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A Constellation of Factors: Uncovering the Causes of Rising Incidence of Early-onset Colorectal Cancer

Researchers at Washington University School of Medicine in St. Louis are studying the increased risk of early-onset colorectal cancer among people younger than 50 years old. Two recent publications from the School of Medicine study the risk factors for early-onset colorectal cancer and its precursors and suggest screening and prevention methods to address this growing problem of national priority.

Colorectal cancer (CRC) starts in the colon or rectum, and is the third most common cancer and cause of cancer death globally, according to the American Cancer Society. Some risks for colon cancer and rectal cancer cannot be avoided. Age, inflammatory bowel disease or an inherited syndrome are out of a person’s control. Other risk factors, including obesity or being overweight, physical inactivity, poor diet, smoking and alcohol use, can be modified.

Research from American Cancer Society (ACS) notes that early-onset cancers, including CRC, have been on the rise since the 1980s, in sharp contrast to the decline in CRC among adults aged 50 and above. Because of such an increase, the median age at diagnosis of CRC has been shifted from 72 years in early 2000s to 66 years. However, the etiology of early-onset CRC remain largely underexplored and emerging evidence suggest that early-onset CRC may have different histology and tumor characteristics compared with cancers of later-onset. The 2018 ACS guideline and recent draft recommendation from the U.S. Preventative Services Task Force (USPSTF) suggest individuals with average risk to begin screening for CRC at age 45. Yet these recommendations have not be widely implemented.

Yin Cao, ScD, MPH, Associate Professor of Surgery in the Division of Public Health Sciences, is researching the factors that put young adults at increasing risk of CRC.

“It’s a really puzzling question,” Cao says. “Why are younger people developing colorectal cancer at an increasing rate, and how do we address this problem with screening and prevention?”

Metabolic Syndrome and Cancer Risk

Obesity and prolonged sitting, are among the first set of risk factors that Cao’s team has identified to be associated with increased risk of early-onset CRC. Recently, Cao led researchers at the School of Medicine studying data from 113 million adults, trying to understand the association between metabolic syndrome and early-onset CRC. Cao describes metabolic syndrome as “a constellation of metabolic disorders”, defined as the presence of three or more conditions among obesity, hypertension, hyperlipidemia and hyperglycemia/type 2 diabetes.

While metabolic syndrome is increasingly common among young adults worldwide, its association with early-onset CRC has not been examined. This study, published in the journal Gut, looked at 4,673 cases of early-onset colorectal cancer diagnosed under age 50, and 14,928 later-onset cases between ages 50-64 with matched controls.

“We found that metabolic syndrome was associated with a 25% increased risk of early-onset colorectal cancer,” says Cao. “In addition, the more the number of metabolic comorbid conditions, the higher the risk. This dose-response relationship was more apparent for early-onset CRC compared to cases at older ages. The totality of these findings indicates that metabolic dysregulation likely plays a stronger role in carcinogenesis at younger ages.”

“This is an important step in our understanding of early-onset CRC,” says Chief of Surgical Oncology Ryan Fields, MD, the Kim and Tim Eberlein Distinguished Professor of Surgery. “If validated, this means that tailored CRC screening among young adults with metabolic syndrome may help prevent and/or detect cancers earlier. We are also working with Dr. Cao’s team to further elucidate the underlying biological mechanisms and genomic landscape of early-onset CRC.”

Dr. Fields, Section Chief of Surgical Oncology
Section Chief of Surgical Oncology Ryan Fields, MD

The Role of Diet

Improving diet quality may be another emerging avenue for the prevention of early-onset CRC. As diet quality declined steadily between 1985 and 2006 and younger adults in the US have had consistently poorer diet quality compared with the older population, understanding the role of diet in the rising incidence of early-onset CRC is imperative.

In a second study recently published in the Journal of the National Cancer Institute, Cao’s team investigated several diets to see if they were associated with increased risk of developing early-onset adenomas. Because adenomas are polyps that can turn into cancer, people with early-onset polyps are at higher risk of developing CRC.

