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

Abstract

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.

• Authors: Leonardo Vinícius Monteiro de Assis, Gabriela Sarti Kinker, Maria Nathália Moraes, Regina P Markus, Pedro Augusto Fernandes, Ana Maria de Lauro Castrucci
• Journal: Frontiers in oncology (Front Oncol) Vol. 8 Pg. 185 ( 2018) ISSN: 2234-943X [Print] Switzerland
• PMID: 29946530 (Publication Type: Journal Article)