Genomics England Research Registry ID: 1067
Registered: 27/02/2024
Abstract
Background
The circadian clock orchestrates the rhythmic physiology of organisms, influencing the expression of up to 40% of protein-coding genes. Circadian disruption has been implicated in cancer for over three decades, yet the identification of genetic variants disrupting the circadian clock in cancer has been sparse. Recent findings have highlighted a somatic structural variant in the CLOCK gene, prevalent in colorectal and endometrial cancers, both of which are linked through Lynch syndrome and characterized by high cellular turnover rates.
Objectives
This study aims to investigate the prevalence and implications of the CLOCK gene variant in colorectal and endometrial cancer patients within the NHS genomic medicine service, utilizing data from Genomics England’s 100,000 Genomes Project. Specifically, we will assess the variant’s impact on patient survival and explore its role in cell growth and the potential for enhanced survival in endometrial cancer patients harbouring the variant.
Methods
We will identify individuals with the CLOCK variant in the cancer cohort of the 100,000 Genomes Project, followed by survival analysis in both colorectal and endometrial cancer cohorts. The cohorts will be further stratified based on the molecular diagnosis of Lynch syndrome to evaluate its association with survival outcomes.
Expected Outcomes
The study anticipates elucidating the role of the CLOCK gene variant in cancer progression and patient survival. By understanding the variant’s effect on cell growth and survival, this research may pave the way for novel circadian-based therapeutic strategies in cancer treatment, particularly for Lynch syndrome-associated cancers.
Significance
Given the established link between circadian disruption and cancer, identifying genetic variants that disrupt the circadian clock in specific cancers could revolutionize our approach to cancer diagnosis, prognosis, and treatment. This research underscores the potential of circadian medicine in oncology, offering new insights into the genetic underpinnings of cancer development and progression.
Lay Summary
Humans have an intrinsic circadian clock that synchronises physiology with the external environment and controls the expression of up to 40% of protein coding genes. Most clinical advances in circadian medicine have been focused on chronotherapeutics and drug dosing. Despite a clear link between circadian disruption and cancer having been identified for over 30 years, few genetic variants causing clock disruption have been identified in cancers. We have identified a somatic structural variant in the gene CLOCK that occurs at very high frequencies in both colorectal and endometrial cancers, these cancers are linked by Lynch syndrome, and are tissues with very high cell turnover. We are studying a cohort of patients in the NHS genomic medicine service data held by Genomics England to see how this variant affects the survival of patients. In this project we will additionally study what effect the variant gives to cell growth, and if this is linked to the enhanced survival of endometrial cancer patients with this somatic variant.
Chronomic Medicine Group 