BEING OVERWEIGHT OR OBESE IS ASSOCIATED with a higher risk of more than a dozen cancers. These malignancies account for four out of ten cancers diagnosed in the United States.

But is the message that simple? Even though multiple cancer-related organizations spread the message that obesity increases cancer risk, we based the observation on imperfect observational studies.

Still, the American Cancer Society offers that being overweight or obese is associated with an increased risk of several cancer types, including:

• Breast cancer (in women past menopause)
• Colorectal cancer
• Esophagus cancer
• Gallbladder cancer
• Kidney cancer
• Liver cancer
• Ovarian cancer
• Pancreas cancer
• Stomach cancer
• Thyroid cancer
• Uterus (endometrial) cancer
• Myeloma
• Meningioma (a tumor of the brain or spinal cord lining)

Being overweight or obese might also raise the risk of other cancers, such as:

• Malignant (Non-Hodgkin) lymphoma
• Male breast cancer
• Mouth, throat, and voice box cancers
• Aggressive forms of prostate cancer

A new study suggests that excessive weight may be causally related to only six types of cancer. Let’s explore this new research, but first, we need to talk about a statistical maneuver known as Mendelian randomization.

Mendelian randomization

How can we examine the relationship between obesity and cancer? Mendelian randomization is a novel epidemiological tool developed over the last two decades, in large part because of the vast quantity of data emerging from genome studies.

With the technique, we can examine the causal effects of a modifiable exposure on disease in observational studies. We will see the increasing use of Mendelian randomization in the future as genetic knowledge of health and disease expands from gene sequencing.

Mendelian randomization can suggest a causal relationship between a risk factor (such as body weight) and disease outcome (for example, cancer incidence). MR uses genetic data as a “proxy” for non-genetic information. This approach allows us to test for causal effects when confounding variables are present.

The downside? Mendelian randomization studies are not actual experiments and rely on some assumptions. We still need to fall back on high-level evidence, such as from randomized clinical trials in this context.

Weight and cancer: New study results

With the brief primer on statistics behind us, let’s turn to a 2022 study based on Mendelian randomization. For the study, Dr. Fang and colleagues reviewed 204 meta-analyses and discovered “strong evidence” pointing to an association between obesity and 11 cancers.

These 11 cancers include esophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney.

But, while the associations may be causal for some cancers, there can be confounding with numerous other risk factors. The researchers turned to Mendelian randomization studies examining the association between genetic variants linked to body mass index to get around this problem.

Here are the new findings of the Mendelian randomization studies:

There is a causal relationship between obesity and six cancer types: colorectal, endometrial (uterus), ovarian, kidney, pancreas cancer, and esophageal adenocarcinoma.

In addition, these studies further establish the inverse relationship between early-life obesity with breast cancer. I would note that post-menopausal weight gain is associated with a higher risk of breast cancer.

The new research approach did not link obesity and gallbladder and stomach cardia (the part closer to the esophagus), cancer, and multiple myeloma.

The new research approach did not link obesity and gallbladder and stomach cardia (the part closer to the esophagus), cancer, and multiple myeloma.

For six cancer types for which a causal relationship with obesity could be established, the effect estimates from the Mendelian randomization studies were more robust than those seen in conventional studies. The magnitude of risk ranged from 1.14-fold for early-life obesity and breast cancer to 1.37-fold for adult obesity and esophageal adenocarcinoma.

This study reminds us of a need for those in the United States and elsewhere to develop strategies to drop childhood, adolescent, and adult obesity.

The Breast Cancer Research Foundation supports one of the study authors. The researchers report no other relevant financial relationships.