An integrative evaluation of circadian gene TIMELESS as a pan-cancer immunological and predictive biomarker

Sep 24, 2026

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Background: TIMELESS, a circadian clock and cell-cycle gene, has been linked to multiple cancers, but its expression–prognosis relationship across pan-cancer is unclear. Objectives: Systematically assess TIMELESS expression patterns, functional roles, prognostic value, and immunological contributions across human cancer types. Methods: Analyze TIMELESS in normal and malignant tissues with clinicopathologic and survival data, genetic alterations, molecular subtypes, immune infiltration, TMB, MSI, and drug sensitivity; use immunohistochemistry to validate clinical expression.

LanguageEnglish

CategoryResearch & Report

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Pages20

Reading Time50 min

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Abstract

Background

Objectives

Methods

Results

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Introduction

Yang et al. European Journal European Journal of Medical Research (2023) 28:563 [https://doi.org/10.1186/s40001-023-01519-3](https://doi.org/10.1186/s40001-023-01519-3 of Medical Research)[ of Medical Research](https://doi.org/10.1186/s40001-023-01519-3 of Medical Research) RESEARCH Open Access An integrative evaluation of circadian gene TIMELESS as a pan-cancer immunological and predictive biomarker Yaocheng Yang1, Xianzhe Tang2, Zhengjun Lin1, Tao Zheng1, Sheng Zhang3, Tang Liu1 and Xiaolun Yang4* Abstract Background The gene TIMELESS, which is involved in the circadian clock and the cell cycle, has recently been linked to various human cancers. Nevertheless, the association between TIMELESS expression and the prognosis of individuals afflicted with pan-cancer remains largely unknown. Objectives The present study aims to exhaustively scrutinize the expression patterns, functional attributes, prognostic implications, and immunological contributions of TIMELESS across diverse types of human cancer. Methods The expression of TIMELESS in normal and malignant tissues was examined, as well as their clinicopathologic and survival data. The characteristics of genetic alteration and molecular subtypes of cancers were also investigated. In addition, the relationship of TIMELESS with immune infiltration, tumor mutation burden (TMB), microsatellite instability (MSI), and drug sensitivity was illustrated. Immunohistochemistry (IHC) was used to validate the expression of TIMELESS in clinical patients with several types of cancer. Results In contrast to the matching normal controls, most tumor types were found to often overexpress TIMELESS. Abnormal expression of TIMELESS was significantly related to more advanced tumor stage and poorer prognosis of breast cancer, as well as infiltrating immune cells such as cancer-associated fibroblast infiltration in various tumors. Multiple cancer types exhibited abnormal expression of TIMELESS, which was also highly correlated with MSI and TMB. More crucially, TIMELESS showed promise in predicting the effectiveness of immunotherapy and medication sensitivity in cancer therapy. Moreover, cell cycle, DNA replication, circadian rhythm, and mismatch repair were involved in the functional mechanisms of TIMELESS on carcinogenesis. Furthermore, immunohistochemical results manifested that the TIMELESS expression was abnormal in some cancers. Conclusions This study provides new insights into the link between the circadian gene TIMELESS and the development of various malignant tumors. The findings suggest that TIMELESS could be a prospective prognostic and immunological biomarker for pan-cancer. Keywords TIMELESS, Pan-cancer, Circadian rhythm, Prognosis, Immunological biomarker *Correspondence: Xiaolun Yang [yangxiaolunyy@csu.edu.cn](yangxiaolunyy@csu.edu.cn) Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ()[. The Creative Commons Public Domain Dedication waiver (](http://creativecommons.org/license

FAQs

What is TIMELESS and why is it studied in pan-cancer?

TIMELESS is a circadian clock and cell-cycle-related gene. It has been associated with various cancers, and this study evaluates whether its expression patterns relate to prognosis and immune features across many cancer types.

Which analyses were used to evaluate TIMELESS?

The study examined TIMELESS expression in normal versus malignant tissues and related it to clinicopathologic and survival outcomes. It also assessed genetic alterations, molecular subtypes, immune infiltration, tumor mutation burden (TMB), microsatellite instability (MSI), and drug sensitivity, with immunohistochemistry validation in clinical samples.

How does TIMELESS relate to prognosis and immunotherapy response?

In many tumors, TIMELESS is overexpressed compared with matched normal controls. Abnormal TIMELESS expression is associated with more advanced stage and poorer prognosis in breast cancer, and the gene shows potential for predicting immunotherapy effectiveness and medication sensitivity.

Sep 24, 2026

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