The study found that a Western dietary pattern—high in meat, pre-packaged foods, sweets and fried foods—was associated with an increased risk of early-onset adenomas, particularly adenomas of high malignant potential.

Individuals who were adherent to prudent dietary pattern—rich in fruits, vegetables, whole grains, legumes, and fish—and some major dietary recommendations, such as, Dietary Approaches to Stop Hypertension, Alternative Mediterranean Diet and Alternative Healthy Eating Index, were less likely to develop these early-onset adenomas.

“Diet quality among younger adults is consistently poorer compared to the older population,” Cao says. “Adopting a healthier diet at a young age could potentially help people lower risk of early-onset CRC. A diet with more fruits, vegetables and whole grains, and fewer foods from the Western pattern diet, seems to be one way of addressing this increasing risk.”

Colorectal Cancer Prevention and Education

As her team continues to lead research on the mysterious rise of early-onset CRC, Cao is vocal about sharing findings and helping people understand their risk. It is the Division of Public Health Science’s aim “to prevent cancer and other diseases, promote population health, and improve quality and access to health care in Missouri and beyond.”

“About 150,000 people are diagnosed each year, and a growing number are younger than 50,” says Graham Colditz, MD, DrPH, Division Chief of Public Health Sciences and Niess-Gain Professor of Surgery. “Yet, countering such sober statistics is the fact that colon cancer is also one of the most preventable cancers. Communicating research findings to both research community and the public in a timely fashion should always be our priority.”

Dr. Colditz, Division Chief of Public Health Sciences, talks with colleague.
Graham Colditz, MD, DrPH, Division Chief of Public Health Sciences

A National Institutes of Health Early Onset Colorectal Cancer Think Tank, supported by the National Cancer Institute and National Institute of Environmental Health Sciences, brought together experts in colorectal cancer from across the country last September. During a session focused on the question “How can observational studies enhance the understanding of early-onset colorectal cancer?” Cao presented her research on putative and emerging risk factors.

Over the past several years, Cao was also invited to speak at the Early Age Onset Colorectal Cancer Summit, AACR Annual virtual meeting, and Digestive Disease Week. She has also been enthusiastic in sharing her research with the public through sources including the New York Times, HealthDay and CNN Health, among others.

Era of Precision Public Health Sciences

As Cao highlights in a recent co-senior authored review in Nature Reviews Clinical Oncology, identifying risk factors throughout the life course and the relevant etiological window will be crucial.

Among the first NCI-funded projects focused on early-onset CRC, Cao’s R37 grant aims to identify personalized screening strategies for early-onset CRC through integrating evidence from life course epidemiology, proteomic discovery, and decision modeling. She will leverage data collected up to 30 years from two large, prospective, and diverse cohort studies. She will also work with the NCI Cancer Intervention and Surveillance Modeling Network, the research team that generated the key modeling evidence to support the ACS/USPSTF CRC screening guidelines, to develop precision-based screening strategies for younger adults through simulating life course risk factor trajectories.

Yin Cao, ScD, MPH

Currently, Cao’s team is also leading efforts to examine the genomic and molecular underpinnings of early-onset CRC including the biological bases of disparities. She has also assembled a team of leading investigators at Washington University to examine microbial/viral alterations associated with early-onset CRC using state-of-the-art multi-omic technologies. In addition to etiology research, her team is also exploring real world evidence from claims and EHR to develop tools for early detection.

“We hope to build a recognized program in early-onset CRC prevention, detection, and molecular-driven therapeutics,” Cao says. “We are excited to work with colleagues in the Departments of Surgery, Internal Medicine, Pathology and Immunology, and McDonnel Genome Institute. Through these provocative projects and seamless collaborations among epidemiologists, clinicians, computational biologists, and basic scientists, we also hope to lay the foundation to study other cancers that are also on the rise in younger populations.”