Researchers determine the relationship between genetically predicted BMI and the risk of breast cancer.


Breast cancer is one of the most common types of cancer in Canada. Affecting mostly women but also men, breast cancer starts when cells in the breast grow out of control and lump together to form a tumor. A tumor is cancerous when the cells invade other tissues or spread to other parts of the body. The tumor may be felt as a lump in the breast or seen on a mammogram. Other signs and symptoms include changes in breast shape or size, changes in the skin of the breast (dimpling, thickening, swelling, itching) and changes in the nipple (inversion, discharge, crusting). Individuals should also look out for late signs and symptoms – such as headache, nausea, and loss of appetite, among others – as the cancer spreads to other parts of the body. Many factors play a role in the development of breast cancer, and researchers believe that breast cancer is a result of a combination of risk factors, rather than a single factor alone. Some of these risk factors include: getting older, inheriting genetic mutations, starting menstruation at an early age, using combination hormone therapy, and being overweight after menopause.

Obesity can be measured by body mass index (BMI), and in a study recently published in PLOS Medicine, researchers investigated BMI as a risk factor for breast cancer. BMI is a measurement often used to assess an individual’s health, by dividing a person’s weight by their height. Lower BMI measurements indicate that the individual is underweight or normal weight, while higher BMI measurements indicate that the person is overweight or obese. Previous population studies have linked BMI to breast cancer, finding that in premenopausal women, a high BMI is associated with a reduced risk for breast cancer while in postmenopausal women, a high BMI is associated with an increased risk for breast cancer.

Since an increased exposure to ovarian hormones raises the risk of breast cancer, scientists suspect that premenopausal women with high BMI have a lower risk because overweight women are more likely to experience anovulatory menstrual cycles. This leads to a lower exposure to ovarian hormones and thus reduces the risk for breast cancer. However, postmenopausal women with a high BMI have a higher risk because their primary source of the ovarian hormone estrogen is from the conversion of androgens in fat tissue. And since overweight women have been found to have higher estrogen levels than normal weight women, this may explain why postmenopausal overweight women have a higher risk for breast cancer.

However, researchers are unclear on whether the opposing risks in pre- and postmenopausal women are caused by BMI itself, or caused by environmental factors associated with BMI.

Genome-wide association studies (GWAS) have previously identified multiple loci (specific locations of a gene’s DNA sequence on a chromosome) associated with BMI. Using this knowledge, the researchers of this study used genetically-predicted BMI to understand BMI’s causal role in breast cancer. They used genetically-predicted BMI because outcomes associated with high BMI predicted by genetic variants are set at birth, and are more likely to be caused by high BMI itself, rather than by environmental factors associated with high BMI.

To genetically predict BMI, they obtained individual genetic sequences and breast cancer diagnoses from a total of 145,000 women of European descent. They obtained the genotype data from two consortia: the Breast Cancer Association Consortium (BCAC) and the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Researchers then used a genetic score to evaluate the association between BMI and breast cancer risk, via Mendelian randomization analysis. Mendelian randomization analysis uses a measured variation in genes to determine the causal effect of a certain factor. In this study, that factor is BMI.

The researchers found that genetically-predicted BMI is inversely associated with the risk of breast cancer in both pre- and postmenopausal women, contradicting the findings of previous studies, which used measured BMI rather than genetically-predicted BMI. They note that the genetically-predicted BMI may reflect an early-life BMI, and would not consider adult weight gain. This would also be consistent with other studies that found early-life BMI to be inversely associated with breast cancer risk, and is consistent in both pre- and postmenopausal women. The study also notes that “it is possible that weight gain during later adulthood, not adult BMI per se, is related to increased postmenopausal breast cancer risk among overweight women as determined using measured BMI.” However, the researchers of this study were unable to evaluate this since adult weight change was not consistently measured in the BCAC consortium.

Nevertheless, the findings of this study suggest that weight gain later in adulthood may at least partially explain the positive association between high measured BMI and postmenopausal breast cancer risk as reported in previous studies. Because of this, they note that the primary prevention of breast cancer should be a lifestyle modification to reduce obesity.




Written By: Jessica Gelar, HBSc

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