinct clinical patterns.

Author

Hu, Hanguang, Cai, Wen, Wu, Dehao, Hu, Wangxiong, Dong Wang, Li, Mao, Jianshan, Zheng, Shu, and Ge, Weiting

Subjects
COLORECTAL cancer, CANCER patients, HEREDITARY nonpolyposis colorectal cancer, EXPERIMENTAL design, ASIANS
Abstract

POLE mutations, which lead to an ultramutated phenotype in colorectal cancer (CRC), have been reported as a promising marker in immunotherapy. We performed sequencing of CRC cases in Zhejiang University (ZJU) and extracted obtainable data from recently published results, including The Cancer Genome Atlas (TCGA), Japanese studies and clinical trials, to present clinical patterns of POLE driver‐mutated CRC and reveal its heterogeneity. The rate of somatic POLE driver mutations has been reported as 2.60% (ZJU cohort), 1.50% (TCGA cohort), 1.00% (Japan cohort), and 1.00% (Lancet cohort). POLE driver mutations show a clearly increased mutation burden (mean TMB: 217.98 mut/Mb in ZJU; 203.13 mut/Mb in TCGA). Based on pooled data, more than 70.00% of patients with POLE driver mutations were diagnosed before they were 55 years old and at an early disease stage (Stage 0–II >70.00%), and more than 70.00% were male. Among Asian patients, 68.40% developed POLE driver mutations in the left‐side colon, whereas 64.00% of non‐Asian patients developed them in the right‐side colon (p < 0.01). The top three amino acid changes due to POLE driver mutations are P286R, V411L, and S459F. Investigators and physicians should ascertain the heterogeneity and clinical patterns of POLE driver mutations to be better equipped to design clinical trials and analyze the data. [ABSTRACT FROM AUTHOR]

Published
2021
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32. High‐risk Stage III colon cancer patients identified by a novel five‐gene mutational signature are characterized by upregulation of IL‐23A and gut bacterial translocation of the tumor microenvironment.

Author

Ge, Weiting, Hu, Hanguang, Cai, Wen, Xu, Jinhong, Hu, Wangxiong, Weng, Xingyue, Qin, Xin, Huang, Yanqin, Han, Weidong, Hu, Yeting, Yu, Jiekai, Zhang, Wufeng, Ye, Sisi, Qi, Lina, Huang, Pingjie, Chen, Lirong, Ding, Kefeng, Wang, Li Dong, and Zheng, Shu

Subjects
TUMOR microenvironment, COLON cancer, CANCER patients, BACTERIAL RNA, REGRESSION analysis, INTESTINAL tumors
Abstract

The heterogeneities of colorectal cancer (CRC) lead to staging inadequately of patients' prognosis. Here, we performed a prognostic analysis based on the tumor mutational profile and explored the characteristics of the high‐risk tumors. We sequenced 338 colorectal carcinomas as the training dataset, constructed a novel five‐gene (SMAD4, MUC16, COL6A3, FLG and LRP1B) prognostic signature, and validated it in an independent dataset from The Cancer Genome Atlas (TCGA). Kaplan–Meier and Cox regression analyses confirmed that the five‐gene signature is an independent predictor of recurrence and prognosis in patients with Stage III colon cancer. The mutant signature translated to an increased risk of death (hazard ratio = 2.45, 95% confidence interval = 1.15–5.22, p = 0.016 in our dataset; hazard ratio = 4.78, 95% confidence interval = 1.33–17.16, p = 0.008 in TCGA dataset). RNA and bacterial 16S rRNA sequencing of high‐risk tumors indicated that mutations of the five‐gene signature may lead to intestinal barrier integrity, translocation of gut bacteria and deregulation of immune response and extracellular related genes. The high‐risk tumors overexpressed IL23A and IL1RN genes and enriched with cancer‐related bacteria (Bacteroides fragilis,Peptostreptococcus, Parvimonas, Alloprevotella and Gemella) compared to the low‐risk tumors. The signature identified the high‐risk group characterized by gut bacterial translocation and upregulation of interleukins of the tumor microenvironment, which was worth further researching. What's new? The heterogeneity of colorectal cancer makes it difficult to determine patients with a poor prognosis or in need of advanced therapy. Here, the authors constructed and validated a novel 5‐gene (SMAD4, MUC16, COL6A3, FLG, and LRP1B) mutational prognostic signature to identify high‐risk patients with Stage III colon cancer. Mutations of these five genes may lead to loss of intestinal barrier integrity, translocation of gut bacteria, and deregulation of interleukins and extracellular‐related genes. Combining tumor genetic characteristics with dynamic tumor microenvironment changes may lead to more promising prognostic signatures, which could help better select cancer patients for systemic therapy after surgery. [ABSTRACT FROM AUTHOR]

Published
2020
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34. Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis

Author

Shao, Yingkuan, primary, Chen, Ting, additional, Zheng, Xi, additional, Yang, Sheng, additional, Xu, Kailun, additional, Chen, Xuewen, additional, Xu, Fei, additional, Wang, Lantian, additional, Shen, Yanwei, additional, Wang, Tingyang, additional, Zhang, Mengwen, additional, Hu, Wangxiong, additional, Ye, Chenyang, additional, Yu, XiaoFang, additional, Shao, Jimin, additional, and Zheng, Shu, additional

