In a recent study published in eBioMedicine, Researchers investigated the causal relationship between epithelial ovarian cancer (EOC) risk or survival and insomnia.
Study: Effect of insomnia on ovarian cancer risk and survival: Mendelian randomization study. Image credit: Gladskikh Tatiana / Shutterstock.com
Sleep and EOC
EOC is a leading cause of cancer death in women, claiming nearly 13,000 lives in the United States alone in 2022. Early detection of EOC remains a challenge due to the lack of specific symptoms that are not apparent until advanced stages. EOC is also associated with a high recurrence rate.
Therefore, there remains an urgent need to identify both modifiable and prognostic risk factors that can facilitate early detection of EOC to improve patient outcomes. Sleep disorders, for example, are known to increase the risk of breast and ovarian cancer, as well as to adversely affect their prognosis.
Sleep is one of the most cyclical and essential human physiological functions. It is intricately involved in endocrine, metabolic and immunoregulatory pathways, which are also involved in various cancers. These common pathways may account for the increased risk of sleep disorders among cancer patients, with insomnia being the most prevalent sleep disorder in this population. In fact, up to 60% of EOC patients also suffer from insomnia.
Previous studies have shown that insomnia and circadian disruption, the latter of which often occurs due to night work, increase the risk of both invasive EOC and end-stage ovarian cancer. Despite these observations, the evidence for this association has been inconsistent, necessitating the need for additional studies to determine causality between insomnia and ovarian cancer risk.
About the study
The present study aimed to examine insomnia using its genetic determinants in a genome-wide association study (GWAS). To this end, the researchers applied two-sample Mendelian randomization (MR), a well-established method for determining the causal effect between a modifiable factor and clinical outcome.
Study participant data were obtained from both UK Biobank and 23andMe, while genetic association data were obtained from the Ovarian Cancer Association (OCAC) GWAS Consortium. In total, the study cohort included nearly 66,500 women, all with clinical history and follow-up.
What did the study show?
The researchers used over 550 single nucleotide polymorphisms (SNPs) for their analysis. This showed a 60% higher risk of endometrial EOC among those with insomnia. In comparison, the risk of other malignancies, including clear cell EOC and high-grade serous EOC (HGSOC), was reduced by 50% and 20%, respectively.
When the survival of these EOC patients was examined, invasive EOC was associated with shorter survival, with the risk of premature death being almost 50% higher. When adjusted for cancer histotype, the risk remained significant but dropped to 26%. For HGSOC, the risk of mortality increased by 40%. However, this association was no longer significant when adjusted for body mass index (BMI), as well as age at both menarche and menopause.
Response to treatment was assessed using genetic association data from The Cancer Genome Atlas (TCGA). To this end, a twofold increase in the risk of premature death was observed in women with insomnia who were prescribed standard chemotherapy for HGSOC after adjustment for stage, the presence of residual disease after treatment, and age at diagnosis. Importantly, this association was no longer significant when response to treatment was considered.
The researchers also performed an entity-based analysis mined from the literature to further explore the biological mechanisms that may link sleep disturbances to ovarian cancer. Melatonin, leptin, AKT serine/threonine kinase 1 (AKT1), and c-akt proteins were most frequently identified in this search.
Both leptin and the Akt signaling pathway have been implicated in cancer biology. Leptin, for example, is a hormone primarily associated with the regulation of hunger and energy and has been shown to promote cell proliferation and inhibit apoptosis. The Akt signaling pathway regulates both cell survival and growth, with dysregulation of this pathway implicated in tumorigenesis.
The activation of leptin and Akt signaling pathways may suggest a potential synergistic effect in enhancing the survival and proliferation of ovarian cancer cells.”
conclusions
The current study used MRI to identify a possible association between insomnia and EOC. To this end, there appears to be a significant genetic predisposition to both insomnia and EOC mortality rates influenced by BMI, as well as other patient characteristics.
Elucidating the causal relationships of these modifiable behaviors could inform clinical prevention strategies and therapeutics for EOC.”
Journal Reference:
- Wang, H., Reid, BM, Richmond, RC, et al. (2024). Effect of insomnia on ovarian cancer risk and survival: Mendelian randomization study. eBioMedicine. doi:10.1016/j.ebiom.2024.105175.
