Genomic sequencing identifies WNK2 as a driver in hepatocellular carcinoma and a risk factor for early recurrence

Zhou, Shao-Lai; Zhou, Zheng‐Jun; Hu, Zhiqiang; Song, Chengli; Luo, Yufeng; Luo, Chu-Bin; Xin, Hao-Yang; Yang, Xin‐Rong; Shi, Ying‐Hong; Wang, Zheng; Huang, Xiaowu; Cao, Yang; Fan, Jia; Zhou, Ji

doi:10.1016/j.jhep.2019.07.014

Cited by 54 publications

(43 citation statements)

References 34 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…WNK2 was also found to be downregulated via epigenetic silencing in early pancreatic ductal adenocarcinoma and may support cell proliferation through the Mitogen-activated protein kinase (MAPK) signaling pathway [30]. WNK2 somatic mutations and copy number loss were reported in hepatocellular carcinoma, resulting in lower WNK2 protein levels, which were associated with early tumor recurrence linked to enhanced ERK1/2 signaling [31]. Moreover, WNK kinases have been linked to Wnt/β-catenin signaling, a known pathway involved in granulosa cell development, and loss-of-function WNK genes resemble canonical Wnt pathway mutants [32].…”

Section: Discussionmentioning

confidence: 99%

Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease

Pilsworth

Cochrane²,

Neilson³

et al. 2021

The Journal of Pathology CR

View full text Add to dashboard Cite

Adult-type granulosa cell tumors (aGCTs) account for 90% of malignant ovarian sex cord-stromal tumors and 2-5% of all ovarian cancers. These tumors are usually diagnosed at an early stage and are treated with surgery. However, one-third of patients relapse between 4 and 8 years after initial diagnosis, and there are currently no effective treatments other than surgery for these relapsed patients. As the majority of aGCTs (>95%) harbor a somatic mutation in FOXL2 (c.C402G; p.C134W), the aim of this study was to identify genetic mutations besides FOXL2 C402G in aGCTs that could explain the clinical diversity of this disease. Whole-genome sequencing of 10 aGCTs and their matched normal blood was performed to identify somatic mutations. From this analysis, a custom amplicon-based panel was designed to sequence 39 genes of interest in a validation cohort of 83 aGCTs collected internationally. KMT2D inactivating mutations were present in 10 of 93 aGCTs (10.8%), and the frequency of these mutations was similar between primary and recurrent aGCTs. Inactivating mutations, including a splice site mutation in candidate tumor suppressor WNK2 and nonsense mutations in PIK3R1 and NLRC5, were identified at a low frequency in our cohort. Missense mutations were identified in cell cycle-related genes TP53, CDKN2D, and CDK1. From these data, we conclude that aGCTs are comparatively a homogeneous group of tumors that arise from a limited set of genetic events and are characterized by the FOXL2 C402G mutation. Secondary mutations occur in a subset of patients but do not explain the diverse clinical behavior of this disease. As the FOXL2 C402G mutation remains the main driver of this disease, progress in the development of therapeutics for aGCT would likely come from understanding the functional consequences of the FOXL2 C402G mutation.

show abstract

Section: Discussionmentioning

confidence: 99%

Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease

Pilsworth

Cochrane²,

Neilson³

et al. 2021

The Journal of Pathology CR

View full text Add to dashboard Cite

show abstract

“…About half of the new cases and deaths of HCC occurring annually in China [16] . Despite various treatments, the prognosis of HCC patients is poor, with a 5-year overall survival rate of less than 50%.…”

