VHL expression level in the pathological tissue is significantly associated with clinical outcomes of platinum-based chemotherapy in non-small cell lung cancer patients. (withdrawn 03/11/2021)
Objective To investigate the association between expression level of VHL in pathological tissue and outcomes of platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients. Methods The pathological samples of NSCLC patients were obtained for immunohistochemical staining to evaluate the expression level of VHL. Furthermore, their clinical data were collected and prognosis was traced by phone. The correlation between gene expression level and the hematotoxicity was evaluated by chi-square test. The influence of VHL expression level on the risk of hematotoxicity was tested by logistic regression model. The survival curve was plotted by Kaplan-Meier method and the survival rate between the two groups was compared by log-rank test. Results A total of 110 NSCLC patients were enrolled in this study, the median follow-up time of these patients was 27.5 months. In the whole group, 31 patients had died by the last date of follow-up to get their survival information (Nov.10,2020), with a median survival time of 24.3 months. Though immunohistochemical analysis,we found that 59 patients(53.6%) had weak expression level of VHL or lack of expression in their tumor tissues,while 51 patients(46.4%) presented moderate or high expression. We found that the patients with weak expression of VHL in their carcinoma tissue or lack of expression had more opportunities to occur neutropenia after platinum-based chemotherapy(OR=0.264,95%CI=0.085-0.818,P-value=0.021).And the expression level of VHL was correlated with OS(Logrank test：P-value= 0.007，HR= 4.219,95%CI: 1.75-10.174, P-value=0.001), while not related with DFS(Logrank test：P-value=0.256，HR= 1.334,95%CI:0.642-2.769, P-value=0.440). Conclusion The expression level of VHL gene in pathological tissue is related with Granulocytosis and leukocytotoxicity after platinum-based chemotherapy in NSCLC patients. It can be used as a biomarker to predict the risk of neutropenia and the prognosis of NSCLC patients.
2. Chen W. Cancer statistics: updated cancer burden in China. Chin J Cancer Res 2015;27:1.
3. Chen W, Hill H, Christie A, et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 2016;539:112-7.
4. Han Y, Liu J, Sun M, et al. A Significant Statistical Advancement on the Predictive Values of ERCC1 Polymorphisms for Clinical Outcomes of Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer: An Updated Meta-Analysis. Dis Markers 2016;2016:7643981.
5. Johnstone TC, Suntharalingam K, Lippard SJ. The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs. Chem Rev 2016;116:3436-86.
6. Du W, Zhang L, Brett-Morris A, et al. HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat Commun 2017;8:1769.
7. Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer 2015;15:55-64.
8. Kang MR, Park KH, Lee CW, et al. Small activating RNA induced expression of VHL gene in renal cell carcinoma. Int J Biochem Cell Biol 2018;97:36-42.
9. Lenglet M, Robriquet F, Schwarz K, et al. Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease. Blood 2018;132:469-83.
10. Li S, Rodriguez J, Li W, et al. EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance. Proc Natl Acad Sci U S A 2019;116:16997-7006.
11. Lv C, Bai Z, Liu Z, et al. Renal cell carcinoma risk is associated with the interactions of APOE, VHL and MTHFR gene polymorphisms. Int J Clin Exp Pathol 2015.
12. Qian CY, Zheng Y, Wang Y, et al. Associations of genetic polymorphisms of the transporters organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), and ATP-binding cassette subfamily C member 2 (ABCC2) with platinum-based chemotherapy response and toxicity in non-small cell lung cancer patients. Chin J Cancer 2016;35:85.
13. Tarade D, Ohh M. The HIF and other quandaries in VHL disease. Oncogene 2018;37:139-47.
14. Wang WC, Tsou MH, Chen HJ,et al.Two single nucleotide polymorphisms in the von Hippel-Lindau tumor suppressor gene in Taiwanese with renal cell carcinoma. BMC Res Notes 2014;7:638.
15. Chen G, Zhou J, Chen J, et al. VHL regulates NEK1 via both HIF-2alpha pathway and ubiquitin-proteasome pathway in renal cancer cell. Biochem Biophys Res Commun 2019;509:797-802.
16. Chen W, Hill H, Christie A, et al. Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 2016;539:112-7.
17. Ding XF, Zhou J, Chen G, Wu YL. VHL loss predicts response to Aurora kinase A inhibitor in renal cell carcinoma cells. Mol Med Rep 2018;18:1206-10.
18. Wu K, House L, Liu W,et al. ersonalized targeted therapy for lung cancer. Zhongguo Fei Ai Za Zhi 2013;16:C21-34.
19. Wu K, House L, Liu W,et al. Personalized targeted therapy for lung cancer. Chin J Lung Cancer 2013;16:C21-34.
20. Yin JY, Li X, Li XP, et al. Prediction models for platinum-based chemotherapy response and toxicity in advanced NSCLC patients. Cancer Lett 2016;377:65-73.
21. Zhao X, Wang X, Wu W, et al. Matrix metalloproteinase-2 polymorphisms and clinical outcome of Chinese patients with nonsmall cell lung cancer treated with first-line, platinum-based chemotherapy. Cancer 2012;118:3587-98.
22. Wu DM , Deng SH , Liu T,et al. TGF-β-mediated exosomal lnc-MMP2-2 regulates migration and invasion of lung cancer cells to the vasculature by promoting MMP2 expression. Cancer Med. 2018 Oct;7(10):5118-5129.
23. Zhao YS,Le Y,Wang SF,et al. The relationship between EGFR gain and VHL loss in lung adenocarcinoma and poor patient survival. Int J Clin Oncol. 2011 Dec;16(6):679-85
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Authors who publish with this journal agree to the following terms:
1. Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
4. In case of virtual slide publication the authors agree to copy the article in a structural modified version to the journal's VS archive.