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Gene expression profile identifies distinct molecular subtypes and potential therapeutic genes in Merkel cell carcinoma.

ABSTRACT: Merkel cell carcinoma (MCC) is a rare primary cutaneous neoplasm of neuroendocrine carcinoma of the skin. About 80% of the MCC occurs due to Merkel cell polyomavirus (MCPyV) and 20% of the tumors usually occur due to severe UV exposure which is a more aggressive type of MCC. It tends to have an increased incidence rate among elderly and immunosuppressed individuals. On therapeutic level, sub-classification of MCC through molecular subtyping has emerged as a promising technique for MCC prognosis. In current study, two consistent distinct molecular subtypes of MCCs were identified using gene expression profiling data. Subtypes I MCCs were associated with spliceosome, DNA replication and cellular pathways. On the other hand, genes overexpressed in subtype II were found active in TNF signalling pathway and MAPK signalling pathway. We proposed different therapeutic targets based on subtype specificity, such as PTCH1, CDKN2A, AURKA in case of subtype I and MCL1, FGFR2 for subtype II. Such findings may provide fruitful knowledge to understand the intrinsic subtypes of MCCs and the pathways involved in distinct subtype oncogenesis, and will further advance the knowledge in developing a specific therapeutic strategy for these MCC subtypes.

SUBMITTER: Saddozai UAK

PROVIDER: S-EPMC7412862 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Gene expression profile identifies distinct molecular subtypes and potential therapeutic genes in Merkel cell carcinoma.

Saddozai Umair Ali Khan UAK Wang Fengling F Cheng Yu Y Lu Zhang Z Akbar Muhammad Usman MU Zhu Wan W Li Yongqiang Y Ji Xinying X Guo Xiangqian X

Translational oncology 20200806 11

Merkel cell carcinoma (MCC) is a rare primary cutaneous neoplasm of neuroendocrine carcinoma of the skin. About 80% of the MCC occurs due to Merkel cell polyomavirus (MCPyV) and 20% of the tumors usually occur due to severe UV exposure which is a more aggressive type of MCC. It tends to have an increased incidence rate among elderly and immunosuppressed individuals. On therapeutic level, sub-classification of MCC through molecular subtyping has emerged as a promising technique for MCC prognosis. ...[more]

PMID: 32771971

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Project description:OPINION STATEMENT:Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

Project description:Immune checkpoint blockade (ICB) has become a promising therapy for multiple cancers. However, only a small proportion of patients display a limited antitumor response. The present study aimed to classify distinct immune subtypes and investigate the tumor microenvironment (TME) of urothelial carcinoma, which may help to understand treatment failure and improve the immunotherapy response. RNA-seq data and clinical parameters were obtained from TCGA-BLCA, E-MTAB-4321, and IMVigor210 datasets. A consensus cluster method was used to distinguish different immune subtypes of patients. Infiltrating immune cells, TME signatures, immune checkpoints, and immunogenic cell death modulators were evaluated in distinct immune subtypes. Dimension reduction analysis was performed to visualize the immune status of urothelial carcinoma based on graph learning. Weighted gene co-expression network analysis (WGCNA) was performed to obtain hub genes to predict responses after immunotherapy. Patients with urothelial carcinoma were classified into four distinct immune subtypes (C1, C2, C3 and C4) with various types of molecular expression, immune cell infiltration, and clinical characteristics. Patients with the C3 immune subtype displayed abundant immune cell infiltrations in the tumor microenvironment and were typically identified as "hot" tumor phenotypes, whereas those with the C4 immune subtype with few immune cell infiltrations were identified as "cold" tumor phenotypes. The immune-related and metastasis-related signaling pathways were enriched in the C3 subtype compared to the C4 subtype. In addition, tumor mutation burden, inhibitory immune checkpoints, and immunogenic cell death modulators were highly expressed in the C3 subtype. Furthermore, patients with the C4 subtype had a better probability of overall survival than patients with the C3 subtype in TCGA-BLCA and E-MTAB-4321 cohorts. Patients with the C1 subtype had the best prognosis when undergoing anti-PD-L1 antibody treatment. Finally, the immune landscape of urothelial carcinoma showed the immune status in each patient, and TGFB3 was identified as a potential biomarker for the prediction of immunotherapy resistance after anti-PD-L1 monoclonal antibody treatment. The present study provided a bioinformatics basis for understanding the immune landscape of the tumor microenvironment of urothelial carcinoma.

Dataset Information

Gene expression profile identifies distinct molecular subtypes and potential therapeutic genes in Merkel cell carcinoma.

Publications

Gene expression profile identifies distinct molecular subtypes and potential therapeutic genes in Merkel cell carcinoma.

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