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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Expression of the Circadian Clock Gene BMAL1 Positively Correlates With Antitumor Immunity and Patient Survival in Metastatic Melanoma

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Monteiro de Assis, Leonardo Vinicius [1] ; Kinker, Gabriela Sarti [2] ; Moraes, Maria Nathalia [1] ; Markus, Regina P. [2] ; Fernandes, Pedro Augusto [2] ; de lauro Castrucci, Ana Maria [3, 1]
Total Authors: 6
[1] Univ Sao Paulo, Inst Biosci, Dept Physiol, Lab Comparat Physiol Pigmentat, Sao Paulo - Brazil
[2] Univ Sao Paulo, Inst Biosci, Dept Physiol, Lab Neuroimmunemodulat, Sao Paulo - Brazil
[3] Univ Virginia, Dept Biol, Charlottesville, VA - USA
Total Affiliations: 3
Document type: Journal article
Source: FRONTIERS IN ONCOLOGY; v. 8, JUN 12 2018.
Web of Science Citations: 6

Introduction: Melanoma is the most lethal type of skin cancer, with increasing incidence and mortality rates worldwide. Multiple studies have demonstrated a link between cancer development/progression and circadian disruption; however, the complex role of tumor-autonomous molecular clocks remains poorly understood. With that in mind, we investigated the pathophysiological relevance of clock genes expression in metastatic melanoma. Methods: We analyzed gene expression, somatic mutation, and clinical data from 340 metastatic melanomas from The Cancer Genome Atlas, as well as gene expression data from 234 normal skin samples from genotype-tissue expression. Findings were confirmed in independent datasets. Results: In melanomas, the expression of most clock genes was remarkably reduced and displayed a disrupted pattern of co-expression compared to the normal skins, indicating a dysfunctional circadian clock. Importantly, we demonstrate that the expression of the clock gene aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) positively correlates with patient overall survival and with the expression of T-cell activity and exhaustion markers in the tumor bulk. Accordingly, high BMAL1 expression in pretreatment samples was significantly associated with clinical benefit from immune checkpoint inhibitors. The robust intratumoral T-cell infiltration/activation observed in patients with high BMAL1 expression was associated with a decreased expression of key DNA-repair enzymes, and with an increased mutational/neoantigen load. Conclusion: Overall, our data corroborate previous reports regarding the impact of BMAL1 expression on the cellular DNA-repair capacity and indicate that alterations in the tumor-autonomous molecular clock could influence the cellular composition of the surrounding microenvironment. Moreover, we revealed the potential of BMAL1 as a clinically relevant prognostic factor and biomarker for T-cell-based immunotherapies. (AU)

FAPESP's process: 13/24337-4 - Clock genes modulation by UVA/blue light stimulation in normal melan-A and transformed B-16 melanocytes
Grantee:Leonardo Vinícius Monteiro de Assis
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 14/27287-0 - Characterization of the melatonergic system of human gliomas and its implication on tumor aggressiveness and invasiveness
Grantee:Gabriela Sarti Kinker
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 12/50214-4 - Biological clock setting by light and temperature: phylogenetic aspects
Grantee:Ana Maria de Lauro Castrucci
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 14/16412-9 - Mechanisms of clock genes thermo-modulation in peripheral tissue of mammals: role of TRP channels
Grantee:Maria Nathália de Carvalho Magalhães Moraes Figueira Borges
Support Opportunities: Scholarships in Brazil - Post-Doctoral