An international team of researchers co-led by Fred Hutchinson Cancer Center’s genetic epidemiologist Ulrike (Riki) Peters, PhD, has pinpointed what’s likely driving many colorectal cancers in people under age 50.

Over the past two decades, multiple studies show that colorectal cancers have increased in young adults, often in sharp contrast to rapid declines of the disease in older adults. So far, no clear answers have emerged as to what’s behind this concerning rise.

But a study just published in the Annals of Oncology co-led by Peters and two international collaborators provides valuable insights into what’s likely driving cancers in people who are often too young to qualify for preventive screening.

While the team found unique genetic risk factors, Peters said, they don’t explain the rise of colorectal cases in people under 50. Instead, the findings point to alcohol consumption and obesity as two important, but modifiable, risk factors.

“Genes do not change that quickly,” Peters said, dismissing the idea that high-risk genes are behind the rise in early-onset colorectal cancer. “It’s important to understand that the same risk factors are there for early-onset colorectal cancer as for late-onset colorectal cancer. It’s just that the risk factors happen at an earlier age now.”

What drives cancers?

Most people understand that cancer is a disease of aging. As Peters puts it, “the older you are, the more the environment wears on the body.” That’s why it’s much more common for cancers in people under 50 — considered young for the disease — to be driven by germline, or inherited, mutations. Questions about early detection of colorectal cancer? Check out Fred Hutch’s CRC Screening & Early Detection program.

Close to 30% of early-onset colorectal cancers are attributable to high-risk genetic variants, such as those found in Lynch syndrome, a cluster of cancers including colorectal that are driven by inherited mutations.

“High-risk genes are rare, but they have strong effects,” said Peters, holder of the Fred Hutch 40th Anniversary Endowed Chair. “If you have these mutations in one of the DNA mismatch repair genes, the chances of getting colorectal cancer and other cancers are much higher.”

But high-risk genes don’t explain the steady rise in early colon cancers.

So Peters, along with co-investigators Ruhina Laskar, PhD, and Neil Murphy, PhD, of the International Agency for Research on Cancer (IARC), part of the World Health Organization, dug in to find answers.

“We knew there must be environmental and lifestyle factors that explain the increase, Peters said. “A change in the last 20 to 50 years is not genetic.”

Many cancers are polygenic in nature; that is, they’re driven by the interaction of mutations in multiple genes, each with a weak effect, in combination with environmental influences.

In this study, the team was able to identify new susceptibility genes — germline mutations that can make someone more prone, but not fated, to develop cancer — along with signaling pathways that increase the risk, specifically insulin signaling, immune- and infection-related pathways. They also found that two exposures had oversized roles in driving early-onset colorectal cancers.

Enter alcohol and obesity.

“We’ve seen substantial changes in our lifestyles and diets, as well as increasing obesity rates in higher income countries,” said Murphy, co-investigator on the study. “But until now, it’s been hard to assess the contribution each of these factors make to someone’s risk of developing early-onset colorectal cancer. Our study presents evidence showing the genes and environmental factors that are driving these cancers.”

Sharing data for more power

Data for the large international collaboration came from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary study (CORECT) and the Colon Cancer Family Registry, or CCFR. Fred Hutch houses the GECCO coordinating center for the genetic data, under Peters’ leadership.

From these sources, the researchers pulled out nearly 6,200 cases of early-onset colorectal cancer and nearly 66,000 healthy “controls.” Then they conducted a genome-wide association meta-analysis.

They then used that genome-wide association study, or GWAS, data to perform a Mendelian randomization, which allowed them to look at causal associations between 28 risk factors and early-onset colorectal cancer. Mendelian randomization uses genetic variants as proxies for risk factors to allow causal inference between an exposure and outcome.

By comparing the genetic variations of the healthy individuals with the genetic variations in those with colorectal cancer, they were able to precisely pinpoint which lifestyle factors were increasing the risk.

“It’s a trick we can use to find genetic risk factors linked to different traits and diseases,” Peters said. “There are hundreds of genetic variants that increase risk of obesity. If a person has a lot of these genetic risk factors, they tend to have a higher risk of obesity. If those individuals also have a higher risk of colorectal cancer, we can infer that obesity is linked to colorectal cancer.”

Peters said this type of analysis is a good way to investigate the impact of lifestyle factors.

“It’s important to see that alcohol and obesity are linked to early-onset colorectal cancer,” she said. “Also, insulin signaling and infection-related biological pathways. These are all really important to understand — it’s helping us to develop interventions.”

None of this could be done, of course, without a large team of international researchers willing to share data.