Section: Discussionmentioning

confidence: 99%

Expression and Prognostic Roles of PRDXs Gene Family in Hepatocellular Carcinoma

Zhu³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: As the second leading cause of cancer-related death in the world, the therapeutic effect and 5-year overall survival of hepatocellular carcinoma (HCC) are not optimistic. Previous researches indicated that the disorder of PRDXs was related to the occurrence and development of cancer. Methods: In this study,analyzing through CCLE, UALCAN, HCCDB and Human Protein Atlas database databases, PRDXs not only existedin various tumor cell lines, but alsohad maladjusted expression on mRNA and protein levelsin HCC tissues. Besides, the correlations between mRNA as well as methylation levels of PRDXs and clinical characterization wereevaluated using UALCAN. Results: Kaplan-Meier Plotter demonstrated that high expression of PRDX1 or low expression of PRDX2/3 suggested poor prognosis for HCC patients. The mutation frequency, type and biological interaction network of PRDXs were obtained from c-Bioportal. By LinkedOmics,PRDXs related differential expressions geneswere obtained, which were involved in several canonical pathways and certain amino acid metabolism, as well as miRNAs targeting PRDXs, some of which may effect on the progression of HCC. Conclusions: In conclusion, using online tools to analyze data based on several public database, it was found that disordered expression of PRDXs was correlated with the prognosis of HCC patients, suggesting that PRDXs may be new molecular targets for HCC therapy and prognosis prediction.

show abstract

“…1A; Supplementary Fig. 1A) [18]. LncRNAs that were frequently ampli ed were mainly located on chromosomes 1q, 8q, 17q, 20q, whereas those that were frequently deleted were mainly located on chromosomes 4q, 9q, 13q, and 16q ( Fig.…”

Section: Identi Cation Of Linc01133 With Cnvs Involved In Hcc Recurrementioning

confidence: 93%

“…We analyzed whole genome sequencing (WGS) data from our previous study to screen for lincRNAs with CNVs involved in HCC recurrence after curative resection [18]. We examined CNVs and expression levels of candidate lincRNAs in HCC tissue samples.…”

Section: Introductionmentioning

confidence: 99%

The Long Non-coding RNA LINC01133 Promotes Hepatocellular Carcinoma Progression by Sponging miR-199a-5p and Activating Annexin A2

Yin

Luo

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Long non-coding RNAs (lncRNAs) have been found to be functionally associated with cancer development and progression. Although copy number variations (CNVs) are common in hepatocellular carcinoma (HCC), little is known about how CNVs in lncRNAs affect HCC progression and recurrence.Methods: We analyzed the whole genome sequencing (WGS) data of matched cancerous and non-cancerous liver samples from 49 patients with HCC to identify lncRNAs with CNVs. The results were validated in another cohort of 238 paired HCC and non-tumor samples by TaqMan copy number assay. Kaplan-Meier analysis and the log-rank test were performed to determine the prognostic value of CNVs in lincRNAs. Loss- and gain-of-function studies were conducted to determine the biological functions of LINC01133 in vitro and in vivo. The competing endogenous RNAs (ceRNAs) mechanism was clarified by microRNA sequencing (miR-seq), quantitative real-time PCR (qRT-PCR), western blot, and dual-luciferase reporter analyses. The protein binding mechanism was confirmed by RNA pull-down, RNA immunoprecipitation (RIP), qRT-PCR, and western blot analyses.Results: Genomic copy number of LINC01133 was increased in HCC, which is positively related with the elevated expression of LINC01133. Increased copy number of LINC01133 predicted the poor prognosis in HCC patients. LINC01133 overexpression promoted proliferation, colony formation, migration, and invasion in vitro, and facilitated tumor growth and lung metastasis in vivo, whereas LINC01133 knockdown had the opposite effects. Mechanistically, LINC01133 acted as a sponge of miR-199a-5p, resulting in enhanced expression of SNAI1, which induced epithelial-mesenchymal transition (EMT) in HCC cells. In addition, LINC01133 interacted with Annexin A2 (ANXA2) to activate ANXA2/STAT3 signaling pathway.Conclusions: LINC01133 promotes HCC progression by sponging miR-199a-5p and interacting with ANXA2. LINC01133 CNV gain is predictive of poor prognosis in HCC patients undergoing curative resection.

show abstract

Genomic sequencing identifies WNK2 as a driver in hepatocellular carcinoma and a risk factor for early recurrence

Cited by 54 publications

References 34 publications

Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease

Adult‐type granulosa cell tumor of the ovary: a FOXL2‐centric disease

Expression and Prognostic Roles of PRDXs Gene Family in Hepatocellular Carcinoma

The Long Non-coding RNA LINC01133 Promotes Hepatocellular Carcinoma Progression by Sponging miR-199a-5p and Activating Annexin A2

Contact Info

Product

Resources

About