MSK thoracic medical oncologist Justin Jee, MD, PhD, (left) and computational oncologist Ed Reznik, PhD, led a team of researchers who found that obesity is linked to driver mutations in tumors that result in specific subtypes of some cancers, including lung and endometrial cancer.
Obesity or being overweight can increase your risk of developing cancer. It can lead to chronic inflammation and hormonal changes, which can damage DNA and cause uncontrolled cell growth.
Now new research at Memorial Sloan Kettering Cancer Center (MSK) suggests obesity may also be linked to some genetic mutations that drive specific subtypes of cancer.
“Our results show that obesity can help tip some mutations in otherwise healthy tissue into full-blown cancer,” says thoracic medical oncologist Justin Jee, MD, PhD.
These insights could open new avenues for using therapies that target those mutations and further personalize treatments for people with lung, endometrial, and other cancers.
Surprise Findings About Cancer Driver Mutations
The research, published in October 2024 in Nature Genetics, started with a hypothesis suggested by computational oncologist Ed Reznik, PhD, and investigated in collaboration with Dr. Jee, lead author and MSK Research Fellow Cerise Tang, PhD, and Venise Jan Castillon, an MSK Bridge Scholar who along with Dr. Tang is in the Department of Epidemiology & Biostatistics.
Cerise Tang, PhD
Dr. Reznik’s hypothesis grew out of two curious wrinkles in cancer biology.
The first involves mutated proteins often called “driver mutations” that can promote the growth of cancer cells. These driver mutations create subtypes in many forms of cancer, such as KRAS-positive lung cancer, which accounts for 25% of lung cancer patients, and EGFR-positive lung cancer, present in 10–15% of lung cancer cases.
Venise Jan Castillon, BS, MSK Bridge Scholar
Attacking these driver mutations with a host of therapies can be lifesaving.
But there is a surprising twist. “What the scientific community is realizing,” says Dr. Jee, “is that a lot of times, even healthy people who don’t have cancer, in fact, have those mutations in their tissue. Up to half of healthy people may have these tumor driver mutations that are just sitting there.”
The second puzzling observation, says Dr. Reznik, involves “what is colloquially called ‘The Obesity Paradox.’ It holds that obesity makes you more disposed to cancer. But once you have it, in some cases, you may actually respond better to treatment if you are obese.”
Dr. Reznik and the team suspected these two phenomena might point to an important new dimension in the relationship between obesity and cancer.
How MSK Researched the Link Between Obesity and Cancer-Causing Genetic Mutations
To investigate the hypothesis “required data on the genomic makeup of people’s tumors, as well as data on obesity,” says Dr. Jee. “Some places have one or the other. But MSK has both, along with key clinical data. MSK has one of the only data sets in the world where this could be studied.”
The team extracted information related to obesity using BMI (Body Mass Index) and other demographic factors in 34,274 MSK patients who had their tumors genetically sequenced by MSK-IMPACT, the first sequencing platform authorized by the U.S. Food and Drug Administration.
They then looked at the statistical association between BMI and 341 cancer-linked genes, eventually focusing on six genes across three separate cancer types that had a statistically significant relationship with BMI:
-
Lung Adenocarcinoma
- KRAS
- EGFR
- SETD2
- PPP2R1A
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Uterine Endometrioid Carcinoma
- POLE
-
Cancer of Unknown Primary (CUP)
- BAP1
The team’s analysis showed, says Dr. Jee, that obesity is a factor “that can take a healthy person with some mutations and determine which of those mutations actually turn into cancer.”
This insight, continues Dr. Jee, is more proof of the powerful effect that obesity can have on human biology. “Obesity affects your metabolism, it affects your immune system, and it is linked to inflammation, which can be a key component of cancer. There’s just so much tied up with obesity.”
Controlling for Variables Like Smoking and Ancestry
The team also analyzed other possible influences on driver mutations, including the most obvious — smoking.
“We found the relationship between obesity and mutation-driven lung cancers held true whether a person was a nonsmoker, a former smoker, or a current smoker,” says Dr. Jee.
Similarly, the team controlled for ancestry. “There is a strong association between some people’s ancestry and EGFR and KRAS mutations in lung cancer,” says Dr. Jee. “But our analysis showed that did not affect the link we found between obesity and driver mutations.”
“We controlled for everything that we could think of as well as anything suggested by reviewers and colleagues,” Dr. Tang explains. “That includes social economic status, air pollution, tumor mutational burden — a measure of how many mutations a cancer tumor has — as well as age, biological sex, and cancer-associated weight changes at diagnosis, known as cachexia.”
This analysis showed, she says, “that our result was consistently significant, meaning it held true no matter what other possible explanations we tested.”
The results were also corroborated in an independent set of data from the Dana-Farber Cancer Institute, thanks to fellow scientist Dr. Sasha Gusev.
Possible Implications for Diagnosing and Treating Cancer
While these are early days for this area of research, Dr. Jee believes there may be important implications. “I divide it into two buckets,” he says. “Pre-cancer diagnosis and post-diagnosis.”
For people at risk of lung cancer, “this research may help identify the really high risk people who may benefit from CT scans or even liquid biopsies for early detection, which is very important for lung cancer.”
After diagnosis, the research may shed new light on the best course of treatment for patients and may help explain why patients with different BMIs might respond differently to immunotherapies or certain targeted therapies.
The work also infuses a fundamentally new idea into the research studying the relationship between obesity and cancer. “We now know that obesity is not only associated with the risk of developing cancer and the subsequent prognosis,” says Dr. Reznik. “It also shapes the kinds of mutations a tumor acquires, and thus the kinds of therapies that a patient may be eligible for.”