In a recent study published in eBioMedicine, researchers investigated the causal association between epithelial ovarian cancer (EOC) risk or survival and insomnia.

Study: Impact of insomnia on ovarian cancer risk and survival: a Mendelian randomization study. Image Credit: Gladskikh Tatiana / Shutterstock.com

Sleep and EOC

EOC is a major cause of death due to cancer in women, as it claimed nearly 13,000 lives in the United States alone in 2022. The early detection of EOC remains challenging due to the lack of specific symptoms that are not evident until advanced stages. EOC is also associated with a high recurrence rate.

Thus, there remains an urgent need to identify both modifiable and prognostic risk factors that can facilitate the early detection of EOC to improve patient outcomes. Sleep disorders, for example, are known to increase the risk of breast and ovarian cancers, as well as negatively affect their prognoses.

Sleep is among the most cyclic and essential human physiological functions. It is intricately involved in endocrine, metabolic, and immunoregulatory pathways, all of which are also implicated in various cancers. These shared pathways may account for the increased risk of sleep disturbances among cancer patients, with insomnia being the most prevalent sleep disorder in this population. In fact, up to 60% of patients with EOC also suffer from insomnia.

Previous studies have shown that insomnia and circadian disruption, the latter of which often arise due to night shift work, increase the risk of both invasive EOC and end-stage ovarian cancer. Despite these observations, evidence of this association has been inconsistent, thus necessitating the need for additional studies to determine the causality between insomnia and ovarian cancer risk.

About the study

The current 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 acquired from both the United Kingdom Biobank and 23andMe, whereas genetic association data were obtained from the Ovarian Cancer Association Consortium (OCAC) GWAS. Taken together, the study cohort included almost 66,500 women, all with clinical histories and follow-ups.

What did the study show?

The researchers used over 550 single nucleotide polymorphisms (SNPs) for their analysis. This showed a 60% higher risk of endometrioid EOC among those with insomnia. Comparatively, 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 patients with EOC was examined, invasive EOC was associated with shorter survival, with the risk of premature death being nearly 50% higher. When adjusted for the cancer histotype, the risk remained significant but was reduced to 26%. For HGSOC, the risk of mortality rose 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 two-fold increase in the risk of premature death was observed in women with insomnia who were prescribed standard chemotherapy for HGSOC after adjusting for the stage, presence of residual disease after treatment, and age at diagnosis. Importantly, this association was no longer significant when the response to treatment was considered.

The researchers also performed a literature-mined entity-based analysis to further explore the biological mechanisms that may connect sleep disorders to ovarian cancer. Melatonin, leptin, AKT serine/threonine kinase 1 (AKT1), and proto-oncogene proteins c-akt 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 regulating hunger and energy, and it has been shown to promote cell proliferation and inhibit apoptosis. The Akt signaling pathway regulates both cell survival and growth, with the dysregulation of this pathway implicated in tumor development.

The activation of leptin and Akt signaling pathways may suggest a potential synergistic effect on enhancing ovarian cancer cell survival and proliferation.”

Conclusions

The current study utilized MR to identify a potential association between insomnia and EOC. To this end, there appears to be a significant genetic predisposition to both insomnia and EOC mortality rates that are affected 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.”