ZNF750 Expression Is a Potential Prognostic Biomarker in Esophageal Squamous Cell Carcinoma

Otsuka, Ryota; Akutsu, Yasunori; Sakata, Haruhito; Hanari, Naoyuki; Murakami, Kentaro; Kano, Masayuki; Toyozumi, Takeshi; Takahashi, Masahīko; Matsumoto, Yasunori; Sekino, Nobufumi; Yokoyama, Masaya; Okada, Kensuke; Shiraishi, Taizo; Komatsu, Aki; Iida, Kei; Matsubara, Hisahiro

doi:10.1159/000484932

Cited by 25 publications

(17 citation statements)

References 27 publications

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“…The present study also detected FGFR2 mutations in iCCA, and demonstrated that they mainly occurred in patients older than 70 years, which implies that the mutation of FGFR2 was associated with the age of Chinese patients with CCA. ZNF750 has been reported as a prognostic biomarker in ESCC (55). Although only two mutations of ZNF750 were detected in the present study, notably, both mutations occurred in group IV (>70 years).…”

Section: Discussioncontrasting

confidence: 68%

Comprehensive genomic profile of cholangiocarcinomas in China

Shi

Liu

et al. 2020

Oncol Lett

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Cholangiocarcinoma (CCA) is a primary malignancy, which is often diagnosed as locally advanced or metastatic. Previous studies have revealed genomic characteristics of CCA in Western patients, however comprehensive genomic features of CCA in Chinese patients have not been well understood. To explore the specific genomic characteristics of Chinese patients with CCA, a total of 66 patients with CCA, including 44 intrahepatic CCA (iCCA) and 22 extrahepatic CCA (exCCA) cases, were studied. The most commonly altered genes in CCAs were TP53 (62.12%, 41/66), KRAS (36.36%, 24/66), SMAD4 (24.24%, 16/66), TERT (21.21%, 14/66), ARID1A (19.70%, 13/66), CDKN2A (19.70%, 13/66), KMT2C (9.09%, 6/66) and RBM10 (9.09%, 6/66), ERBB2 (7.58%, 5/66) and BRAF (7.58%, 5/66). Many gene mutations, including STK11, CCND1 and FGF19, were only found in iCCA. RBM10 mutations were found to be significantly higher in exCCA. The gene mutations of neurofibromin 1, STK11, CCND1 and FBXW7 specifically occurred in males, whereas gene mutations of ERBB2, AXIN2 and CREBBP specifically occurred in females. ERBB2 mutations were significantly associated with the sex of patients with CCA. Mutations in PIK3CA, FGFR2 and ZNF750 were significantly associated with the age of patients with CCA and TERT mutations were significantly associated with tumor differentiation. Alterations in KMT2C, PBRM1, AXIN2, MAGI2, BRCA2 and SPTA1 were associated with tumor mutational burden. The findings of the present study suggest that targeted sequencing, using next-generation sequencing technology, provides comprehensive and accurate information on genomic alterations, which will provide novel potential biomarkers for the diagnosis of CCA and may guide precise therapeutic strategies for Chinese patients with CCA.

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Section: Discussioncontrasting

confidence: 68%

Comprehensive genomic profile of cholangiocarcinomas in China

Shi

Liu

et al. 2020

Oncol Lett

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“…633 (95% CI, 0.557 to 0.709). Figure 3D and 3E showed the prognosis ability of our CHRNB4 and prognostic nomogram (AUC=0.84) are as good as or even better than TNM, CD59, and ZNF750 (AUC=0.64, 0.64, respectively), which were previously published biomarkers in ESCC (22,23). The survival curve for the probability of survival of the nomogram is shown in Figure 3F (P =0.03).…”

Section: Chrnb4-based Forecast Model and Prognostic Nomogram To Predimentioning

confidence: 57%

Identification of CHRNB4 as a Diagnostic/Prognostic Indicator and Therapeutic Target in Human Esophageal Squamous Cell Carcinoma

Liu

Dong

et al. 2020

Front. Oncol.

