Rise in GI Cancers in Younger Adults: Unraveling the Why

Liam Davenport

July 12, 2019

BARCELONA — The increase in younger-onset gastrointestinal cancer is creating an ever-growing population of patients who have substantial unmet needs, says an expert.

Irit Ben-Aharon, MD, PhD, Rambam Health Care Campus, Haifa, Israel, called for greater consultation and discussion with these younger adult patients (aged 29 to 49 years) on the role of fertility preservation, as well as on the subsequent risk for cardiovascular morality and issues related to quality of life.

However, she also emphasized that elucidating the "possibly unique biology and etiology" of young-onset gastrointestinal cancer is "essential" if better and more personalized treatments are to be identified in the future.

Speaking here at the World Conference on Gastrointestinal Cancer (WCGC) 2019, Ben-Aharon highlighted recent data that show an increase in incidence in younger adults. She also discussed several possible causes that have been proposed — obesity, antibiotic use, and epigenetic changes related to lifestyle.

Increase in Younger-Onset CRC Incidence

A recent analysis of a US population–based cancer registry showed that the incidence of six obesity-related cancers increased significantly among younger adults (aged 25 to 49 years) from 1995 through 2014.

Gastrointestinal cancers accounted for most of those; the incidence of colorectal, pancreatic, gall bladder, and other biliary cancers also increased markedly, Ben Aharon noted. There was an increase in the incidence of gastric noncardia cancer in younger adults, and although this increase was smaller than that for the other GI cancers, the incidence is rising in successively younger generations.

The increase in the incidence of colorectal cancer (CRC) in persons younger than 50 in the United States has been reported widely during the past 2 years, and experts have told Medscape Medical News that this is "an issue screaming for attention."

A study published earlier this year showed that a significant increase in the incidence of CRC in people younger than 50 years has also been reported in many countries in Europe, as well as in Australia, New Zealand, and Canada. The researchers said their data suggest that "there has been a real increase in risk and that the trends do not represent a shift in age at diagnosis attributable to earlier detection."

In her talk, however, Ben-Aharon pointed out that although this trend has been observed in North America and Western Europe, it is not seen everywhere.

In the Middle East, the picture is more mixed. Cancer rates among younger adults in the Mediterranean tend to be more stable, and in East Asia, cancer rates across age groups are not homogeneous.

With regard to CRC, Ben-Aharon showed results from another recent study of almost 30,000 cases diagnosed among adults aged 40 to 49 years from 1975 to 2015 in the United States.

This study revealed that among younger adults, there were annual percentage increases of CRC of 2.9% for distant disease, 1.4% for localized disease, and 1.3% for regional disease.

These figures suggest that "there has been a real increase in risk," she commented.

This leads to the question, what is underlying this increase in cancer among young adults?

To date, young-onset cancer has been considered a hallmark of an inherited predisposition to cancer. However, a recent study of 450 patients younger than 50 who had early-onset CRC found that only 16% had hereditary genetic mutations, such as in Lynch syndrome.

This suggests that environmental factors are involved, Ben Aharon commented.

Obesity Increases Risk for CRC

Regarding the reasons for this increase, many researchers have pointed to obesity, which is a known risk factor for cancer.

In her talk, Ben Aharon highlighted two recent studies that suggest that carrying extra weight is associated with an increase in CRC.

A study that analyzed data from two large US cohort studies found that, particularly among women, there appeared to be an association between early-life body fatness and CRC risk.

Also, an analysis of data from more than 85,000 women who took part in the Nurses' Health Study II showed that obese women had almost double the risk for early-onset CRC and that the risk was increased for overweight women compared to women who had a healthy weight (body mass index of 18.5 kg/m2 to 22.9 kg/m2).

Increase in Antibiotic Use

One theory that has been put forward to explain the increase in early-onset CRC is that it may be due to a rise in antibiotic use.

Ben-Aharon said that several studies have presented evidence that antibiotic use, particularly long-term use during early to middle adulthood, is associated with an increased risk for CRC, possibly through alterations in the gut microbiome.

Moreover, the use of antibiotics during infancy or childhood, which increased markedly in the 1970s and 1980s, may affect microbial diversity and increase cancer risk.

It is not clear, however, whether the use of antibiotics has a direct effect on early-onset CRC, Ben-Aharon commented.

Epigenetic Changes

Another area of exploration regards epigenetic changes that occur in response to factors such as an increase in the consumption of sugary drinks and foods, increases in pollution levels, or increases in sedentary habits associated with gaming and the use of smartphones.

Although the genomic landscape of early-onset CRC does not differ significantly from that of late-onset disease, there are data that show striking differences in DNA methylation profiles, Ben-Aharon told the audience.

DNA hypomethylation is typically the first epigenetic abnormality that is recognized in human tumors in high-resolution genome-wide studies, although, again, its relevance to early-onset disease is not clear.

The case is different for pancreatic cancer. As Ben-Aharon and colleagues recently reported, in early-onset pancreatic cancer (patients younger than 55 years), the molecular landscape was quite different from that of pancreatic cancer of average-age onset (older than 70 years).

Comparing gene expression in early-onset and average-age-onset pancreatic cancer, they found that there was a host of genes with increased expression in younger-onset disease across several pathways that gave it a highly distinct profile.

"What Is Going On in This Disease?"

After the presentation, Sharlene Gill, MD, professor of medicine, British Columbia Cancer Agency, University of British Columbia, Vancouver, Canada, praised Ben-Aharon for offering an "insightful perspective."

Ben-Aharon was asked whether dietary factors such as folic acid deficiency could contribute to DNA hypomethylation and thereby increase the incidence of early-onset gastrointestinal cancer.

Ben-Aharon replied: "We don't know much about the biology.

"Compared to pancreatic cancer, for example, in which you can really define pathways, in colorectal cancer, if you look for the patient profile of the genomic signature in the tumor itself, there are subtle changes, but it's not something very striking.

"But we know that it's something that probably goes with the environment that may induce epigenetic changes, and hypomethylation may reflect it."

She added that other possible factors include air pollution, stress, or the microbiome.

To further examine the question, she noted, requires large multinational studies, because the increase in incidence varies between countries and regions.

Only when demographic data are assessed in conjunction with characteristics of normal tissue and diseased tissue; changes in the microbiome; dietary factors; and genetic information from biobanks will researchers possibly "have a clue of what is going on in this disease," she said.

The investigators have disclosed no relevant financial relationships.

World Conference on Gastrointestinal Cancer (WCGC) 2019. Presented July 4, 2019.

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