Published
2018
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37. Incidence, Surgical Treatment, and Prognosis of Anorectal Melanoma From 1973 to 2011

Author

Chen, Haiyan, Cai, Yibo, Liu, Yue, He, Jinjie, Hu, Yeting, Xiao, Qian, Hu, Wangxiong, and Ding, Kefeng

Subjects
Aged, 80 and over, Male, Incidence, Observational Study, Middle Aged, Anus Neoplasms, Prognosis, United States, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Humans, Female, Melanoma, Research Article, Aged, SEER Program
Abstract

Supplemental Digital Content is available in the text, Anorectal melanoma (AM) is a rare type of melanoma that accounts for 0.4% to 1.6% of total malignant melanomas. The incidence of AM increases over time, and it remains highly lethal, with a 5-year survival rate of 6% to 22%. Considering the rare nature of this disease, most studies on AM comprise isolated case reports and single-center trials, which could not provide comprehensive assessment of the disease. Therefore, we conducted a population-based study by using the Surveillance, Epidemiology, and End Results (SEER) program to provide the latest and best available evidence of AM. We extracted all cases of AM registered in the SEER database from 1973 to 2011 (April 2014 release) and calculated age-adjusted incidence. Only cases with active follow-up were included to predict factors associated with prognosis. Survival outcomes were also compared among different types of surgery. We identified 640 AM cases, which consisted of 265 rectal melanoma and 375 anal melanoma. The estimated annual incidence rates of AM per 1 million population were 0.259 in males and 0.407 in females, and it increased with advanced age and over time. Tumor stage and surgical treatment were independent predictors of survival. Results implied that surgery improved the prognosis of patients with local- and regional-stage AM but could not prolong the survival of patients with distant-stage AM. Moreover, the outcome of less extensive excision was not statistically different from that of more extensive excision. This study provides an up-to-date estimation of the incidence and prognosis of AM by using SEER data. The incidence of AM continuously increases over time, despite its rarity. This disease also exhibits poor prognosis. Thus, AM must be further investigated in future studies. We also recommend surgery as the optimal treatment for local- and regional-stage AM patients but not for those with distant metastasis.

Published
2016

38. Heterogeneity of MSI-H gastric cancer identifies a subtype with worse survival

Author

Yang, Yanmei, Shi, Zhong, Bai, Rui, and Hu, Wangxiong

Abstract

BackgroundMicrosatellite instability-high (MSI-H) tumour patients generally have a better prognosis than microsatellite-stable (MSS) ones due to the large number of non-synonymous mutations. However, an increasing number of studies have revealed that less than half of MSI-H patients gain survival benefits or symptom alleviation from immune checkpoint-blockade treatment. Thus, an in-depth inspection of heterogeneous MSI-H tumours is urgently required.MethodsHere, we used non-negative matrix factorisation (non-NMF)-based consensus clustering to define stomach adenocarcinoma (STAD) MSI-H subtypes in samples from The Cancer Genome Atlas and an Asian cohort, GSE62254.ResultsMSI-H STAD samples are basically clustered into two subgroups (MSI-H1 and MSI-H2). Further examination of the immune landscape showed that immune suppression factors were enriched in the MSI-H1 subgroup, which may be associated with the poor prognosis in this subgroup.ConclusionsOur results illustrate the genetic heterogeneity within MSI-H STADs, with important implications for cancer patient risk stratification, prognosis and treatment.

Published
2021
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40. ANGPTL1 attenuates colorectal cancer metastasis by up-regulating microRNA-138

Author

Chen, Haiyan, primary, Xiao, Qian, additional, Hu, Yeting, additional, Chen, Liubo, additional, Jiang, Kai, additional, Tang, Yang, additional, Tan, Yinuo, additional, Hu, Wangxiong, additional, Wang, Zhanhuai, additional, He, Jinjie, additional, Liu, Yue, additional, Cai, Yibo, additional, Yang, Qi, additional, and Ding, Kefeng, additional

Published
2017
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43. Deciphering molecular properties of hypermutated gastrointestinal cancer.

Author

Hu, Wangxiong, Yang, Yanmei, Ge, Weiting, and Zheng, Shu

Subjects
GASTROINTESTINAL cancer, CANCER genetics, COLON cancer, DNA methylation, HIERARCHICAL clustering (Cluster analysis)
Abstract

Great mutational heterogeneity is observed both across cancer types (>1000‐fold) and within a given cancer type, with a fraction harboring >10 mutations per million bases, thus termed hypermutation. We determined the genome‐wide effects of high mutation load on the transcriptome and methylome of two cancer types; namely, colorectal cancer (CRC) and stomach adenocarcinoma (STAD). Briefly, hierarchical clustering of the expression and methylation profiles showed that the majority of CRC and STAD hypermutated samples were mixed and separated from their respective non‐hypermutated samples, exceeding the boundary of tissue specificity. Further in‐detailed exploration uncovered that the underlying molecular mechanism may be related to the perturbation of chromatin remodeling genes. [ABSTRACT FROM AUTHOR]

Published
2019
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