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Glucose-6-Phosphate Dehydrogenase as a Prognostic Predictor Correlates with the Tumor Immune Activity Including Programmed Death Ligand-1 Expression in Merkel Cell Carcinoma

ABSTRACT: Purpose: Merkel cell carcinoma (MCC) is a rare but highly malignant skin cancer. However, it is well known that some cases have a good prognosis including spontaneously regression. To precise such a different patient’s outcome, reported prognostic markers, e.g. Merkel cell polyoma virus infection or programmed death ligand-1 (PD-L1) expression, are still insufficient. Here we performed RNA sequencing to evaluate immune response and comprehensively estimate prognostic values of immunogenic factors in MCC.　 Experimental Design: We collected 90 specimens from 71 patients and 53 blood serum samples from 21 patients with MCC from 9 facilities. mRNA was extracted from formalin fixed paraffin embedded (FFPE) tissues. Analyses of next generation sequencing data, immunohistochemical staining and blood serum tests were performed. Results: Next generation sequencing revealed that MCC samples could be divided into two types. “immune active type” showed better clinical outcomes than “cell division type”. Glucose-6-Phosphate Dehydrogenase (G6PD) was one of the most significantly up-regulated gene in “cell division type”. G6PD expression correlated with the presence or absence of lymph node or distant metastases during the course and negatively correlated with high or low of PD-L1 expression with the top significance in 395 genes both. Immunohistochemical staining of G6PD was also correlated with disease specific survival and showed less heterogeneity compared with PD-L1 expression. G6PD activity was measurable by the blood serum test and detection values significantly increased as the cancer stage progression and significantly decreased after treatment. Conclusion: G6PD expression was an immunohistochemically and serum-detectable prognostic marker and negatively correlated with immune activity including PD-L1 associate with the prediction of immunotherapy response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154938 | GEO | 2020/12/13

REPOSITORIES: GEO

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Project description:Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor with high mortality rates. Merkel cell polyomavirus (MCPyV), identified in the majority of MCC, may drive tumorigenesis via viral T antigens. However, mechanisms underlying pathogenesis in MCPyV-negative MCC remain poorly understood. To nominate genes contributing to pathogenesis of MCPyV-negative MCC, we performed DNA microarray analysis on 30 MCCs. MCPyV status of MCCs was determined by PCR for viral DNA and RNA. 1593 probe-sets were differentially expressed between MCPyV-negative and -positive MCC, with significant differential expression defined as at least 2-fold change in either direction and p-value of ≤ 0.05. MCPyV-negative tumors showed decreased RB1 expression, whereas MCPyV-positive tumors were enriched for immune response genes. Validation studies included immunohistochemistry demonstration of decreased RB protein expression in MCPyV-negative tumors and increased peritumoral CD8+ T lymphocytes surrounding MCPyV-positive tumors. In conclusion, our data suggest that loss of RB1 expression may play an important role in tumorigenesis of MCPyV-negative MCC. Functional and clinical validation studies are needed to determine whether this tumor suppressor pathway represents an avenue for targeted therapy. We used microarrays to characterize global gene expression patterns related to Merkel cell polyomavirus status in Merkel cell carcinoma. Furthermore, we compared Merkel cell carcinoma to less aggressive primary cutaneous carcinomas. We utilized flash-frozen tumor tissue from primary Merkel cell carcinomas, metastatic Merkel cell carcinomas, primary cutaneous squamous cell carcinomas, and basal cell carcinomas. Merkel cell carcinoma cell lines, which represent a pure population of tumor cells, were also included. Merkel cell polyomavirus status was determined at the DNA and RNA level using multiple primers for viral T-antigen and capsid protein sequences. This Series represents two analyses - one with new Samples normalized together, and another with some of the new Samples re-normalized with Samples previously submitted under Series GSE13355. The latter group contain 'renormalized' in the titles.

Dataset Information

Glucose-6-Phosphate Dehydrogenase as a Prognostic Predictor Correlates with the Tumor Immune Activity Including Programmed Death Ligand-1 Expression in Merkel Cell Carcinoma

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