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Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumors and there is a lack of biomarkers for ESCC diagnosis and prognosis. Family subunits of cholinergic nicotinic receptor genes (CHRNs) are involved in smoking behavior and tumor cell proliferation. Previous researches have shown similar molecular features and pathogenic mechanisms among ESCC, head and neck squamous cell carcinoma (HNSC), and lung squamous cell carcinoma (LUSC). Using edgeR, three mutual differentially expressed genes of CHRNs were found to be significantly upregulated at the mRNA level in ESCC, LUSC, and HNSC compared to matched normal tissues. Kaplan–Meier survival analysis showed that high expression of CHRNB4 was associated with unfavorable prognosis in ESCC and HNSC. The specific expression analysis revealed that CHRNB4 is highly expressed selectively in squamous cell carcinomas compared to adenocarcinoma. Cox proportional hazards regression analysis was performed to find that just the single gene CHRNB4 has enough independent prognostic ability, with the area under curve surpassing the tumor-node-metastasis (TNM) staging-based model, the most commonly used model in clinical application in ESCC. In addition, an effective prognostic nomogram was established combining the TNM stage, gender of patients, and expression of CHRNB4 for ESCC patients, revealing an excellent prognostic ability when compared to the model of CHRNB4 alone or TNM. Gene Set Enrichment Analysis results suggested that the expression of CHRNB4 was associated with cancer-related pathways, such as the mTOR pathway. Cell Counting Kit-8, cloning formation assay, and western blot proved that CHRNB4 knockdown can inhibit the proliferation of ESCC cells via the Akt/mTOR and ERK1/2/mTOR pathways, which might facilitate the prolonged survival of patients. Furthermore, we conducted structure-based molecular docking, and potential modulators against CHRNB4 were screened from FDA approved drugs. These findings suggested that CHRNB4 specifically expressed in SCCs, and may serve as a promising biomarker for diagnosis and prognosis prediction, and it can even become a therapeutic target of ESCC patients.

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“…However downstream targets of ZNF750 have been recently discovered, elucidating possible alternative targeting strategies for this pathway. Reduced ZNF750 expression also predicts more aggressive esophageal SCC, making it possible that detecting its loss in SeC may help identify the small proportion of tumors that recur and metastasize. Additional study correlating ZNF750 expression with clinical follow‐up data is necessary to assess if ZNF750 truly correlates with clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Loss of ZNF750 in ocular and cutaneous sebaceous carcinoma

North

Solomon

Golovato³

et al. 2019

J Cutan Pathol

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Background: Sebaceous carcinoma (SeC) is an uncommon malignancy arising from sebaceous glands of the conjunctiva and skin. Recurrent mutations in the ZNF750 were recently identified in ocular SeC. We assessed whether ZNF750 loss is a specific feature of ocular SeC or a general feature of sebaceous tumors.Methods: Immunostaining for ZNF750 expression was performed in 54 benign and malignant sebocytic proliferations. Staining for ZNF750 was scored on a three-tier scale: positive (>75%), partially positive (5%-74%), and negative (<5%).Results: ZNF750 expression was negative in 4/11 ocular SeC, and partially positive in 4/11 ocular SeC and 6/13 cutaneous SeC. No extraocular tumors were negative.No loss was found in sebaceous adenoma or sebaceous hyperplasia. In nine previously sequenced ocular SeCs, two lacked detectable somatic mutations in ZNF750, but showed complete loss of staining, indicating non-mutational inactivation of ZNF750. Conclusion:We show complete loss of the ZNF750 epidermal differentiation regulator in about half of ocular SeC, highlighting the most common genetic defect in this cancer type. Loss of ZNF750 expression is seen even in tumors without truncating mutations and reduced in many of the remaining ocular and cutaneous SeC. In contrast, no ZNF750 loss was detected in benign sebaceous proliferations. K E Y W O R D Ssebaceous adenoma, sebaceous carcinoma, ZNF750

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ZNF750 Expression Is a Potential Prognostic Biomarker in Esophageal Squamous Cell Carcinoma

Cited by 25 publications

References 27 publications

Comprehensive genomic profile of cholangiocarcinomas in China

Comprehensive genomic profile of cholangiocarcinomas in China

Identification of CHRNB4 as a Diagnostic/Prognostic Indicator and Therapeutic Target in Human Esophageal Squamous Cell Carcinoma

Loss of ZNF750 in ocular and cutaneous sebaceous carcinoma

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