“This was the first comprehensive genome-wide association study for early-onset colorectal cancer,” Peters said. “We have been fortunate to closely collaborate with investigators across many studies from over 130 institutes across the globe who are willing to put their data together. No single study is powered to investigate this important question alone. We can find these associations because we have large numbers and because we measure it precisely.”

There are data gaps in the study, Peters acknowledged, primarily with regard to whether the findings apply to all ancestry groups.

“The vast majority of research is done in European-descent individuals, so we don’t know if there are specific genetic risk factors that are contributing to risk in other racial and ethnic groups that are either absent or at low frequency in European descent populations,” she said.

Similarly, there could also be unique lifestyle or environmental factors that contribute to high risk in other racial and ethnic groups. Alaska Native people, for instance, have some of the highest rates of colorectal cancer and the highest increase in early-onset colorectal cancer in the world.

“This cannot be explained by lack of access to screening as the tribal community is very concerned and is investing a lot in colorectal screening,” Peters said, adding that further study should elucidate the risk for all racial and ethnic groups. “There could be unique genetic, lifestyle or environmental factors that explain these high rates.”

“We are not blaming anybody”

Peters stressed the findings are not saying people are overeating and overdrinking their way to early colorectal cancers.

“We are not blaming anybody,” she said. “People are not to blame for obesity. Obesity is highly heritable — 30% to 60% is explained by genetics — plus we live in an obesogenic environment. There are many things that are not helping individuals stay at a healthy weight.”

Case in point: Triple bacon cheddar cheeseburgers, mocha Frappuccinos and the much-heralded return of the Choco Taco.

Obesity is also happening at earlier and earlier ages, she said, which makes it even more important for people to understand the connection between these exposures and early colon cancers.

“Avoiding early-onset colorectal cancer is tremendously important,” she said. “We have already lowered preventive screening to age 45. But we can only screen our way out of this to a certain extent. We need more prevention efforts.”

Toward that end, Peters and Fred Hutch colleagues Li Hsu, PhD, Jeroen Huyghe, PhD, and others have been working to create risk calculators in order to help people assess their colorectal cancer risk with much more precision.

“We hope this risk calculator, which we plan to offer free to the public, will go online later this year,” Peters said. “It will allow people to upload their genetic data and answer question about lifestyle factors to calculate their risk to develop colorectal cancer.”

By gathering germline genetic risk data — those inherited mutations are sometimes high risk, sometimes not so much — and folding it together with data representing the genetic damage wrought by environmental exposures like air pollution, processed meat, smoking, obesity and alcohol, researchers can create polygenic or multi-gene risk scores to see how likely a person might be to develop a cancer. Read more about Peters’ work to create polygenic risk scores.

Can colorectal cancer be prevented?

Peters is also interested in a chemical workaround similar to the way people with high cholesterol at risk for cardiovascular disease can take a daily statin, a common cholesterol-lowering medication, to prevent a heart attack or stroke.

“We need more agents for preventing cancer,” she said. “We need to give people more tools. Our findings point to specific genes, and some are targetable by drugs providing new avenues for prevention.”

Although cancer has no early-rising biomarker that’s equivalent to cholesterol, she thinks the idea of developing an anti-cancer “chemo preventive” drug based on clues from genetic predisposition studies is doable.

“The focus on chemoprevention to lower blood pressure and/or cholesterol … have been the main driver to lower mortality in cardiovascular disease,” Peters and University of Oxford geneticist Ian Tomlinson wrote in a recent commentary in Cancer Prevention Research. “There seems little doubt that genetically targeted chemoprevention could in principle prevent cancer, without the issues of adaptive cancer cell evolution that cause the development of resistance to targeted therapy.”

Murphy, her co-investigator, pointed to more tailored screening as another option.

“This research could lead to new ways to assess the risk of these cancers in younger people,” he said, “opening the door to more targeted screening approaches in the future.”

Until these new approaches are developed, Peters said it’s crucial for younger people to understand the increased risk that alcohol and obesity can play — and that they talk to their doctor about any concerning symptoms and get their recommended preventive screenings, via colonoscopy or an at-home fecal immunochemical test (FIT) kit, including any necessary follow-ups.

Medical providers, too, should pay attention to these findings, she said.

“We’ve lowered the screening age to 45, but more than half the people diagnosed with early-onset colorectal cancer were under 45,” she said. “We need to be cognizant of this.”

Funding for this study came from several sources including Fonds Mondial de Recherche contre le Cancer (the French affiliate of World Cancer Research Fund International); French National Cancer Institute and Cancer Research UK.

This article was originally published March 5, 2024, by Fred Hutch News Service. It is republished with permission.