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Longevity Briefs: Is This Why Obese Women Get More Uterine Cancer?

Posted on 21 April 2022

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: Endometrial cancer is the most common type of uterine cancer, and begins in the layer of cells that form the lining (endometrium) of the uterus. We know that having a high body mass index (BMI) increases cancer risk, but the relationship between high BMI and endometrial cancer seems to be stronger than any other type of cancer. Studies suggest that each 5 kg/m2 increase in BMI is associated with an approximate 54% increase in endometrial cancer risk. What’s happening here on a molecular level? Answering that question could allow the development of drugs to reduce the occurrence of endometrial cancer in high-risk groups.

What did the researchers do: In this study, researchers used a Mendelian randomisation approach to study the relationship between BMI, endometrial cancer risk, and 14 key hormones and other molecules in nearly 13 000 endometrial cancer cases and 109 000 controls.

Mendelian randomisation is a technique in which scientists look at genetic variants to establish whether one variable causes another. For example, let’s say researchers discover a correlation between high levels of molecule X in the blood and cancer. There’s no way of knowing whether molecule X caused cancer, cancer caused molecule X to increase, or whether something else entirely is causing both cancer and molecule X to increase. However, suppose that some individuals carry a gene that increases their levels of molecule X. If these individuals get more cancer, researchers can reasonably assume that molecule X causes cancer, since the gene responsible was randomly inherited and cannot have been influenced by other factors.

Key takeaway(s) from this research: Researchers found a stronger association between BMI and endometrial cancer than had been suggested in previous studies: a 5 kg/m2 increase in BMI was associated with an 88% increase in risk. They also found evidence for three molecules that seem to be important mediators of the relationship between BMI and endometrial cancer risk:

  • Fasting insulin: Insulin is the hormone that lowers blood sugar. Elevated fasting insulin is usually an indication that cells aren’t responding to insulin as well as they should (insulin resistance).
  • Testosterone: The male sex hormone, which women also have in smaller amounts.
  • Sex hormone binding globulin (SHBG): A molecule produced by the liver that binds, transports and regulates sex hormones.

What do all of these molecules have in common? They all affect the levels of the hormone oestrogen: testosterone is converted into oestrogen, while SHBG effectively lowers the available testosterone and oestrogen by binding to them. Insulin increases testosterone while decreasing SHBG, and may also directly promote proliferation of endometrial cells. These findings are consistent with a hypothesis that excess oestrogen promotes endometrial cancer, though the researchers weren’t able to look for a relationship between oestrogen and endometrial cancer directly, as they were unable to find a reliable genetic variant for oestrogen levels. In light of these findings, the authors suggested that antidiabetic drugs like metformin might reduce the risk of endometrial cancer, as these drugs can reverse insulin resistance and lower fasting insulin.

The study also produced some findings that went against those of previous studies. Notably, not much evidence was found for a relationship between endometrial cancer and cholesterol levels or inflammation, both of which had been identified as risk factors in previous analyses. This could be because those analyses were regular observational studies, which are more prone to confounding factors.

This study is one of the largest of it’s kind, but it looked almost exclusively at people of European ancestry, so the results might not be generalised to the wider population. It would be good to see future research into the effects of BMI on cancer risk at different stages of life, such as pre- and post- menopause.

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    Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk: a Mendelian randomization analysis:

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