乌鸦传媒

Interventions that might reduce risk for endometrial cancer in obese women are suggested by findings from a study that identifies the potential mechanisms linking body mass index (BMI) to endometrial cancer risk.¹ 

By applying Mendelian randomization to 14 possible molecular risk factors for endometrial cancer, a team from the United Kingdom uncovered 鈥渟trong evidence鈥� that fasting insulin, bioavailable testosterone, and sex hormone-binding globulin (SHBG) mediated the effect of BMI on endometrial cancer risk.

乌鸦传媒 asked lead author Emma Hazelwood, PhD candidate, why her team decided to apply Mendelian randomization to investigate these potential molecular risk factors. 

鈥淎lthough the association between obesity and endometrial cancer is well established, we don鈥檛 have a clear explanation for this link. Many of the proposed ideas are based on observational data, which can be biased by confounding and reverse causation,鈥� replied Ms. Hazelwood, a researcher at the University of Bristol in the United Kingdom. 

She explained that Mendelian randomization can identify causal effects with less bias because: 鈥淭his genetic epidemiology technique uses germline genetic variants as proxies for risk factors, with the advantage being that these are randomly assorted across a population and fixed at conception, so this approach should suffer less from these biases.鈥� 

Molecular mechanisms analyzed

The investigators鈥� analytic strategy began with attempts to corroborate evidence of BMI鈥檚 effect on endometrial cancer risk from previous Mendelian randomization studies. They then performed literature reviews to identify molecular traits previously suggested to link BMI to endometrial cancer.

To proxy each molecular trait, the team used single nucleotide polymorphisms (SNPs) previously associated with each risk factor in genome-wide association studies (GWAS) from 12,906 patients with endometrial cancer and 108,979 controls. 

鈥淲e then used Mendelian randomization to find which of these traits had evidence for a causal effect on endometrial cancer risk, and which of those traits BMI had a causal effect on,鈥� Ms. Hazelwood commented. 

The final step: The investigators did a mediation analysis to determine how much each trait (the proportion) mediated the total effect of BMI on endometrial cancer risk.

Reasons BMI increases endometrial cancer risk revealed

Systematic Mendelian randomization analysis corroborated the link between elevated BMI and increased risk for endometrial cancer and provided evidence that fasting insulin, total and bioavailable testosterone, and SHBG also increased this. risk.

• BMI: odds ratio (OR) per standard deviation (SD) (4.7 kg/m²) increase in BMI 1.88, 95% confidence interval (CI) 1.69 to 2.09, P=3.87 脳 10^鈭�31
• Total testosterone: OR per inverse-normal transformed nmol/L increase 1.64, 95% CI 1.43 to 1.88, P=1.71 脳 10^鈭�12 
• Bioavailable testosterone: OR per natural log transformed nmol/L increase: 1.46, 95% CI 1.29 to 1.65, P=3.48 脳 10^鈭�9
• Fasting insulin: OR per natural log transformed pmol/L increase: 3.93, 95% CI 2.29 to 6.74, P=7.18 脳 10^鈭�7 
• SHBG: OR per inverse-normal transformed nmol/L increase 0.71, 95% CI 0.59 to 0.85, P=2.07 脳 10^鈭�4
  

Evidence regarding the degree to which these factors mediated the effect of BMI on risk for endometrial cancer was revealed by mediation analysis. 

• Fasting insulin: mediated 19% of total effect (95% CI 5 to 34%, P=9.17 脳 10^鈭�3)
• Bioavailable testosterone: mediated 15% (95% CI 10 to 20%, P=1.43 脳 10^鈭�8) 
• SHBG: mediated 7% (95% CI 1 to 12%, P = 1.81 脳 10^鈭�2) 

Interestingly, the investigators found 鈥渓ittle evidence鈥� that several previously reported molecular risk factors had a causal effect on endometrial cancer risk. These included LDL cholesterol, HDL cholesterol, leptin, adiponectin, Insulin-like Growth Factor 1 (IGF-1), C-reactive protein (CRP), and interleukin-6 (IL-6).

Commenting on her team鈥檚 findings, Ms. Hazelwood said:

鈥淥ur findings demonstrate that insulin levels may explain a large proportion of the effect of BMI on endometrial cancer risk, as well as confirming that sex hormone-binding globulin and testosterone also play an important role. This is consistent with the 鈥榰nopposed oestrogen鈥� hypothesis for endometrial cancer development, although insulin may cause endometrial cancer development through additional, independent pathways.鈥�

What are the potential clinical implications?

We posed this question to Andrea R. Hagemann, MD, MSCI, an independent expert not involved in the study. 鈥淲e've known that medicines like metformin can help modify the endometrium, but the effect has been smaller than we've hoped. Perhaps we've used it too late鈥攐nce diagnosis has already been established. With more targeted understanding, we can start a medication like metformin earlier.鈥�

鈥淢ost exciting,鈥� added Dr. Hagemann, member, 鈥淚f we can improve insulin resistance with anti-diabetic medications, this may set the stage for use of GLP-1 receptor agonists, which are now FDA approved for the treatment of obesity. We could test the effect of these agents on the endometrium and circulating metabolic markers.鈥� Dr. Hagemann is Associate Professor of Obstetrics and Gynecology and a practicing gynecologic oncologist at Washington University School of Medicine, St. Louis.

Ms. Hazelwood also sees promise in the potential use of anti-diabetic agents prescribed for obesity to reduce risk for endometrial cancer. 鈥淔urther studies are needed to determine whether these agents actually do decrease risk for development of endometrial cancer,鈥� said Ms. Hazelwood. But she added, 鈥淚 would recommend that clinicians be aware that this analysis sits within a wider body of evidence suggesting that insulin levels may play an important role in explaining the link between obesity and endometrial cancer risk.鈥�

Ms. Hazelwood also pointed out that, 鈥淐linical trials looking at combining contraceptive intrauterine devices with metformin as a treatment option for early stage endometrial cancer patients with obesity are currently underway.鈥�

What about findings regarding testosterone and SHBG?

鈥淎gents targeting bioavailable testosterone and SHBG may also be effective in reducing endometrial cancer risk in individuals with obesity,鈥� replied Ms. Hazelwood. She added, however, 鈥淚t is anticipated that these agents may have more unwanted off-target effects than those targeting insulin due to the wide variety of roles of these sex hormones.鈥�

Published: November 16, 2022